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Bibliography on: The Denisovans, Another Human Ancestor

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ESP: PubMed Auto Bibliography 29 Jun 2022 at 01:49 Created: 

The Denisovans, Another Human Ancestor

Wikipedia: The Denisovans are an extinct species or subspecies of human in the genus Homo. In March 2010, scientists announced the discovery of a finger bone fragment of a juvenile female who lived about 41,000 years ago, found in the remote Denisova Cave in the Altai Mountains in Siberia, a cave that has also been inhabited by Neanderthals and modern humans. Two teeth belonging to different members of the same population have since been reported. In November 2015, a tooth fossil containing DNA was reported to have been found and studied. A bone needle dated to 50,000 years ago was discovered at the archaeological site in 2016 and is described as the most ancient needle known. Analysis of the mitochondrial DNA (mtDNA) of the finger bone showed it to be genetically distinct from the mtDNAs of Neanderthals and modern humans. Subsequent study of the nuclear genome from this specimen suggests that Denisovans shared a common origin with Neanderthals, that they ranged from Siberia to Southeast Asia, and that they lived among and interbred with the ancestors of some modern humans. A comparison with the genome of a Neanderthal from the same cave revealed significant local interbreeding with local Neanderthal DNA representing 17% of the Denisovan genome, while evidence was also detected of interbreeding with an as yet unidentified ancient human lineage.

Created with PubMed® Query: denisovan OR denisova NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2022-06-27

Theofanopoulou C, Andirkó A, Boeckx C, et al (2022)

Oxytocin and vasotocin receptor variation and the evolution of human prosociality.

Comprehensive psychoneuroendocrinology, 11:100139 pii:S2666-4976(22)00030-3.

Modern human lifestyle strongly depends on complex social traits like empathy, tolerance and cooperation. These diverse facets of social cognition have been associated with variation in the oxytocin receptor (OTR) and its sister genes, the vasotocin/vasopressin receptors (VTR1A/AVPR1A and AVPR1B/VTR1B). Here, we compared the available genomic sequences of these receptors between modern humans, archaic humans, and 12 non-human primate species, and identified sites that show heterozygous variation in modern humans and archaic humans distinct from variation in other primates, and for which we could find association studies with clinical implications. On these sites, we performed a range of analyses (variant clustering, pathogenicity prediction, regulation, linkage disequilibrium frequency), and reviewed the literature on selection data in different modern-human populations. We found five sites with modern human specific variation, where the modern human allele is the major allele in the global population (OTR: rs1042778, rs237885, rs6770632; VTR1A: rs10877969; VTR1B: rs33985287). Among them, variation in the OTR-rs6770632 site was predicted to be the most functional. Two alleles (OTR: rs59190448 and rs237888) present only in modern humans and archaic humans were putatively under positive selection in modern humans, with rs237888 predicted to be a highly functional site. Three sites showed convergent evolution between modern humans and bonobos (OTR: rs2228485 and rs237897; VTR1A: rs1042615), with OTR-rs2228485 ranking highly in terms of functionality and reported to be under balancing selection in modern humans (Schaschl, 2015) [1]. Our findings have implications for understanding hominid prosociality, as well as the similarities between modern human and bonobo social behavior.

RevDate: 2022-06-27

Ponomarev GV, Fatykhov B, Nazarov VA, et al (2022)

APOBEC mutagenesis is low in most types of non-B DNA structures.

iScience, 25(7):104535 pii:S2589-0042(22)00806-9.

While somatic mutations are known to be enriched in genome regions with non-canonical DNA secondary structure, the impact of particular mutagens still needs to be elucidated. Here, we demonstrate that in human cancers, the APOBEC mutagenesis is not enriched in direct repeats, mirror repeats, short tandem repeats, and G-quadruplexes, and even decreased below its level in B-DNA for cancer samples with very high APOBEC activity. In contrast, we observe that the APOBEC-induced mutational density is positively associated with APOBEC activity in inverted repeats (cruciform structures), where the impact of cytosine at the 3'-end of the hairpin loop is substantial. Surprisingly, the APOBEC-signature mutation density per TC motif in the single-stranded DNA of a G-quadruplex (G4) is lower than in the four-stranded part of G4 and in B-DNA. The APOBEC mutagenesis, as well as the UV-mutagenesis in melanoma samples, are absent in Z-DNA regions, owing to the depletion of their mutational signature motifs.

RevDate: 2022-06-21

Kulikovskaya NS, Denisova EA, VP Ananikov (2022)

A novel approach to study catalytic reactions via Electrophoretic NMR on the example of Pd/NHC-catalyzed Mizoroki-Heck cross-coupling reaction.

Magnetic resonance in chemistry : MRC [Epub ahead of print].

NMR investigation of catalytic reactions is a crucial task, which is often challenging to perform due to rather complex transformations at the metal center. In this work, it was shown that electrophoretic NMR can be a suitable method for studying catalytic reactions and for observing the changes in the catalyst nature. As an important example involving palladium catalysts with N-heterocyclic carbine ligands (NHCs), the breakage of the Pd-NHC bond can occur during the catalytic process. Electrophoretic NMR allows the distinction of compounds in the spectra depending on the charge, thus bringing new opportunities to mechanistic studies. Here, we present independent evidence of R-NHC product formation in the Pd-catalyzed Mizoroki-Heck reaction - the key process for catalyst change from the molecular to nano-scale type.

RevDate: 2022-06-20

Rusina PV, Lisov AA, Denisova AA, et al (2022)

Clinical CDK2 Inhibitors: Trends To Selectivity and Efficacy.

Recent patents on anti-cancer drug discovery pii:PRA-EPUB-124561 [Epub ahead of print].

RevDate: 2022-06-06

Denisova NP, JA Rzaev (2022)

Psychiatric mimics of neurosurgical disorders.

Progress in brain research, 272(1):153-171.

Every year there are about 22.6 million people in need of neurosurgical care around the world, and one or several interventions are required to save lives and restore functional losses in more than half of these cases (13.8 million). Most neurosurgical interventions are performed in patients with traumatic brain and spinal cord injuries, strokes, central nervous system (CNS) tumors, hydrocephalus, and epilepsy. In addition to neurological symptoms, many CNS disorders are often accompanied by cognitive and/or behavioral changes. Physical and psychological symptoms can be intertwined as follows: 1) neurological symptoms may be manifested as a result of complex psychological processes; 2) psychological disorders may be manifested as neurological symptoms; 3) neurological disorders commonly cause secondary psychological responses; 4) psychological disorder may be induced more or less directly by an organic brain disease. In the present paper, we focus on the psychiatric conditions occurring in the patients with neurosurgical disorders who either get prepared for surgery or have already received it.

RevDate: 2022-05-27

Sobolev VV, Denisova EV, Chebysheva SN, et al (2022)

IL-6 Gene Expression as a Marker of Pathological State in Psoriasis and Psoriatic Arthritis.

Bulletin of experimental biology and medicine [Epub ahead of print].

The expression of the IL-6 gene in mononuclear blood cells of 45 patients with psoriatic arthritis and 31 patients with plaque psoriasis was studied for possible differential diagnosis of the pathologies. The expression level of IL-6 in psoriatic arthritis and psoriasis surpassed that in healthy controls by 192 and 147 times, respectively. Significant differences in the gene expression were revealed between the patients with psoriatic arthritis and mild psoriasis. The level of IL-6 in patients with severe psoriasis approached that in patients with psoriatic arthritis. High level of IL-6 gene expression can be a marker of possible joint damage in patients with psoriasis and a signal for revising the therapeutic approach in a particular patient.

RevDate: 2022-05-20

Shchenkov SV, Sokolov SG, Tsushko KM, et al (2022)

Is Gymnophallus Odhner, 1900 (Trematoda: Gymnophallidae) polyphyletic? A new hypothesis based on phylogenetic position of Gymnophallus deliciosus (Olsson, 1893).

Parasitology research [Epub ahead of print].

Gymnophallus deliciosus is a type species of the genus Gymnophallus. We collected this trematode species from gallbladder of Larus argentatus caught in the White Sea (Kandalaksha Bay, Chupa Inlet) and obtained the sequences of its nuclear 18S and 28S rDNA genes. Our recently obtained phylogenetic data support a sister group relationship of this species with G. choledochus. However, other species of the genus Gymnophallus-G. australis (KM246854) and G. minutus (KM268111)-do not branch with the group G. choledochus + G. deliciosus or with each other. Our study revealed that the genus Gynmnophallus is probably a polyphyletic taxon, and the genus affiliation of its representatives should be re-examined in future.

RevDate: 2022-05-17

Demeter F, Zanolli C, Westaway KE, et al (2022)

A Middle Pleistocene Denisovan molar from the Annamite Chain of northern Laos.

Nature communications, 13(1):2557.

The Pleistocene presence of the genus Homo in continental Southeast Asia is primarily evidenced by a sparse stone tool record and rare human remains. Here we report a Middle Pleistocene hominin specimen from Laos, with the discovery of a molar from the Tam Ngu Hao 2 (Cobra Cave) limestone cave in the Annamite Mountains. The age of the fossil-bearing breccia ranges between 164-131 kyr, based on the Bayesian modelling of luminescence dating of the sedimentary matrix from which it was recovered, U-series dating of an overlying flowstone, and U-series-ESR dating of associated faunal teeth. Analyses of the internal structure of the molar in tandem with palaeoproteomic analyses of the enamel indicate that the tooth derives from a young, likely female, Homo individual. The close morphological affinities with the Xiahe specimen from China indicate that they belong to the same taxon and that Tam Ngu Hao 2 most likely represents a Denisovan.

RevDate: 2022-04-12

Skryabin GO, Komelkov AV, Zhordania KI, et al (2022)

Extracellular Vesicles from Uterine Aspirates Represent a Promising Source for Screening Markers of Gynecologic Cancers.

Cells, 11(7): pii:cells11071064.

Extracellular vesicles (EVs), including exosomes, are key factors of intercellular communication, performing both local and distant transfers of bioactive molecules. The increasingly obvious role of EVs in carcinogenesis, similarity of molecular signatures with parental cells, precise selection and high stability of cargo molecules make exosomes a promising source of liquid biopsy markers for cancer diagnosis. The uterine cavity fluid, unlike blood, urine and other body fluids commonly used to study EVs, is of local origin and therefore enriched in EVs secreted by cells of the female reproductive tract. Here, we show that EVs, including those corresponding to exosomes, could be isolated from individual samples of uterine aspirates (UA) obtained from epithelial ovarian cancer (EOC) patients and healthy donors using the ultracentrifugation technique. First, the conducted profiling of small RNAs (small RNA-seq) from UA-derived EVs demonstrated the presence of non-coding RNA molecules belonging to various classes. The analysis of the miRNA content in EVs from UA performed on a pilot sample revealed significant differences in the expression levels of a number of miRNAs in EVs obtained from EOC patients compared to healthy individuals. The results open up prospects for using UA-derived EVs as a source of markers for the diagnostics of gynecological cancers, including EOC.

RevDate: 2022-04-01

Molodtseva AS, Makunin AI, Salomashkina VV, et al (2022)

Phylogeography of ancient and modern brown bears from eastern Eurasia.

Biological journal of the Linnean Society. Linnean Society of London, 135(4):722-733 pii:blac009.

The brown bear (Ursus arctos) is an iconic carnivoran species of the Northern Hemisphere. Its population history has been studied extensively using mitochondrial markers, which demonstrated signatures of multiple waves of migration, arguably connected with glaciation periods. Among Eurasian brown bears, Siberian populations remain understudied. We have sequenced complete mitochondrial genomes of four ancient (~4.5-40 kya) bears from South Siberia and 19 modern bears from South Siberia and the Russian Far East. Reconstruction of phylogenetic relationships between haplotypes and evaluation of modern population structure have demonstrated that all the studied samples belong to the most widespread Eurasian clade 3. One of the ancient haplotypes takes a basal position relative to the whole of clade 3; the second is basal to the haplogroup 3a (the most common subclade), and two others belong to clades 3a1 and 3b. Modern Siberian bears retain at least some of this diversity; apart from the most common haplogroup 3a, we demonstrate the presence of clade 3b, which was previously found mainly in mainland Eurasia and Northern Japan. Our findings highlight the importance of South Siberia as a refugium for northern Eurasian brown bears and further corroborate the hypothesis of several waves of migration in the Pleistocene.

RevDate: 2022-03-25

Sobolev VV, Soboleva AG, Denisova EV, et al (2022)

Proteomic Studies of Psoriasis.

Biomedicines, 10(3): pii:biomedicines10030619.

In this review paper, we discuss the contribution of proteomic studies to the discovery of disease-specific biomarkers to monitor the disease and evaluate available treatment options for psoriasis. Psoriasis is one of the most prevalent skin disorders driven by a Th17-specific immune response. Although potential patients have a genetic predisposition to psoriasis, the etiology of the disease remains unknown. During the last two decades, proteomics became deeply integrated with psoriatic research. The data obtained in proteomic studies facilitated the discovery of novel mechanisms and the verification of many experimental hypotheses of the disease pathogenesis. The detailed data analysis revealed multiple differentially expressed proteins and significant changes in proteome associated with the disease and drug efficacy. In this respect, there is a need for proteomic studies to characterize the role of the disease-specific biomarkers in the pathogenesis of psoriasis, develop clinical applications to choose the most efficient treatment options and monitor the therapeutic response.

RevDate: 2022-03-23

Dengler NF, Ferraresi S, Rochkind S, et al (2022)

Thoracic Outlet Syndrome Part I: Systematic Review of the Literature and Consensus on Anatomy, Diagnosis, and Classification of Thoracic Outlet Syndrome by the European Association of Neurosurgical Societies' Section of Peripheral Nerve Surgery.

Neurosurgery [Epub ahead of print].

BACKGROUND: Although numerous articles have been published not only on the classification of thoracic outlet syndrome (TOS) but also on diagnostic standards, timing, and type of surgical intervention, there still remains some controversy because of the lack of level 1 evidence. So far, attempts to generate uniform reporting standards have not yielded conclusive results.

OBJECTIVE: To systematically review the body of evidence and reach a consensus among neurosurgeons experienced in TOS regarding anatomy, diagnosis, and classification.

METHODS: A systematic literature search on PubMed/MEDLINE was performed on February 13, 2021, yielding 2853 results. Abstracts were screened and classified. Recommendations were developed in a meeting held online on February 10, 2021, and refined according to the Delphi consensus method.

RESULTS: Six randomized controlled trials (on surgical, conservative, and injection therapies), 4 "guideline" articles (on imaging and reporting standards), 5 observational studies (on diagnostics, hierarchic designs of physiotherapy vs surgery, and quality of life outcomes), and 6 meta-analyses were identified. The European Association of Neurosurgical Societies' section of peripheral nerve surgery established 18 statements regarding anatomy, diagnosis, and classification of TOS with agreement levels of 98.4 % (±3.0).

CONCLUSION: Because of the lack of level 1 evidence, consensus statements on anatomy, diagnosis, and classification of TOS from experts of the section of peripheral nerve surgery of the European Association of Neurosurgical Societies were developed with the Delphi method. Further work on reporting standards, prospective data collections, therapy, and long-term outcome is necessary.

RevDate: 2022-03-04
CmpDate: 2022-03-04

Zavgorudko VN, Sidorenko SV, Kortelev VV, et al (2022)

[Tumnin mineral spring. History of development].

Voprosy kurortologii, fizioterapii, i lechebnoi fizicheskoi kultury, 99(1):64-68.

The article dwells upon the history of the discovery of the Tumnin mineral spring, the establishment and development of the Far Eastern health resort «Goryachy Klyuch,» located in the basin of Chope creek, a tributary of the largest river in the eastern macroslope of Sikhote Alin, Tumnin river, located 25 km from the Strait of Tartary. A historical sketch since the first mentioning of the Tumnin mineral spring from 1903 to the present day, as well as the results of hydrogeological expeditions to determine the chemical composition and α-activity of Tumnin mineral water at different periods, are presented. A contribution of a geological expedition that established a large deep-lying tectonic structure permeable to upwelling thermal water flows is described. The role of the staff of the physiotherapy and balneology department of the Khabarovsk Medical Institute in the study of the mechanism of action and clinical effectiveness of the Tumnin mineral water is addressed. A balneological characteristic of nitric and siliceous thermal water, the basic therapeutic factor of «Goryachy Klyuch» health resort, which has always been popular among the Far East residents, but gained special importance and appreciation of patients during the pandemic of new coronavirus infection, is given. Currently, in the health resort «Goryachy Klyuch», patients with skin diseases, musculoskeletal, gynecologic, neurologic diseases, digestive tract disorders, metabolic conditions, upper airways, cardiovascular disorders, occupational diseases are treated using balneotherapy and other methods of non-drug therapy. At present, the health resort «Goryachy Klyuch» is going through a difficult but interesting period of improvement of recreation opportunities for the Far East residents.

RevDate: 2022-03-04

Saitou M, Masuda N, O Gokcumen (2022)

Similarity-Based Analysis of Allele Frequency Distribution among Multiple Populations Identifies Adaptive Genomic Structural Variants.

Molecular biology and evolution, 39(3):.

Structural variants have a considerable impact on human genomic diversity. However, their evolutionary history remains mostly unexplored. Here, we developed a new method to identify potentially adaptive structural variants based on a similarity-based analysis that incorporates genotype frequency data from 26 populations simultaneously. Using this method, we analyzed 57,629 structural variants and identified 576 structural variants that show unusual population differentiation. Of these putatively adaptive structural variants, we further showed that 24 variants are multiallelic and overlap with coding sequences, and 20 variants are significantly associated with GWAS traits. Closer inspection of the haplotypic variation associated with these putatively adaptive and functional structural variants reveals deviations from neutral expectations due to: 1) population differentiation of rapidly evolving multiallelic variants, 2) incomplete sweeps, and 3) recent population-specific negative selection. Overall, our study provides new methodological insights, documents hundreds of putatively adaptive variants, and introduces evolutionary models that may better explain the complex evolution of structural variants.

RevDate: 2022-02-24

Yogeswaran K, Furtado JM, Bodaghi B, et al (2022)

Current practice in the management of ocular toxoplasmosis.

The British journal of ophthalmology pii:bjophthalmol-2022-321091 [Epub ahead of print].

BACKGROUND: Ocular toxoplasmosis is common across all regions of the world. Understanding of the epidemiology and approach to diagnosis and treatment have evolved recently. In November 2020, an international group of uveitis-specialised ophthalmologists formed the International Ocular Toxoplasmosis Study Group to define current practice.

METHODS: 192 Study Group members from 48 countries completed a 36-item survey on clinical features, use of investigations, indications for treatment, systemic and intravitreal treatment with antiparasitic drugs and corticosteroids, and approach to follow-up and preventive therapy.

RESULTS: For 77.1% of members, unilateral retinochoroiditis adjacent to a pigmented scar accounted for over 60% of presentations, but diverse atypical presentations were also reported. Common complications included persistent vitreous opacities, epiretinal membrane, cataract, and ocular hypertension or glaucoma. Most members used clinical examination with (56.8%) or without (35.9%) serology to diagnose typical disease but relied on intraocular fluid testing-usually PCR-in atypical cases (68.8%). 66.1% of members treated all non-pregnant patients, while 33.9% treated selected patients. Oral trimethoprim-sulfamethoxazole was first-line therapy for 66.7% of members, and 60.9% had experience using intravitreal clindamycin. Corticosteroid drugs were administered systemically by 97.4%; 24.7% also injected corticosteroid intravitreally, almost always in combination with an antimicrobial drug (72.3%). The majority of members followed up all (60.4%) or selected (35.9%) patients after resolution of acute disease, and prophylaxis against recurrence with trimethoprim-sulfamethoxazole was prescribed to selected patients by 69.8%.

CONCLUSION: Our report presents a current management approach for ocular toxoplasmosis, as practised by a large international group of uveitis-specialised ophthalmologists.

RevDate: 2022-02-17

Voron'ko OE, Baskaev KK, Sobolev VV, et al (2022)

Genetic Markers of Therapeutic Efficacy of Methotrexate in Patients with Psoriasis.

Bulletin of experimental biology and medicine [Epub ahead of print].

We studied the effect of C677T and A1298C polymorphisms of the MTHFR gene and 2R/3R polymorphisms of the TYMS gene on the sensitivity to methotrexate in patients with psoriasis (n=139). It was shown that genotype 3R/3R TYMS (OR 8.86, 95%CI 2.00-39.22) and complex genotypes MTHFR1298:A;TYMS:3R (OR 8.20, 95%CI 2.36-28.48) and MTHFR677:C;TYMS:3R (OR 5.40, 95%CI 1.95-14.94) were associated with sensitivity to methotrexate, while genotype 2R/2R TYMS (OR 8.20, 95%CI 2.36-28.48) and complex genotypes MTHFR1298:C;MTHFR677:T;TYMS:2R (OR 0.18, 95%CI 0.06-0.56) and MTHFR1298:C;MTHFR677:T (OR 0.23, 95%CI 0.09-0.59) were associated with resistance to methotrexate. The results can be used for preventive assessment of the effectiveness of methotrexate treatment in patients with psoriasis.

RevDate: 2022-02-15

Denisova KR, Orlov NA, Yakimov SA, et al (2022)

GFP-Margatoxin, a Genetically Encoded Fluorescent Ligand to Probe Affinity of Kv1.3 Channel Blockers.

International journal of molecular sciences, 23(3): pii:ijms23031724.

Peptide pore blockers and their fluorescent derivatives are useful molecular probes to study the structure and functions of the voltage-gated potassium Kv1.3 channel, which is considered as a pharmacological target in the treatment of autoimmune and neurological disorders. We present Kv1.3 fluorescent ligand, GFP-MgTx, constructed on the basis of green fluorescent protein (GFP) and margatoxin (MgTx), the peptide, which is widely used in physiological studies of Kv1.3. Expression of the fluorescent ligand in E. coli cells resulted in correctly folded and functionally active GFP-MgTx with a yield of 30 mg per 1 L of culture. Complex of GFP-MgTx with the Kv1.3 binding site is reported to have the dissociation constant of 11 ± 2 nM. GFP-MgTx as a component of an analytical system based on the hybrid KcsA-Kv1.3 channel is shown to be applicable to recognize Kv1.3 pore blockers of peptide origin and to evaluate their affinities to Kv1.3. GFP-MgTx can be used in screening and pre-selection of Kv1.3 channel blockers as potential drug candidates.

RevDate: 2022-02-15

Roenko AV, Nikiforov RY, Gringolts ML, et al (2022)

Olefin-Metathesis-Derived Norbornene-Ethylene-Vinyl Acetate/Vinyl Alcohol Multiblock Copolymers: Impact of the Copolymer Structure on the Gas Permeation Properties.

Polymers, 14(3): pii:polym14030444.

Commercial metathesis polynorbornene is used for the fabrication of high-damping coatings and bulk materials that dissipate vibration and impact energies. Functionalization of this non-polar polymer can improve its adhesive, gas barrier, and other properties, thereby potentially expanding its application area. With this aim, the post-modification of polynorbornene was carried out by inserting ethylene-vinyl acetate-vinyl alcohol blocks into its backbone via the cross-metathesis of polynorbornene with poly(5-acetoxy-1-octenylene) and subsequent deacetylation and hydrogenation of the obtained multiblock copolymers. For the first time, epoxy groups were introduced into the main chains of these copolymers, followed by the oxirane ring opening reaction. The influence of post-modification on the thermal, gas separation, and mechanical properties of the new copolymers was studied. It was shown that the gas permeability of the copolymer significantly depends on its composition, as well as on the amounts of hydroxyl and epoxy groups. The developed methods efficiently improve the barrier properties, reducing the oxygen permeability by 15-33 times in comparison with polynorbornene. The obtained results are promising for various applications and can be extended to a broader family of polydienes and other polymers containing backbone double bonds.

RevDate: 2022-02-10

Göllner T, Larena M, Kutanan W, et al (2022)

Unveiling the Genetic History of the Maniq, a primary hunter-gatherer society.

Genome biology and evolution pii:6526392 [Epub ahead of print].

The Maniq of southern Thailand is one of the last remaining practicing hunter-gatherer communities in the world. However, our knowledge on their genetic origins and demographic history is still largely limited. We present here the genotype data covering ∼2.3 million SNPs of eleven unrelated Maniq individuals. Our analyses reveal the Maniq to be closely related to the Semang populations of Malaysia (Malay Negritos), who altogether carry an Andamanese-related ancestry linked to the ancient Hòabìnhian hunter-gatherers of Mainland Southeast Asia (MSEA). Moreover, the Maniq possess ∼35% East Asian-related ancestry, likely brought about by recent admixture with surrounding agriculturist communities in the region. In addition, the Maniq exhibit one of the highest levels of genetic differentiation found among living human populations, indicative of their small population size and historical practice of endogamy. Similar to other hunter-gatherer populations of MSEA, we also find the Maniq to possess low levels of Neanderthal ancestry and undetectable levels of Denisovan ancestry. Altogether, we reveal the Maniq to be a Semang group that experienced intense genetic drift and exhibits signs of ancient Hòabìnhian ancestry.

RevDate: 2022-01-25

Morley MW, Goldberg P, Uliyanov VA, et al (2022)

Author Correction: Hominin and animal activities in the microstratigraphic record from Denisova Cave (Altai Mountains, Russia).

Scientific reports, 12(1):1545 pii:10.1038/s41598-021-03251-6.

RevDate: 2022-01-03

Shchenkov SV, Sokolov SG, SA Denisova (2021)

Phylogenetic position of Atriophallophorus minutus (Trematoda: Microphallidae), the type-species of the genus Atriophallophorus Deblock & Rosé, 1964, based on partial 28S rDNA gene sequence.

Parasitology international, 87:102534 pii:S1383-5769(21)00252-X [Epub ahead of print].

We found metacercariae of a microphallid trematode Atriophallophorus minutus in freshwater snails Bithynia tentaculata. In this study, we provide a morphological description of whole-mount specimens and semi-thin sections of experimentally grown adults of this species. Our morphological examination supports the idea that the adults of Atriophallophorus spp. have a ventral sucker with a sinistral interruption of the outer edge. In the 28S rDNA gene-based phylogenetic analyses, our specimens of A. minutus were grouped into Atriophallophorus spp. clade, as a sister taxon to Atriophallophorus winterbourni + Atriophallophorus sp. Analysis of the pairwise genetic distances between coI mtDNA gene sequences revealed a low divergence between the two specimens of A. minutus (1.1%) and a greater divergence (up to 16.6%) between them and A. winterbourni. Since other Atriophallophorus spp. are known to have a strict specificity to the polyvalent intermediate host, we suggest that A. minutus reported from different snail species may represent a complex of cryptic species.

RevDate: 2021-12-31

Massilani D, Morley MW, Mentzer SM, et al (2022)

Microstratigraphic preservation of ancient faunal and hominin DNA in Pleistocene cave sediments.

Proceedings of the National Academy of Sciences of the United States of America, 119(1):.

Ancient DNA recovered from Pleistocene sediments represents a rich resource for the study of past hominin and environmental diversity. However, little is known about how DNA is preserved in sediments and the extent to which it may be translocated between archaeological strata. Here, we investigate DNA preservation in 47 blocks of resin-impregnated archaeological sediment collected over the last four decades for micromorphological analyses at 13 prehistoric sites in Europe, Asia, Africa, and North America and show that such blocks can preserve DNA of hominins and other mammals. Extensive microsampling of sediment blocks from Denisova Cave in the Altai Mountains reveals that the taxonomic composition of mammalian DNA differs drastically at the millimeter-scale and that DNA is concentrated in small particles, especially in fragments of bone and feces (coprolites), suggesting that these are substantial sources of DNA in sediments. Three microsamples taken in close proximity in one of the blocks yielded Neanderthal DNA from at least two male individuals closely related to Denisova 5, a Neanderthal toe bone previously recovered from the same layer. Our work indicates that DNA can remain stably localized in sediments over time and provides a means of linking genetic information to the archaeological and ecological records on a microstratigraphic scale.

RevDate: 2021-12-29

Soldatskiy YL, Bulynko SA, Denisova OA, et al (2021)

[Features of the clinic, diagnosis and treatment of parapharyngeal abscesses in children: analysis of 121 observations].

Vestnik otorinolaringologii, 86(6):62-68.

Parapharyngeal and retropharyngeal abscesses (PPA) in children are a rare pathology, for the diagnosis of which it is necessary to use additional instrumental examination methods. The tactics of treating patients remains a subject of discussion.

OBJECTIVE: To analyze the features of the clinic, diagnosis and treatment of PPA in children.

MATERIAL AND METHODS: According to the hospital database, a retrospective analysis of the medical histories of children discharged from the clinic with a diagnosis of "J39.0 Retropharyngeal and parapharyngeal abscess" was carried out in the period from 01.01.14 to 31.12.19. In all cases, the diagnosis was confirmed by computed tomography (CT) data with contrast enhancement. Complaints at the time of treatment, anamnesis and instrumental diagnosis data, clinical features of the course of the disease and the effectiveness of treatment were analyzed.

RESULTS: 121 children were treated for PPA (average age 73±41 months; Me=52.5 months), which is 0.4% of all hospitalized in the otorhinolaryngological department, 0.7% of the number of emergency hospitalizations, 0.8% of the number of hospitalized children with pharyngeal diseases, and 8.3% of the number of patients with pharyngeal abscess. Abscesses were more often localized in the upper pharynx, at the level of the I-II cervical vertebrae (49.6% of all observations); abscesses were found least often in the pharyngeal space (5.8%), there was no statistically significant difference between the right-sided and left-sided location: 47.9% and 46.2%, respectively. Surgical treatment was performed in 98 (81%) patients in the presence of an abscess capsule or an abscess diameter of more than 2 cm according to CT; the remaining 23 (19%) children were treated conservatively. The opening of the abscess was performed endopharyngeal, in the case of a pronounced deep lateral location of the abscess and its proximity to large blood vessels - with access through the tonsillar niche after preliminary tonsillectomy (19.4% of those operated).

CONCLUSION: The final diagnosis of parapharyngeal and retropharyngeal abscess can be established by contrast-enhanced computed tomography. Conservative treatment is indicated for a limited group of patients at the initial stages of the disease, most patients need surgical treatment.

RevDate: 2021-12-24

Filippenkov IB, Stavchansky VV, Denisova AE, et al (2021)

Genome-Wide RNA-Sequencing Reveals Massive Circular RNA Expression Changes of the Neurotransmission Genes in the Rat Brain after Ischemia-Reperfusion.

Genes, 12(12): pii:genes12121870.

Ischemic brain stroke is one of the most serious and socially significant diseases. In addition to messenger RNAs (mRNAs), encoding protein, the study of regulatory RNAs in ischemic has exceptional importance for the development of new strategies for neuroprotection. Circular RNAs (circRNAs) have a closed structure, predominantly brain-specific expression, and remain highly promising targets of research. They can interact with microRNAs (miRNAs), diminish their activity and thereby inhibit miRNA-mediated repression of mRNA. Genome-wide RNA-Seq analysis of the subcortical structures of the rat brain containing an ischemic damage focus and penumbra area revealed 395 circRNAs changed their expression significantly at 24 h after transient middle cerebral artery occlusion model (tMCAO) conditions. Furthermore, functional annotation revealed their association with neuroactive signaling pathways. It was found that about a third of the differentially expressed circRNAs (DECs) originate from genes whose mRNA levels also changed at 24 h after tMCAO. The other DECs originate from genes encoding non-regulated mRNAs under tMCAO conditions. In addition, bioinformatic analysis predicted a circRNA-miRNA-mRNA network which was associated with the neurotransmission signaling regulation. Our results show that such circRNAs can persist as potential miRNA sponges for the protection of mRNAs of neurotransmitter genes. The results expanded our views about the neurotransmission regulation in the rat brain after ischemia-reperfusion with circRNA action.

RevDate: 2021-12-24

Makarova E, Kazantseva A, Dubinina A, et al (2021)

Fibroblast Growth Factor 21 (FGF21) Administration Sex-Specifically Affects Blood Insulin Levels and Liver Steatosis in Obese Ay Mice.

Cells, 10(12): pii:cells10123440.

FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the Ay mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese Ay males and females. Ay mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of Fgf21 and Ucp1 in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of Cpt1 and Irs1 only in males. Thus, FGF21's beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.

RevDate: 2021-12-23

Bouaziz M, Cheng T, Minuti A, et al (2021)

Shared Decision Making in Ophthalmology: A Scoping Review.

American journal of ophthalmology pii:S0002-9394(21)00644-9 [Epub ahead of print].

PURPOSE: Shared decision making (SDM) has been associated with improved patient satisfaction and outcomes in both medical and surgical specialties, but its role in ophthalmology has not been systematically examined. Using a scoping review of the literature, the purpose of this study was to explore the characteristics, implementation, and outcomes of SDM in ophthalmology.

DESIGN: Scoping review of the literature.

METHODS: Searches were conducted in PubMed, Embase, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) through August of 2021 for SDM in ophthalmology. The resulting 1602 studies were screened by two independent reviewers with 57 full-text articles examined for inclusion of an ophthalmologic diagnosis, as well as discussion of SDM or patient decision aids (PDAs). Nineteen studies were eligible and qualitatively coded for 11 predetermined codes, which included patient outcomes, patient and physician requests for SDM, and methods of implementation.

RESULTS: Of the 19 included studies, all emphasized the value of SDM for ophthalmology and two studies reported improved patient outcomes. The most commonly examined topics were chronic ophthalmic diseases, such as cataracts, and glaucoma. Limitations to SDM implementation were also universally discussed, including patients' lack of disease knowledge, communication barriers, and time restrictions. Although PDAs are an effective tool to mitigate these, these have only been established for the subjects of cataracts and glaucoma.

CONCLUSION: SDM is a methodology for patient-centered care that is regarded as a potentially useful tool in the field of ophthalmology. However, significant barriers exist to its effective implementation. Evidence-based research on if and how these barriers should be attenuated, as well as the development of additional PDA's for different ophthalmic diseases, are needed.

RevDate: 2021-12-23

Zhur KV, Trifonov VA, EB Prokhortchouk (2021)

Progress and Prospects in Epigenetic Studies of Ancient DNA.

Biochemistry. Biokhimiia, 86(12):1563-1571.

Development of technologies for high-throughput whole-genome sequencing and improvement of sample preparation techniques made it possible to study ancient DNA (aDNA) from archaeological samples over a million year old. The studies of aDNA have shed light on the history of human migration, replacement of populations, interbreeding of Cro-Magnons with Neanderthals and Denisovans, evolution of human pathogens, etc. Equally important is the possibility to investigate epigenetic modifications of ancient genomes, which has allowed to obtain previously inaccessible information on gene expression, nucleosome positioning, and DNA methylation. Analysis of methylation status of certain genomic sites can predict an individual's age at death and reconstruct some phenotypic features, as it was done for the Denisovan genome, and even to elucidate unfavorable environmental factors that had affected this archaic individual. In this review, we discuss current progress in epigenetic studies of aDNA, including methodological approaches and promising research directions in this field.

RevDate: 2021-12-23

Yarmolinskaya M, Denisova A, Tkachenko N, et al (2021)

Vitamin D significance in pathogenesis of endometriosis.

Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 37(sup1):40-43.

 : Genital endometriosis (GE) is a widespread multifactorial disease thus making it necessary to carry on studying its pathogeny in order to work out target therapy techniques. Studying vitamin D role in GE pathogeny is a new promising research trend.

PATIENTS AND TECHNIQUE: 25(ОН)D level was determined in peripheral blood (PB) of 440 patients with GE and in peritoneal fluid (PF) - in 49 GE patients; the same test in PB was performed in 30 patients of the control group with the ovulatory menstrual cycle and no gynecologic pathology. 129 patients with GE, as well as 82 women of the control, underwent examination of vitamin D receptor (VDR) polymorphism gene in BsmI, FokI, and TaqI polymorphic locus. We examined vitamin D receptor expression in the eutopic and ectopic endometrium in 32 women with GE and in the endometrium of 20 women from the control group. We also compared the efficacy of combined therapy involving colecalciferol to the standard hormone modulating therapy.

RESULTS: It was established that the prevalent GE forms are characterized by lower 25(ОН)D levels both in PB and in PF. It was also found that G/G genotype of VDR BsmI gene polymorphic variant 1.9 times increases GE occurrence risk. VDR expression was authentically lower in the ectopic endometrium compared to the eutopic endometrium. Patients with GE show no VDR expression cyclic variations in the endometrium which is contrary to the control. Therapy in combination with colecalciferol promotes a more expressed decrease of endometriosis-associated pain syndrome and psycho-emotional stabilization of GE patients compared to the standard hormone modulating therapy.

CONCLUSION: Vitamin D deficiency plays a significant role in the pathogenesis of GE and Vit D may be applied as its targeted therapy.

RevDate: 2021-12-17

Natri HM, Hudjashov G, Jacobs G, et al (2021)

Genetic architecture of gene regulation in Indonesian populations identifies QTLs associated with global and local ancestries.

American journal of human genetics pii:S0002-9297(21)00437-7 [Epub ahead of print].

Lack of diversity in human genomics limits our understanding of the genetic underpinnings of complex traits, hinders precision medicine, and contributes to health disparities. To map genetic effects on gene regulation in the underrepresented Indonesian population, we have integrated genotype, gene expression, and CpG methylation data from 115 participants across three island populations that capture the major sources of genomic diversity in the region. In a comparison with European datasets, we identify eQTLs shared between Indonesia and Europe as well as population-specific eQTLs that exhibit differences in allele frequencies and/or overall expression levels between populations. By combining local ancestry and archaic introgression inference with eQTLs and methylQTLs, we identify regulatory loci driven by modern Papuan ancestry as well as introgressed Denisovan and Neanderthal variation. GWAS colocalization connects QTLs detected here to hematological traits, and further comparison with European datasets reflects the poor overall transferability of GWAS statistics across diverse populations. Our findings illustrate how population-specific genetic architecture, local ancestry, and archaic introgression drive variation in gene regulation across genetically distinct and in admixed populations and highlight the need for performing association studies on non-European populations.

RevDate: 2021-12-13

Shunatova N, Serova K, Denisova S, et al (2021)

Small, but smart: fine structure of an avicularium in Dendrobeania fruticosa (Bryozoa: Cheilostomata).

Journal of morphology [Epub ahead of print].

Bryozoans are small benthic suspension-feeding colonial animals. Among this phylum, there are representatives showing a lesser or greater degree of polymorphism, and the most common type of polymorphic zooids is the avicularium. Here we present a detailed description of the bird's-head shaped avicularium in Dendrobeania fruticosa. The body cavity of the avicularium demonstrates an acoelomate condition: along the cystid walls, there is neither the layer of extracellular matrix towards the epidermis, nor coelomic lining. However, a layer of an extracellular matrix and epithelialized cells lie under the epidermis of the tentacle sheath. Probably, such construction helps the tentacle sheath to acquire some rigidity - it is the only region of the body wall without an ectocyst. We did not find typical funicular strands in the avicularium, but there is a delicate mesh composed of stellate cells with thin and long projections, which sometimes isolate the spaces filled with a heterogeneous matrix. The proximal ends of the adductors, abductors, and polypide retractors are attached to the body wall via typical epidermal tendon cells, which possess numerous bundles of tonofilaments. The distal ends of the abductors and adductors attach to the frontal membrane or upper vestibular membrane, respectively. The inner organic layer of the ectocyst in these regions forms large protrusions, from which numerous thin outgrowths branch off. We suggest them to be a functional analogue of apodemes and apodemal filaments in arthropods. "Apodemal" tendon cells have long and thin projections that line the outgrowths of the ectocyst and surround the distal ends of the muscle cells. At these sites, "apodemal" tendon cells possess numerous tonofilaments. The vestigial polypide includes the tentacle sheath, rudimentary lophophore, cerebral ganglion, and polypide retractors. The sensory part of 5HT-positive cells of the frontal membrane is dendrite-shaped and embedded in the inner organic layer of the ectocyst. This article is protected by copyright. All rights reserved.

RevDate: 2021-12-07

Hubert L, Paganini J, Picard C, et al (2021)

HLA-H*02:07 Is a Membrane-Bound Ligand of Denisovan Origin That Protects against Lysis by Activated Immune Effectors.

Journal of immunology (Baltimore, Md. : 1950) pii:jimmunol.2100358 [Epub ahead of print].

The biological relevance of genes initially categorized as "pseudogenes" is slowly emerging, notably in innate immunity. In the HLA region on chromosome 6, HLA-H is one such pseudogene; yet, it is transcribed, and its variation is associated with immune properties. Furthermore, two HLA-H alleles, H*02:07 and H*02:14, putatively encode a complete, membrane-bound HLA protein. Here we thus hypothesized that HLA-H contributes to immune homeostasis similarly to tolerogenic molecules HLA-G, -E, and -F. We tested if HLA-H*02:07 encodes a membrane-bound protein that can inhibit the cytotoxicity of effector cells. We used an HLA-null human erythroblast cell line transduced with HLA-H*02:07 cDNA to demonstrate that HLA-H*02:07 encodes a membrane-bound protein. Additionally, using a cytotoxicity assay, our results support that K562 HLA-H*02:07 inhibits human effector IL-2-activated PBMCs and human IL-2-independent NK92-MI cell line activity. Finally, through in silico genotyping of the Denisovan genome and haplotypic association with Denisovan-derived HLA-A*11, we also show that H*02:07 is of archaic origin. Hence, admixture with archaic humans brought a functional HLA-H allele into modern European and Asian populations.

RevDate: 2021-12-05

Zhang P, Zhang X, Zhang X, et al (2021)

Denisovans and Homo sapiens on the Tibetan Plateau: dispersals and adaptations.

Trends in ecology & evolution pii:S0169-5347(21)00307-4 [Epub ahead of print].

Recent archaeological discoveries suggest that both archaic Denisovans and Homo sapiens occupied the Tibetan Plateau earlier than expected. Genetic studies show that a pulse of Denisovan introgression was involved in the adaptation of Tibetan populations to high-altitude hypoxia. These findings challenge the traditional view that the plateau was one of the last places on earth colonized by H. sapiens and warrant a reappraisal of the population history of this highland. Here, we integrate archaeological and genomic evidence relevant to human dispersal, settlement, and adaptation in the region. We propose two testable models to address the peopling of the plateau in the broader context of H. sapiens dispersal and their encounters with Denisovans in Asia.

RevDate: 2021-12-01

Koloda YA, Denisova YV, NM Podzolkova (2021)

Genetic polymorphisms of reproductive hormones and their receptors in assisted reproduction technology for patients with polycystic ovary syndrome.

Drug metabolism and personalized therapy pii:dmdi-2021-0123 [Epub ahead of print].

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of childbearing, which is defined by the accumulation of multiple, small fluid-filled ovarian cysts without the selection of a single dominant follicle. Most PCOS phenotypes are characterized by the absence of spontaneous ovulation, resistance toward ovulation inductors, the production of a large immature oocytes number, and the high prevalence of ovarian hyperstimulation syndrome, resulting in reduced assisted reproductive technologies (ART) programs effectiveness. The review analyses current data about the relationship between polymorphism genotypes of KISS genes, follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH) and their receptors genes, gonadotropin-releasing hormone (GnRH), estrogen, and progesterone receptors genes, the PCOS risk and the features of ovarian response to stimulation during ART cycles. The use of single nucleotide polymorphisms (SNPs) as prognostic markers of ART programs outcomes would provide a personalized approach to the drugs and doses choice for ovarian stimulation and significantly increase the chance of pregnancy.

RevDate: 2021-11-26

Brown S, Massilani D, Kozlikin MB, et al (2021)

The earliest Denisovans and their cultural adaptation.

Nature ecology & evolution [Epub ahead of print].

Since the initial identification of the Denisovans a decade ago, only a handful of their physical remains have been discovered. Here we analysed ~3,800 non-diagnostic bone fragments using collagen peptide mass fingerprinting to locate new hominin remains from Denisova Cave (Siberia, Russia). We identified five new hominin bones, four of which contained sufficient DNA for mitochondrial analysis. Three carry mitochondrial DNA of the Denisovan type and one was found to carry mtDNA of the Neanderthal type. The former come from the same archaeological layer near the base of the cave's sequence and are the oldest securely dated evidence of Denisovans at 200 ka (thousand years ago) (205-192 ka at 68.2% or 217-187 ka at 95% probability). The stratigraphic context in which they were located contains a wealth of archaeological material in the form of lithics and faunal remains, allowing us to determine the material culture associated with these early hominins and explore their behavioural and environmental adaptations. The combination of bone collagen fingerprinting and genetic analyses has so far more-than-doubled the number of hominin bones at Denisova Cave and has expanded our understanding of Denisovan and Neanderthal interactions, as well as their archaeological signatures.

RevDate: 2021-11-19

Liston A, Humblet-Baron S, Duffy D, et al (2021)

Human immune diversity: from evolution to modernity.

Nature immunology [Epub ahead of print].

The extreme diversity of the human immune system, forged and maintained throughout evolutionary history, provides a potent defense against opportunistic pathogens. At the same time, this immune variation is the substrate upon which a plethora of immune-associated diseases develop. Genetic analysis suggests that thousands of individually weak loci together drive up to half of the observed immune variation. Intense selection maintains this genetic diversity, even selecting for the introgressed Neanderthal or Denisovan alleles that have reintroduced variation lost during the out-of-Africa migration. Variations in age, sex, diet, environmental exposure, and microbiome each potentially explain the residual variation, with proof-of-concept studies demonstrating both plausible mechanisms and correlative associations. The confounding interaction of many of these variables currently makes it difficult to assign definitive contributions. Here, we review the current state of play in the field, identify the key unknowns in the causality of immune variation, and identify the multidisciplinary pathways toward an improved understanding.

RevDate: 2021-11-16

Denisova EI, Savinkova MM, EN Makarova (2021)

Influence of leptin administration to pregnant female mice on obesity development, taste preferences, and gene expression in the liver and muscles of their male and female offspring.

Vavilovskii zhurnal genetiki i selektsii, 25(6):669-676.

. The consumption of food rich in sugar and fat provokes obesity. Prenatal conditions have an impact on taste preferences and metabolism in the adult offspring, and this impact may manifest differently in different sexes. An increase in blood leptin level in pregnant females reduces the risk of obesity and insulin resistance in the offspring, although the mechanisms mediating this effect are unknown. Neither is it known whether maternal leptin affects taste preferences. In this study, we investigated the effect of leptin administration to pregnant mice on the development of diet-induced obesity, food choice, and gene expression in the liver and muscles of the offspring with regard to sex. Leptin was administered to female mice on days 11, 12, and 13 of pregnancy. In male and female offspring, growth rate and intake of standard chow after weaning, obesity development, gene expression in the liver and muscles, and food choice when kept on a high-calorie diet (standard chow, lard, sweet cookies) were recorded. Leptin administration to pregnant females reduced body weight in the female offspring fed on the standard diet. When the offspring were given a high-calorie diet, leptin administration inhibited obesity development and reduced the consumption of cookies only in males. It also increased the consumption of standard chow and the mRNA levels of genes for the insulin receptor and glucose transporter type 4 in the muscles of both male and female offspring. The results demonstrate that an increase in blood leptin levels in pregnant females has a sex-specif ic effect on the metabolism of the offspring increasing resistance to obesity only in male offspring. The mechanism underlying this effect includes a shift in food preference in favor of a balanced diet and maintenance of insulin sensitivity in muscle tissues.

RevDate: 2021-11-15

Grin IR, Mechetin GV, Kasymov RD, et al (2021)

A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme.

Molecules (Basel, Switzerland), 26(21): pii:molecules26216668.

Uracil-DNA glycosylases are enzymes that excise uracil bases appearing in DNA as a result of cytosine deamination or accidental dUMP incorporation from the dUTP pool. The activity of Family 1 uracil-DNA glycosylase (UNG) activity limits the efficiency of antimetabolite drugs and is essential for virulence in some bacterial and viral infections. Thus, UNG is regarded as a promising target for antitumor, antiviral, antibacterial, and antiprotozoal drugs. Most UNG inhibitors presently developed are based on the uracil base linked to various substituents, yet new pharmacophores are wanted to target a wide range of UNGs. We have conducted virtual screening of a 1,027,767-ligand library and biochemically screened the best hits for the inhibitory activity against human and vaccinia virus UNG enzymes. Although even the best inhibitors had IC50 ≥ 100 μM, they were highly enriched in a common fragment, tetrahydro-2,4,6-trioxopyrimidinylidene (PyO3). In silico, PyO3 preferably docked into the enzyme's active site, and in kinetic experiments, the inhibition was better consistent with the competitive mechanism. The toxicity of two best inhibitors for human cells was independent of the presence of methotrexate, which is consistent with the hypothesis that dUMP in genomic DNA is less toxic for the cell than strand breaks arising from the massive removal of uracil. We conclude that PyO3 may be a novel pharmacophore with the potential for development into UNG-targeting agents.

RevDate: 2021-11-10

Derenko M, Denisova G, Dambueva I, et al (2021)

Mitogenomics of modern Mongolic-speaking populations.

Molecular genetics and genomics : MGG [Epub ahead of print].

Here, we present a comprehensive data set of 489 complete mitogenomes (211 of which are new) from four Mongolic-speaking populations (Mongols, Barghuts, Khamnigans, and Buryats) to investigate their matrilineal genetic structure, ancestry and relationship with other ethnic groups. We show that along with very high levels of genetic diversity and lack of genetic differentiation, Mongolic-speaking populations exhibit strong genetic resemblance to East Asian populations of Chinese, Japanese, and Uyghurs. Phylogeographic analysis of complete mitogenomes reveals the presence of different components in the gene pools of modern Mongolic-speaking populations-the main East Eurasian component is represented by mtDNA lineages of East Asian, Siberian and autochthonous (the Baikal region/Mongolian) ancestry, whereas the less pronounced West Eurasian component can be ascribed to Europe and West Asia/Caucasus. We also observed that up to one third of the mtDNA subhaplogroups identified in Mongolic-speaking populations can be considered as Mongolic-specific with the coalescence age of most of them not exceeding 1.7 kya. This coincides well with the population size growth which started around 1.1 kya and is detectable only in the Bayesian Skyline Plot constructed based on Mongolic-specific mitogenomes. Our data suggest that the genetic structure established during the Mongol empire is still retained in present-day Mongolic-speaking populations.

RevDate: 2021-10-30

Di Pietro L, Barba M, Palacios D, et al (2021)

Shaping modern human skull through epigenetic, transcriptional and post-transcriptional regulation of the RUNX2 master bone gene.

Scientific reports, 11(1):21316.

RUNX2 encodes the master bone transcription factor driving skeletal development in vertebrates, and playing a specific role in craniofacial and skull morphogenesis. The anatomically modern human (AMH) features sequence changes in the RUNX2 locus compared with archaic hominins' species. We aimed to understand how these changes may have contributed to human skull globularization occurred in recent evolution. We compared in silico AMH and archaic hominins' genomes, and used mesenchymal stromal cells isolated from skull sutures of craniosynostosis patients for in vitro functional assays. We detected 459 and 470 nucleotide changes in noncoding regions of the AMH RUNX2 locus, compared with the Neandertal and Denisovan genomes, respectively. Three nucleotide changes in the proximal promoter were predicted to alter the binding of the zinc finger protein Znf263 and long-distance interactions with other cis-regulatory regions. By surface plasmon resonance, we selected nucleotide substitutions in the 3'UTRs able to affect miRNA binding affinity. Specifically, miR-3150a-3p and miR-6785-5p expression inversely correlated with RUNX2 expression during in vitro osteogenic differentiation. The expression of two long non-coding RNAs, AL096865.1 and RUNX2-AS1, within the same locus, was modulated during in vitro osteogenic differentiation and correlated with the expression of specific RUNX2 isoforms. Our data suggest that RUNX2 may have undergone adaptive phenotypic evolution caused by epigenetic and post-transcriptional regulatory mechanisms, which may explain the delayed suture fusion leading to the present-day globular skull shape.

RevDate: 2021-10-30

Yuan K, Ni X, Liu C, et al (2021)

Refining models of archaic admixture in Eurasia with ArchaicSeeker 2.0.

Nature communications, 12(1):6232.

We developed a method, ArchaicSeeker 2.0, to identify introgressed hominin sequences and model multiple-wave admixture. The new method enabled us to discern two waves of introgression from both Denisovan-like and Neanderthal-like hominins in present-day Eurasian populations and an ancient Siberian individual. We estimated that an early Denisovan-like introgression occurred in Eurasia around 118.8-94.0 thousand years ago (kya). In contrast, we detected only one single episode of Denisovan-like admixture in indigenous peoples eastern to the Wallace-Line. Modeling ancient admixtures suggested an early dispersal of modern humans throughout Asia before the Toba volcanic super-eruption 74 kya, predating the initial peopling of Asia as proposed by the traditional Out-of-Africa model. Survived archaic sequences are involved in various phenotypes including immune and body mass (e.g., ZNF169), cardiovascular and lung function (e.g., HHAT), UV response and carbohydrate metabolism (e.g., HYAL1/HYAL2/HYAL3), while "archaic deserts" are enriched with genes associated with skin development and keratinization.

RevDate: 2021-10-29

Dzhafarov VM, Guzeeva AS, Amelina EV, et al (2021)

[Invasive EEG for temporal lobe epilepsy: selection of technique].

Zhurnal voprosy neirokhirurgii imeni N. N. Burdenko, 85(5):23-29.

BACKGROUND: Non-invasive EEG reveals epileptogenic zone in 70% of patients. In other cases, invasive EEG monitoring is indicated. Various implantation strategies and techniques of intracranial EEG (icEEG) potentially provide different outcomes. Choosing the optimal icEEG technique may be challenging.

OBJECTIVE: To analyze the results of icEEG in adults with temporal lobe epilepsy and to determine the algorithm for selection of optimal invasive EEG technique.

MATERIAL AND METHODS: The study included 82 patients with temporal lobe epilepsy who underwent invasive EEG. Effectiveness of invasive EEG was determined by detection of epileptogenic zone and post-resection outcomes. Postoperative results were analyzed throughout more than 6-month follow-up period using the Engel grading system. Statistical analysis was conducted using the Fisher's exact test.

RESULTS: Epileptogenic zone was revealed in 72 (88%) cases. Invasive EEG was supplemented by another modality in 3 (4%) patients. Mean follow-up period after resection was 17 months in 45 patients. Favorable outcomes were achieved in 31 (69%) cases. Statistical analysis showed that identification of epileptogenic zone depends existing of lesion and symptoms of seizures. Selection algorithm for optimal technique of invasive EEG was determined considering own results and literature data.

CONCLUSION: Invasive EEG results and post-resection outcomes demonstrated favorable efficacy of original algorithm. The last one may be used in decision-making on optimal technique of invasive EEG in adults with temporal lobe epilepsy.

RevDate: 2021-10-25

Ouzhuluobu, He Y, Lou H, et al (2020)

De novo assembly of a Tibetan genome and identification of novel structural variants associated with high-altitude adaptation.

National science review, 7(2):391-402.

Structural variants (SVs) may play important roles in human adaptation to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50 length of 58.80 Mb. The ZF1 assembly filled 80 remaining N-gaps (0.25 Mb in total length) in the reference human genome (GRCh38). Markedly, we detected 17 900 SVs, among which the ZF1-specific SVs are enriched in GTPase activity that is required for activation of the hypoxic pathway. Further population analysis uncovered a 163-bp intronic deletion in the MKL1 gene showing large divergence between highland Tibetans and lowland Han Chinese. This deletion is significantly associated with lower systolic pulmonary arterial pressure, one of the key adaptive physiological traits in Tibetans. Moreover, with the use of the high-quality de novo assembly, we observed a much higher rate of genome-wide archaic hominid (Altai Neanderthal and Denisovan) shared non-reference sequences in ZF1 (1.32%-1.53%) compared to other East Asian genomes (0.70%-0.98%), reflecting a unique genomic composition of Tibetans. One such archaic hominid shared sequence-a 662-bp intronic insertion in the SCUBE2 gene-is enriched and associated with better lung function (the FEV1/FVC ratio) in Tibetans. Collectively, we generated the first high-resolution Tibetan reference genome, and the identified SVs may serve as valuable resources for future evolutionary and medical studies.

RevDate: 2021-10-07

Kraef C, Bentzon A, Panteleev A, et al (2021)

Delayed diagnosis of tuberculosis in persons living with HIV in Eastern Europe: associated factors and effect on mortality-a multicentre prospective cohort study.

BMC infectious diseases, 21(1):1038.

BACKGROUND: Early diagnosis of tuberculosis (TB) is important to reduce transmission, morbidity and mortality in people living with HIV (PLWH).

METHODS: PLWH with a diagnosis of TB were enrolled from HIV and TB clinics in Eastern Europe and followed until 24 months. Delayed diagnosis was defined as duration of TB symptoms (cough, weight-loss or fever) for ≥ 1 month before TB diagnosis. Risk factors for delayed TB diagnosis were assessed using multivariable logistic regression. The effect of delayed diagnosis on mortality was assessed using Kaplan-Meier estimates and Cox models.

FINDINGS: 480/740 patients (64.9%; 95% CI 61.3-68.3%) experienced a delayed diagnosis. Age ≥ 50 years (vs. < 50 years, aOR = 2.51; 1.18-5.32; p = 0.016), injecting drug use (IDU) (vs. non-IDU aOR = 1.66; 1.21-2.29; p = 0.002), being ART naïve (aOR = 1.77; 1.24-2.54; p = 0.002), disseminated TB (vs. pulmonary TB, aOR = 1.56, 1.10-2.19, p = 0.012), and presenting with weight loss (vs. no weight loss, aOR = 1.63; 1.18-2.24; p = 0.003) were associated with delayed diagnosis. PLWH with a delayed diagnosis were at 36% increased risk of death (hazard ratio = 1.36; 1.04-1.77; p = 0.023, adjusted hazard ratio 1.27; 0.95-1.70; p = 0.103).

CONCLUSION: Nearly two thirds of PLWH with TB in Eastern Europe had a delayed TB diagnosis, in particular those of older age, people who inject drugs, ART naïve, with disseminated disease, and presenting with weight loss. Patients with delayed TB diagnosis were subsequently at higher risk of death in unadjusted analysis. There is a need for optimisation of the current TB diagnostic cascade and HIV care in PLWH in Eastern Europe.

RevDate: 2021-09-28

Sobolev V, Soboleva A, Denisova E, et al (2021)

Differential Expression of Estrogen-Responsive Genes in Women with Psoriasis.

Journal of personalized medicine, 11(9): pii:jpm11090925.

In women, the flow of psoriasis is influenced by each phase of a woman's life cycle. According to previous findings, significant changes in the levels of sex hormones affect the severity of the disease. Aim: The aim of this study was to identify the estrogen-responsive genes that could be responsible for the exacerbation of psoriasis in menopausal women. Methods: Skin samples of lesional skin donated by psoriasis patients (n = 5) were compared with skin samples of healthy volunteers (n = 5) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The set of differentially expressed proteins was subjected to protein ontology analysis to identify differentially expressed estrogen-responsive proteins. The expression of discovered proteins was validated by qPCR and ELISA on four groups of female participants. The first group included ten psoriasis patients without menopause; the second included eleven postmenopausal patients; the third included five healthy volunteers without menopause; and the fourth included six postmenopausal volunteers. Moreover, the participants' blood samples were used to assess the levels of estradiol, progesterone, and testosterone. Results: We found that the levels of estradiol and progesterone were significantly lower and the levels of testosterone were significantly higher in the blood of patients compared to the control. The protein ontology analysis of LC-MS/MS data identified six proteins, namely HMOX1, KRT19, LDHA, HSPD1, MAPK1, and CA2, differentially expressed in the lesional skin of female patients compared to male patients. ELISA and qPCR experiments confirmed differential expression of the named proteins and their mRNA. The genes encoding the named proteins were differentially expressed in patients compared to volunteers. However, KRT19 and LDHA were not differentially expressed when we compared patients with and without menopause. All genes, except MAPK1, were differentially expressed in patients with menopause compared to the volunteers with menopause. HMOX1, KRT19, HSPD1, and LDHA were differentially expressed in patients without menopause compared to the volunteers without menopause. However, no significant changes were found when we compared healthy volunteers with and without menopause. Conclusion: Our experiments discovered a differential expression of six estrogen-controlled genes in the skin of female patients. Identification of these genes and assessment of the changes in their expression provide insight into the biological effects of estrogen in lesional skin. The results of proteomic analysis are available via ProteomeXchange with identifier PXD021673.

RevDate: 2021-08-31

Deņisova A, Pilmane M, Eņģelis A, et al (2021)

Gallbladder Interleukins in Children with Calculous Cholecystitis.

Pediatric reports, 13(3):470-482.

Calculous cholecystitis connects to inflammation and various complications. It is a common disease in the paediatric population, yet it is still uncertain how inflammation factors are involved in its morphopathogenesis. Twenty calculous cholecystitis surgery tissue samples were obtained from 20 children. As a control, seven unaffected gallbladders were used. Tissues were immunohistochemically stained for IL-1α, IL-4, IL-6, IL-7, IL-8, IL-10, and IL-17A, and the slides were inspected by light microscopy. To evaluate statistical differences and correlations between interleukins, Mann-Whitney U and Spearman's tests were used. Statistically significant difference between patient and control gallbladder epithelium was for IL-1α and IL-17A, but connective tissue-IL-1α, IL-4, IL-6, IL-7, IL-8, and IL-17A positive structures. A strong positive correlation in patients was detected between epithelial IL-1α and IL-1α in connective tissue, epithelial IL-6 and IL-7, IL-6 and IL-17A, IL-7 and IL-10, IL-7 and IL-17A, as well as between IL-6 and IL-7, IL-7 and IL-10 in connective tissue. The increase of IL-1α, IL-4, IL-6, IL-7, IL-8 and IL-17A positive structures suggests their role in the morphopathogenesis of calculous cholecystitis. The correlations between interleukins in epithelium and in connective tissues prove that the epithelial barrier function and inflammatory response in deeper layers are sustained through intercellular signalling pathways.

RevDate: 2021-09-08
CmpDate: 2021-09-08

Sobolev V, Nesterova A, Soboleva A, et al (2021)

Analysis of PPARγ Signaling Activity in Psoriasis.

International journal of molecular sciences, 22(16):.

In our previous work, we built the model of PPARγ dependent pathways involved in the development of the psoriatic lesions. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which regulates the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPARγ expression promote the development of psoriatic lesions triggering the IL17-related signaling cascade. Skin samples of normally looking and lesional skin donated by psoriasis patients and psoriatic CD3+ Tcells samples (n = 23) and samples of healthy CD3+ T cells donated by volunteers (n = 10) were analyzed by real-time PCR, ELISA and immunohistochemistry analysis. We found that the expression of PPARγ is downregulated in human psoriatic skin and laser treatment restores the expression. The expression of IL17, STAT3, FOXP3, and RORC in psoriatic skin before and after laser treatment were correlated with PPARγ expression according to the reconstructed model of PPARγ pathway in psoriasis.In conclusion, we report that PPARγ weakens the expression of genes that contribute in the development of psoriatic lesion. Our data show that transcriptional regulation of PPARγ expression by FOSL1 and by STAT3/FOSL1 feedback loop may be central in the psoriatic skin and T-cells.

RevDate: 2021-09-16

Carlhoff S, Duli A, Nägele K, et al (2021)

Genome of a middle Holocene hunter-gatherer from Wallacea.

Nature, 596(7873):543-547.

Much remains unknown about the population history of early modern humans in southeast Asia, where the archaeological record is sparse and the tropical climate is inimical to the preservation of ancient human DNA1. So far, only two low-coverage pre-Neolithic human genomes have been sequenced from this region. Both are from mainland Hòabìnhian hunter-gatherer sites: Pha Faen in Laos, dated to 7939-7751 calibrated years before present (yr cal BP; present taken as AD 1950), and Gua Cha in Malaysia (4.4-4.2 kyr cal BP)1. Here we report, to our knowledge, the first ancient human genome from Wallacea, the oceanic island zone between the Sunda Shelf (comprising mainland southeast Asia and the continental islands of western Indonesia) and Pleistocene Sahul (Australia-New Guinea). We extracted DNA from the petrous bone of a young female hunter-gatherer buried 7.3-7.2 kyr cal BP at the limestone cave of Leang Panninge2 in South Sulawesi, Indonesia. Genetic analyses show that this pre-Neolithic forager, who is associated with the 'Toalean' technocomplex3,4, shares most genetic drift and morphological similarities with present-day Papuan and Indigenous Australian groups, yet represents a previously unknown divergent human lineage that branched off around the time of the split between these populations approximately 37,000 years ago5. We also describe Denisovan and deep Asian-related ancestries in the Leang Panninge genome, and infer their large-scale displacement from the region today.

RevDate: 2021-08-13

Larena M, McKenna J, Sanchez-Quinto F, et al (2021)

Philippine Ayta possess the highest level of Denisovan ancestry in the world.

Current biology : CB pii:S0960-9822(21)00977-5 [Epub ahead of print].

Multiple lines of evidence show that modern humans interbred with archaic Denisovans. Here, we report an account of shared demographic history between Australasians and Denisovans distinctively in Island Southeast Asia. Our analyses are based on ∼2.3 million genotypes from 118 ethnic groups of the Philippines, including 25 diverse self-identified Negrito populations, along with high-coverage genomes of Australopapuans and Ayta Magbukon Negritos. We show that Ayta Magbukon possess the highest level of Denisovan ancestry in the world-∼30%-40% greater than that of Australians and Papuans-consistent with an independent admixture event into Negritos from Denisovans. Together with the recently described Homo luzonensis, we suggest that there were multiple archaic species that inhabited the Philippines prior to the arrival of modern humans and that these archaic groups may have been genetically related. Altogether, our findings unveil a complex intertwined history of modern and archaic humans in the Asia-Pacific region, where distinct Islander Denisovan populations differentially admixed with incoming Australasians across multiple locations and at various points in time.

RevDate: 2021-08-02

Brown S, Wang N, Oertle A, et al (2021)

Zooarchaeology through the lens of collagen fingerprinting at Denisova Cave.

Scientific reports, 11(1):15457.

Denisova Cave, a Pleistocene site in the Altai Mountains of Russian Siberia, has yielded significant fossil and lithic evidence for the Pleistocene in Northern Asia. Abundant animal and human bones have been discovered at the site, however, these tend to be highly fragmented, necessitating new approaches to identifying important hominin and faunal fossils. Here we report the results for 8253 bone fragments using ZooMS. Through the integration of this new ZooMS-based data with the previously published macroscopically-identified fauna we aim to create a holistic picture of the zooarchaeological record of the site. We identify trends associated with climate variability throughout the Middle and Upper Pleistocene as well as patterns explaining the process of bone fragmentation. Where morphological analysis of bones from the site have identified a high proportion of carnivore bones (30.2%), we find that these account for only 7.6% of the ZooMS assemblage, with large mammals between 3 and 5 more abundant overall. Our analysis suggests a cyclical pattern in fragmentation of bones which sees initial fragmentation by hominins using percussive tools and secondary carnivore action, such as gnawing and digestion, likely furthering the initial human-induced fragmentation.

RevDate: 2021-08-01

Condemi S, Mazières S, Faux P, et al (2021)

Blood groups of Neandertals and Denisova decrypted.

PloS one, 16(7):e0254175.

Blood group systems were the first phenotypic markers used in anthropology to decipher the origin of populations, their migratory movements, and their admixture. The recent emergence of new technologies based on the decoding of nucleic acids from an individual's entire genome has relegated them to their primary application, blood transfusion. Thus, despite the finer mapping of the modern human genome in relation to Neanderthal and Denisova populations, little is known about red cell blood groups in these archaic populations. Here we analyze the available high-quality sequences of three Neanderthals and one Denisovan individuals for 7 blood group systems that are used today in transfusion (ABO including H/Se, Rh (Rhesus), Kell, Duffy, Kidd, MNS, Diego). We show that Neanderthal and Denisova were polymorphic for ABO and shared blood group alleles recurrent in modern Sub-Saharan populations. Furthermore, we found ABO-related alleles currently preventing from viral gut infection and Neanderthal RHD and RHCE alleles nowadays associated with a high risk of hemolytic disease of the fetus and newborn. Such a common blood group pattern across time and space is coherent with a Neanderthal population of low genetic diversity exposed to low reproductive success and with their inevitable demise. Lastly, we connect a Neanderthal RHD allele to two present-day Aboriginal Australian and Papuan, suggesting that a segment of archaic genome was introgressed in this gene in non-Eurasian populations. While contributing to both the origin and late evolutionary history of Neanderthal and Denisova, our results further illustrate that blood group systems are a relevant piece of the puzzle helping to decipher it.

RevDate: 2021-08-03

Schaefer NK, Shapiro B, RE Green (2021)

An ancestral recombination graph of human, Neanderthal, and Denisovan genomes.

Science advances, 7(29):.

Many humans carry genes from Neanderthals, a legacy of past admixture. Existing methods detect this archaic hominin ancestry within human genomes using patterns of linkage disequilibrium or direct comparison to Neanderthal genomes. Each of these methods is limited in sensitivity and scalability. We describe a new ancestral recombination graph inference algorithm that scales to large genome-wide datasets and demonstrate its accuracy on real and simulated data. We then generate a genome-wide ancestral recombination graph including human and archaic hominin genomes. From this, we generate a map within human genomes of archaic ancestry and of genomic regions not shared with archaic hominins either by admixture or incomplete lineage sorting. We find that only 1.5 to 7% of the modern human genome is uniquely human. We also find evidence of multiple bursts of adaptive changes specific to modern humans within the past 600,000 years involving genes related to brain development and function.

RevDate: 2021-08-24

Bezverbnaya K, Moogk D, Cummings D, et al (2021)

Development of a B-cell maturation antigen-specific T-cell antigen coupler receptor for multiple myeloma.

Cytotherapy, 23(9):820-832.

BACKGROUND AIMS: T cells engineered with synthetic receptors have delivered powerful therapeutic results for patients with relapsed/refractory hematologic malignancies. The authors have recently described the T-cell antigen coupler (TAC) receptor, which co-opts the endogenous T-cell receptor (TCR) and activates engineered T cells in an HLA-independent manner. Here the authors describe the evolution of a next-generation TAC receptor with a focus on developing a TAC-engineered T cell for multiple myeloma.

METHODS: To optimize the TAC scaffold, the authors employed a bona fide antigen-binding domain derived from the B-cell maturation antigen-specific monoclonal antibody C11D5.3, which has been used successfully in the clinic. The authors first tested humanized versions of the UCHT1 domain, which is used by the TAC to co-opt the TCR. The authors further discovered that the signal peptide affected surface expression of the TAC receptor. Higher density of the TAC receptor enhanced target binding in vitro, which translated into higher levels of Lck at the immunological synapse and stronger proliferation when only receptor-ligand interactions were present.

RESULTS: The authors observed that the humanized UCHT1 improved surface expression and in vivo efficacy. Using TAC T cells derived from both healthy donors and multiple myeloma patients, the authors determined that despite the influence of receptor density on early activation events and effector function, receptor density did not impact late effector functions in vitro, nor did the receptor density affect in vivo efficacy.

CONCLUSIONS: The modifications to the TAC scaffold described herein represent an important step in the evolution of this technology, which tolerates a range of expression levels without impacting therapeutic efficacy.

RevDate: 2021-07-07
CmpDate: 2021-07-07

Gibbons A (2021)

'Dragon Man' may be an elusive Denisovan.

Science (New York, N.Y.), 373(6550):11-12.

RevDate: 2021-07-26
CmpDate: 2021-07-26

Sudarkina OY, Filippenkov IB, Stavchansky VV, et al (2021)

Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4-7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia-Reperfusion.

International journal of molecular sciences, 22(12):.

The Semax (Met-Glu-His-Phe-Pro-Gly-Pro) peptide is a synthetic melanocortin derivative that is used in the treatment of ischemic stroke. Previously, studies of the molecular mechanisms underlying the actions of Semax using models of cerebral ischemia in rats showed that the peptide enhanced the transcription of neurotrophins and their receptors and modulated the expression of genes involved in the immune response. A genome-wide RNA-Seq analysis revealed that, in the rat transient middle cerebral artery occlusion (tMCAO) model, Semax suppressed the expression of inflammatory genes and activated the expression of neurotransmitter genes. Here, we aimed to evaluate the effect of Semax in this model via the brain expression profiling of key proteins involved in inflammation and cell death processes (MMP-9, c-Fos, and JNK), as well as neuroprotection and recovery (CREB) in stroke. At 24 h after tMCAO, we observed the upregulation of active CREB in subcortical structures, including the focus of the ischemic damage; downregulation of MMP-9 and c-Fos in the adjacent frontoparietal cortex; and downregulation of active JNK in both tissues under the action of Semax. Moreover, a regulatory network was constructed. In conclusion, the suppression of inflammatory and cell death processes and the activation of recovery may contribute to the neuroprotective action of Semax at both the transcriptome and protein levels.

RevDate: 2021-06-29

Graham F (2021)

Daily briefing: DNA in Denisova Cave soil records several human species.

RevDate: 2021-07-27

Zavala EI, Jacobs Z, Vernot B, et al (2021)

Pleistocene sediment DNA reveals hominin and faunal turnovers at Denisova Cave.

Nature, 595(7867):399-403.

Denisova Cave in southern Siberia is the type locality of the Denisovans, an archaic hominin group who were related to Neanderthals1-4. The dozen hominin remains recovered from the deposits also include Neanderthals5,6 and the child of a Neanderthal and a Denisovan7, which suggests that Denisova Cave was a contact zone between these archaic hominins. However, uncertainties persist about the order in which these groups appeared at the site, the timing and environmental context of hominin occupation, and the association of particular hominin groups with archaeological assemblages5,8-11. Here we report the analysis of DNA from 728 sediment samples that were collected in a grid-like manner from layers dating to the Pleistocene epoch. We retrieved ancient faunal and hominin mitochondrial (mt)DNA from 685 and 175 samples, respectively. The earliest evidence for hominin mtDNA is of Denisovans, and is associated with early Middle Palaeolithic stone tools that were deposited approximately 250,000 to 170,000 years ago; Neanderthal mtDNA first appears towards the end of this period. We detect a turnover in the mtDNA of Denisovans that coincides with changes in the composition of faunal mtDNA, and evidence that Denisovans and Neanderthals occupied the site repeatedly-possibly until, or after, the onset of the Initial Upper Palaeolithic at least 45,000 years ago, when modern human mtDNA is first recorded in the sediments.

RevDate: 2021-06-22

Amos W (2021)

Correlated and geographically predictable Neanderthal and Denisovan legacies are difficult to reconcile with a simple model based on inter-breeding.

Royal Society open science, 8(6):201229.

Although the presence of archaic hominin legacies in humans is taken for granted, little attention has been given as to how the data fit with how humans colonized the world. Here, I show that Neanderthal and Denisovan legacies are strongly correlated and that inferred legacy size, like heterozygosity, exhibits a strong correlation with distance from Africa. Simulations confirm that, once created, legacy size is extremely stable: it may reduce through admixture with lower legacy populations but cannot increase significantly through neutral drift. Consequently, populations carrying the highest legacies are likely to be those whose ancestors inter-bred most with archaics. However, the populations with the highest legacies are globally scattered and are unified, not by having origins within the known Neanderthal range, but instead by living in locations that lie furthest from Africa. Furthermore, the Simons Genome Diversity Project data reveal two distinct correlations between Neanderthal and Denisovan legacies, one that starts in North Africa and increases west to east across Eurasia and into some parts of Oceania, and a second, much steeper trend that starts in Africa, peaking with the San and Ju/'hoansi and which, if extrapolated, predicts the large inferred legacies of both archaics found in Oceania/Australia. Similar 'double' trends are observed for the introgression statistic f 4 in a second large dataset published by Qin and Stoneking (Qin & Stoneking 2015 Mol. Biol. Evol. 32, 2665-2674 (doi:10.1093/molbev/msv141)). These trends appear at odds with simple models of how introgression occurred though more complicated patterns of introgression could potentially generate better fits. Moreover, substituting archaic genomes with those of great apes yields similar but biologically impossible signals of introgression, suggesting that the signals these metrics capture arise within humans and are largely independent of the test group. Interestingly, the data do appear to fit a speculative model in which the loss of diversity that occurred when humans moved further from Africa created a gradient in heterozygosity that in turn progressively reduced mutation rate such that populations furthest from Africa have diverged less from our common ancestor and hence from the archaics. In this light, the two distinct trends could be interpreted in terms of two 'out of Africa' events, an early one ending in Oceania and Australia and a later one that colonized Eurasia and the Americas.

RevDate: 2021-06-09
CmpDate: 2021-06-09

Dergunova LV, Dmitrieva VG, Filippenkov IB, et al (2021)

[The Peptide Drug ACTH(4-7)PGP (Semax) Suppresses mRNA Transcripts Encoding Proinflammatory Mediators Induced by Reversible Ischemia of the Rat Brain].

Molekuliarnaia biologiia, 55(3):402-411.

Due to its nootropic, neuroprotective, and immunomodulatory effects, the peptide Semax is utilized in the treatment of ischemic stroke. Our earlier RNA-Seq analysis of the transcriptome in an ischemic model of transient occlusion of the middle cerebral artery showed an increase in the mRNA levels of many proinflammatory genes, and the suppression of their induction by Semax. However, for many relevant genes, including Il1a, Il1b, Il6 and Tnfa, the levels of their expression were too low for detailed quantitative evaluation. Here we utilize qRT-PCR to analyze the effects of the Semax peptide on the expression of weakly expressed mRNAs encoding several proinflammatory mediators, and show that exposure to Semax leads to a statistically significant decrease in the Il1a, Il1b, Il6, Ccl3, and Cxcl2 mRNAs, which compensates for the increase in the transcription of these genes induced by ischemia-reperfusion. We conclude that the observed protective effect of Semax in the model of stroke may be due to its anti-inflammatory effects. We also discuss the limitations of the RNA-Seq when applied to quantifying less abundant transcripts as compared to the real-time RT-PCR method.

RevDate: 2021-06-08

Zhou Y, SR Browning (2021)

Protocol for detecting introgressed archaic variants with SPrime.

STAR protocols, 2(2):100550.

The SPrime program detects the variants in current-day populations that were introgressed from an archaic source in the past. It is optimized for detecting introgression from Neanderthals and Denisovans in modern humans. We provide a protocol for detecting Neanderthal and Denisovan introgression in 1000 Genomes Project data, specifically focusing on the CHB (Han Chinese in Beijing) population. For complete details on the use and execution of this protocol, please refer to Browning et al. (2018).

RevDate: 2021-06-11

Shtratnikova V, Naumov V, Bezuglov V, et al (2021)

Optimization of small RNA extraction and comparative study of NGS library preparation from low count sperm samples.

Systems biology in reproductive medicine, 67(3):230-243.

Recent studies demonstrate that sperm epigenome is a vehicle that conveys paternal experiences to offspring phenotype. That evidence triggers interest of both experimental and epidemiological studies of epigenetic markers in sperm. Since samples are often unique in epidemiological studies, a careful and efficient use of the material is a critical requirement. The goal of this study was to provide optimization of methods for the isolation of small RNAs from spermatozoa and library preparation for sequencing. A total 67 fractionated sperm samples from the Russian Children's Study biobank prospectively collected at 18-20 years of age were used to isolate small RNAs with median (IQR) input total sperm count 17.0 (7.4-35.9) million. Twenty-four pairs of libraries were prepared using the NEBNext and NEXTFlex kits, 19 libraries using NEBNext and 6 using NEXTFlex. All libraries were sequenced on NextSeq 500, and the results were evaluated as a function of the number of small non-coding RNA (sncRNA) detected, quality parameters of sequencing libraries, as well as technical features of sample preparation. Although the same amount of miRNA input was used for NEBNext and NEXTFlex libraries, the concentration of DNA in NEBNext libraries was significantly higher in comparison with NEXTFlex libraries. In high input (sperm count >28 million and more than 25 ng miRNA in library) NEXTFlex Small RNA-Seq kit detected more microRNAs. In low input, the NEBNext proved more effective. The tricks and traps to protocol optimization are presented, including an efficient and effector gel-based system for the removal of sequencing library adaptors.

RevDate: 2021-06-15

Denisova YI, Shandryuk GA, Arinina MP, et al (2021)

Multiblock Copolymers of Norbornene and Cyclododecene: Chain Structure and Properties.

Polymers, 13(11):.

We investigate the structure-property relations of the multiblock copolymers of norbornene with cyclododecene synthesized via the macromolecular cross-metathesis reaction between amorphous polynorbornene and semicrystalline polydodecenamer in the presence of the first-generation Grubbs catalyst. By adjusting the reaction time, catalyst amount, and composition of the initial system, we obtain a set of statistical multiblock copolymers that differ in the composition and average length of norbornene and dodecenylene unit sequences. Structural, thermal, and mechanical characterization of the copolymers with NMR, XRD, DSC (including thermal fractionation by successive self-nucleation and annealing), and rotational rheology allows us to relate the reaction conditions to the average length of crystallizable unit sequences, thicknesses of corresponding lamellas, and temperatures of their melting. We demonstrate that isolated dodecenylene units can be incorporated into crystalline lamellas so that even nearly random copolymers should retain crystallinity. Weak high-temperature endotherms observed in the multiblock copolymers of norbornene with cyclododecene and other cycloolefins could indicate that the corresponding systems are microphase-separated in the melt state.

RevDate: 2021-06-18

Zhang X, Witt KE, Bañuelos MM, et al (2021)

The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans.

Proceedings of the National Academy of Sciences of the United States of America, 118(22):.

Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000-59,500) y ago, and selection started around 9,000 (2,500-42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.

RevDate: 2021-05-28

Denisova E, Westphal D, Surowy HM, et al (2021)

Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies.

Cancer gene therapy [Epub ahead of print].

Malignant sweat gland tumours are rare, with the most common form being Eccrine porocarcinoma (EP). To investigate the mutational landscape of EP, we performed whole-exome sequencing (WES) on 14 formalin-fixed paraffin-embedded samples of matched primary EP and healthy surrounding tissue. Mutational profiling revealed a high overall median mutation rate. This was attributed to signatures of mutational processes related to ultraviolet (UV) exposure, APOBEC enzyme dysregulation, and defective homologous double-strand break repair. All of these processes cause genomic instability and are implicated in carcinogenesis. Recurrent driving somatic alterations were detected in the EP candidate drivers TP53, FAT2, CACNA1S, and KMT2D. The analyses also identified copy number alterations and recurrent gains and losses in several chromosomal regions including that containing BRCA2, as well as deleterious alterations in multiple HRR components. In accordance with this reduced or even a complete loss of BRCA2 protein expression was detected in 50% of the investigated EP tumours. Our results implicate crucial oncogenic driver pathways and suggest that defective homologous double-strand break repair and the p53 pathway are involved in EP aetiology. Targeting of the p53 axis and PARP inhibition, and/or immunotherapy may represent promising treatment strategies.

RevDate: 2021-08-02

Ahlquist KD, Bañuelos MM, Funk A, et al (2021)

Our Tangled Family Tree: New Genomic Methods Offer Insight into the Legacy of Archaic Admixture.

Genome biology and evolution, 13(7):.

The archaic ancestry present in the human genome has captured the imagination of both scientists and the wider public in recent years. This excitement is the result of new studies pushing the envelope of what we can learn from the archaic genetic information that has survived for over 50,000 years in the human genome. Here, we review the most recent ten years of literature on the topic of archaic introgression, including the current state of knowledge on Neanderthal and Denisovan introgression, as well as introgression from other as-yet unidentified archaic populations. We focus this review on four topics: 1) a reimagining of human demographic history, including evidence for multiple admixture events between modern humans, Neanderthals, Denisovans, and other archaic populations; 2) state-of-the-art methods for detecting archaic ancestry in population-level genomic data; 3) how these novel methods can detect archaic introgression in modern African populations; and 4) the functional consequences of archaic gene variants, including how those variants were co-opted into novel function in modern human populations. The goal of this review is to provide a simple-to-access reference for the relevant methods and novel data, which has changed our understanding of the relationship between our species and its siblings. This body of literature reveals the large degree to which the genetic legacy of these extinct hominins has been integrated into the human populations of today.

RevDate: 2021-07-22

Mualim K, Theunert C, M Slatkin (2021)

Estimation of coalescence probabilities and population divergence times from SNP data.

Heredity, 127(1):1-9.

We present a method called the G(A|B) method for estimating coalescence probabilities within population lineages from genome sequences when one individual is sampled from each population. Population divergence times can be estimated from these coalescence probabilities if additional assumptions about the history of population sizes are made. Our method is based on a method presented by Rasmussen et al. (2014) to test whether an archaic genome is from a population directly ancestral to a present-day population. The G(A|B) method does not require distinguishing ancestral from derived alleles or assumptions about demographic history before population divergence. We discuss the relationship of our method to two similar methods, one introduced by Green et al. (2010) and called the F(A|B) method and the other introduced by Schlebusch et al. (2017) and called the TT method. When our method is applied to individuals from three or more populations, it provides a test of whether the population history is treelike because coalescence probabilities are additive on a tree. We illustrate the use of our method by applying it to three high-coverage archaic genomes, two Neanderthals (Vindija and Altai) and a Denisovan.

RevDate: 2021-09-20
CmpDate: 2021-09-20

Villanea FA, Huerta-Sanchez E, K Fox (2021)

ABO Genetic Variation in Neanderthals and Denisovans.

Molecular biology and evolution, 38(8):3373-3382.

Variation at the ABO locus was one of the earliest sources of data in the study of human population identity and history, and to this day remains widely genotyped due to its importance in blood and tissue transfusions. Here, we look at ABO blood type variants in our archaic relatives: Neanderthals and Denisovans. Our goal is to understand the genetic landscape of the ABO gene in archaic humans, and how it relates to modern human ABO variation. We found two Neanderthal variants of the O allele in the Siberian Neanderthals (O1 and O2), one of these variants is shared with an European Neanderthal, who is a heterozygote for this O1 variant and a rare cis-AB variant. The Denisovan individual is heterozygous for two variants of the O1 allele, functionally similar to variants found widely in modern humans. Perhaps more surprisingly, the O2 allele variant found in Siberian Neanderthals can be found at low frequencies in modern Europeans and Southeast Asians, and the O1 allele variant found in Siberian and European Neanderthal is also found at very low frequency in modern East Asians. Our genetic distance analyses suggest both alleles survive in modern humans due to inbreeding with Neanderthals. We find that the sequence backgrounds of the surviving Neanderthal-like O alleles in modern humans retain a higher sequence divergence than other surviving Neanderthal genome fragments, supporting a view of balancing selection operating in the Neanderthal ABO alleles by retaining highly diverse haplotypes compared with portions of the genome evolving neutrally.

RevDate: 2021-09-13
CmpDate: 2021-09-13

Weiss CV, Harshman L, Inoue F, et al (2021)

The cis-regulatory effects of modern human-specific variants.

eLife, 10:.

The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells, and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression.

RevDate: 2021-04-22

Anonymous (2020)

Podcast: Denisovan DNA in modern Europeans, and the birth of an unusual celestial object.

RevDate: 2021-04-21

Denisova K (2021)

Genetic vulnerability of exposures to antenatal maternal treatments in 1- to 2-month-old infants.

Infancy : the official journal of the International Society on Infant Studies, 26(3):515-532.

The growth and maturation of the nervous system are vulnerable during pregnancy. The impact of antenatal exposures to maternal treatments, in the context of genetic vulnerability of the fetus, on sensorimotor functioning in early infancy remains unexplored. Statistical features of head movements obtained from resting-state sleep fMRI scans are examined in 1- to 2-month-old infants, both those at high risk (HR) for autism spectrum disorder (ASD) due to a biological sibling with ASD and at low risk (LR) (N = 56). In utero exposures include maternal prescription medications (psychotropic Rx: N = 3HR ; N = 5LR vs. non-psychotropic Rx: N = 11HR ; N = 9LR vs. none: N = 11HR ; N = 16LR), psychiatric diagnoses (two or more Dx2 : N = 5HR ; N = 1LR ; one Dx1 : N = 4HR ; N = 5LR ; no Dx: N = 12HR ; N = 19LR), infections requiring antibiotics (infection: N = 5HR ; N = 8LR ; no infection: N = 20HR ; N = 22LR), or high fever (fever: N = 2HR ; N = 2LR ; no fever: N = 23HR ; N = 27LR). Movements with significantly higher variability are detected in infants exposed to psychotropics (e.g., opioid analgesics) and those whose mothers had fever, and this effect is significantly worse for infants at HR for ASD. Movements are significantly less variable in HR infants with non-psychotropic exposures (e.g., antibiotics). Heightened number of psychiatric or mental health conditions is associated with noisier movements in both risk groups. Genetic vulnerability due to in utero exposure to maternal treatments is an important future approach to be advanced in the field of early mind and brain development.

RevDate: 2021-04-22

Choin J, Mendoza-Revilla J, Arauna LR, et al (2021)

Genomic insights into population history and biological adaptation in Oceania.

Nature, 592(7855):583-589.

The Pacific region is of major importance for addressing questions regarding human dispersals, interactions with archaic hominins and natural selection processes1. However, the demographic and adaptive history of Oceanian populations remains largely uncharacterized. Here we report high-coverage genomes of 317 individuals from 20 populations from the Pacific region. We find that the ancestors of Papuan-related ('Near Oceanian') groups underwent a strong bottleneck before the settlement of the region, and separated around 20,000-40,000 years ago. We infer that the East Asian ancestors of Pacific populations may have diverged from Taiwanese Indigenous peoples before the Neolithic expansion, which is thought to have started from Taiwan around 5,000 years ago2-4. Additionally, this dispersal was not followed by an immediate, single admixture event with Near Oceanian populations, but involved recurrent episodes of genetic interactions. Our analyses reveal marked differences in the proportion and nature of Denisovan heritage among Pacific groups, suggesting that independent interbreeding with highly structured archaic populations occurred. Furthermore, whereas introgression of Neanderthal genetic information facilitated the adaptation of modern humans related to multiple phenotypes (for example, metabolism, pigmentation and neuronal development), Denisovan introgression was primarily beneficial for immune-related functions. Finally, we report evidence of selective sweeps and polygenic adaptation associated with pathogen exposure and lipid metabolism in the Pacific region, increasing our understanding of the mechanisms of biological adaptation to island environments.

RevDate: 2021-04-09
CmpDate: 2021-04-09

Gulaĭ IS, Snegirev AI, Denisova NP, et al (2021)

[Chronic spinal stimulation in treatment of lower limb critical ischaemia syndrome].

Angiologiia i sosudistaia khirurgiia = Angiology and vascular surgery, 27(1):128-135.

Obliterating peripheral artery disease is a commonly occurring pathological condition, most often resulting from an atherosclerotic lesion of vessels with progressive narrowing of their lumens. The consequences of decompensation of chronic arterial insufficiency such as ischaemic pain, claudication, and trophic impairments are in some instances difficult to treat, despite using multicomponent medicamentous therapy and/or performing revascularizing interventions. This article describes a clinical case report regarding the use of spinal stimulation in a patient presenting with stage IV chronic lower limb ischaemia according to the Fontaine classification. This is accompanied and followed by depicting the dynamics of the laboratory, instrumental, and clinical parameters over a two-year follow-up period. In order to explain the choice of the intervention and the causes of the described picture, discussed are the existing theories of the mechanisms of action of spinal stimulation. To this is added a literature review of using this method in treatment of lower limb critical ischaemia when performing reconstructive angiosurgical treatment is unavailable. Mention is also made of the incidence and types of probable complications, as well as possibilities and limitations of the method.

RevDate: 2021-09-16

Shunatova N, Denisova S, S Shchenkov (2021)

Ultrastructure of rhizoids in the marine bryozoan Dendrobeania fruticosa (Gymnolaemata: Cheilostomata).

Journal of morphology, 282(6):847-862.

Bryozoans form colonies of iterated modules, termed zooids, and display varying degrees of polymorphism. Polymorphic colonies comprise autozooids (or feeding zooids) and heteromorphic zooids, among which the most common types are avicularia and kenozooids. Kenozooids differ in shape, size, and presumed function. Among this diversity, there are rhizoids, which serve to attach colonies to the substrate or to lift them above it. To date, only general data on anatomy of kenozooids at light microscopy level are available. Here, we present the first description of the ultrastructure of the holdfast-like rhizoids of the cheilostome bryozoan Dendrobeania fruticosa. The rhizoid wall is composed of a single-layered epidermis, which produces the ectocyst. The voluminous cavity is acoelomate: it has no special cellular lining, nor any signs of an extracellular matrix toward the epidermis. It is traversed by delicate branching funicular strands that originate from the pore plate. The only cells in contact with the epidermis are the cells of the funicular system and the storage cells. The pore plate between the rhizoid and autozooid includes a variable number of communication pores. Each pore is plugged with a rosette complex, which includes a cincture cell and four special cells extending through the pore. The limiting cells are absent, and the special cells are in direct contact with the funicular strands. Cell contacts between special cells are absent; moreover, there are spaces between their proximal lobes filled with a heterogeneous matrix similar to that in the lumen of the funicular strands. Such matrix is also found outside of the extracellular matrix surrounding the special cells. These findings allow us to suggest that nutrient transport most likely occurs between, rather than through, the special cells. However, further studies are needed to understand how the rosette complex functions.

RevDate: 2021-07-31
CmpDate: 2021-05-19

Teixeira JC, Jacobs GS, Stringer C, et al (2021)

Widespread Denisovan ancestry in Island Southeast Asia but no evidence of substantial super-archaic hominin admixture.

Nature ecology & evolution, 5(5):616-624.

The hominin fossil record of Island Southeast Asia (ISEA) indicates that at least two endemic 'super-archaic' species-Homo luzonensis and H. floresiensis-were present around the time anatomically modern humans arrived in the region >50,000 years ago. Intriguingly, contemporary human populations across ISEA carry distinct genomic traces of ancient interbreeding events with Denisovans-a separate hominin lineage that currently lacks a fossil record in ISEA. To query this apparent disparity between fossil and genetic evidence, we performed a comprehensive search for super-archaic introgression in >400 modern human genomes, including >200 from ISEA. Our results corroborate widespread Denisovan ancestry in ISEA populations, but fail to detect any substantial super-archaic admixture signals compatible with the endemic fossil record of ISEA. We discuss the implications of our findings for the understanding of hominin history in ISEA, including future research directions that might help to unlock more details about the prehistory of the enigmatic Denisovans.

RevDate: 2021-05-27
CmpDate: 2021-05-27

Denisova K, A Barmettler (2021)

Evaluating the Thyroid Eye Disease Patient.

International ophthalmology clinics, 61(2):33-52.

RevDate: 2021-03-17
CmpDate: 2021-03-17

Soldatsky YL, Denisova OA, Vitkovskaya IP, et al (2021)

[Modern causes of tracheostomy in children].

Vestnik otorinolaringologii, 86(1):36-40.

The purpose of work is to analyze the causes of tracheostomy in children hospitalized in a large multidisciplinary pediatric hospital.

MATERIAL AND METHODS: Retrospective analysis of case of children treated in a multidisciplinary urgent hospital - GBUZ «Morozovskaya CCCH of MDH», which in the period from 01.01.16 to 31.12.18 was made operation «tracheostomy» was conducted.

RESULTS: Tracheostomy was performed in 138 (0.064%) among 216 469 hospitalized children. Age at the time of tracheostomy ranged from 2 weeks to 17.5 years (on average 67.9±59.84 months, Me=47.5 months), and 36.2% of children had tracheostomy was done on the 1st year of life. 126 (91.3%) patients required prolonged tracheal intubation prior to tracheostomy placement; the duration of intubation ranged from 1 to 95 days (on average 19.9±13.42 days, Me=14 days). The main reasons of tracheostomy were the need for long-term mechanical ventilation/respiratory support; the need for constant sanitation of the lower respiratory tract with bulbar/pseudobulbar disorders; upper respiratory paths obstruction. The diseases that led to this condition can be grouped into 4 categories: CNS pathology - 76 (55.1%) patients; brain / spinal cord tumors - 36 (26.1%); neurodystrophy and stenosis of the upper respiratory tract of various etiology - 13 (9.4% each) patients. 68.1% of patients were found incurable and required palliative care. Mortality among patients with a known catamnesis was 39.1%, mainly due to progression of the underlying disease; the lethality associated with tracheal cannulation was 1.4%.

CONCLUSION: Currently, pediatric tracheostomy is moving into the category of predominantly planned surgical interventions. More than 2/3 of children requiring tracheostomy are patients in need of palliative care with severe pathology of the central nervous system; in which the main indications for surgery are the need for respiration support and regular tracheobronchial care..

RevDate: 2021-03-04

Makarova EN, Yakovleva TV, Balyibina NY, et al (2020)

Pharmacological effects of fibroblast growth factor 21 are sex-specific in mice with the lethal yellow (Ay) mutation.

Vavilovskii zhurnal genetiki i selektsii, 24(2):200-208.

Hypothalamic melanocortin 4 receptors (MC4R) regulate energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans. Fibroblast growth factor 21 (FGF21) is a promising antiobesity agent, but its effects on melanocortin obesity are unknown. Sex is an important biological variable that must be considered when conducting preclinical studies; however, in laboratory animal models, the pharmacological effects of FGF21 are well documented only for male mice. We aimed at investigating whether FGF21 affects metabolism in male and female mice with the lethal yellow (Ay) mutation, which results in MC4R blockage and obesity development. Obese C57Bl-Ay male and female mice were administered subcutaneously for 10 days with vehicle or FGF21 (1 mg per 1 kg). Food intake (FI), body weight (BW), blood parameters, and gene expression in the liver, muscles, brown adipose tissue, subcutaneous and visceral white adipose tissues, and hypothalamus were measured. FGF21 action strongly depended on the sex of the animals. In the males, FGF21 decreased BW and insulin blood levels without affecting FI. In the females, FGF21 increased FI and liver weight, but did not affect BW. In control Ay-mice, expression of genes involved in lipid and glucose metabolism (Ppargc1a, Cpt1, Pck1, G6p, Slc2a2) in the liver and genes involved in lipogenesis (Pparg, Lpl, Slc2a4) in visceral adipose tissue was higher in females than in males, and FGF21 administration inhibited the expression of these genes in females. FGF21 administration decreased hypothalamic POMC mRNA only in males. Thus, the pharmacological effect of FGF21 were significantly different in male and female Ay-mice; unlike males, females were resistant to catabolic effects of FGF21.

RevDate: 2021-02-16
CmpDate: 2021-02-16

Gusev EI, Blokhin VE, Vartanov SA, et al (2021)

[Development of early diagnosis of Parkinson's disease and comprehensive economic analysis of the effect of its implementation].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 121(1):9-20.

The paper summarizes the literature and author's data on the development of early (preclinical) diagnosis of Parkinson's disease (PD). Implementation of this diagnosis will promote the use of preventive therapy and change investments in diagnosis and treatment of patients. The paper declares that at present the only approach to early diagnosis of PD is positron-emission tomography of the nigrostriatal dopaminergic system, but it cannot be used for preventive examination due to its high cost. The authors consider that a less specific, but more promising approach to the development of early diagnosis of PD is the search for markers in body fluids, mainly in the blood, in patients at the prodromal stage of PD. Indeed, a number of markers as changes in the level of metabolites of monoamines, sphingolipids, urates, and indicators of oxidative stress were found in patients selected for the risk group of the prodromal stage of PD, according to characteristic premotor symptoms. In addition, it is assumed that the search for blood markers at an earlier - pre-prodromal stage is possible only in animal models of PD at the early preclinical stage. This approach can also be used to verify blood markers identified in patients at the clinical stage of PD. It is also evident that the complex socio-economic factors influencing the incidence of PD is different in developed versus developing countries. The societal and medical costs of Parkinson's are huge and efforts to improve early preclinical diagnosis of PD will lead to considerable economical and societal benefits. For instance this will allow efficient selection of patients for preclinical diagnostic tests. To assess the effectiveness of this strategy considering the uncertainty of socio-economic issues, a modification of the «cost-utility» analysis is proposed. For the first time, a Markov model of PD including preclinical diagnostic tests and possible neuroprotective therapy was developed and studied. Analytical outcomes of this process suggest that the idea of developing a new multimodal strategy is promising from a socio-economic point of view.

RevDate: 2021-05-21
CmpDate: 2021-02-26

Trujillo CA, Rice ES, Schaefer NK, et al (2021)

Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment.

Science (New York, N.Y.), 371(6530):.

The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (NOVA1) plays a key role in neural development and function. NOVA1 also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance of an amino acid change in humans, we reintroduced the archaic allele into human induced pluripotent cells using genome editing and then followed their neural development through cortical organoids. This modification promoted slower development and higher surface complexity in cortical organoids with the archaic version of NOVA1 Moreover, levels of synaptic markers and synaptic protein coassociations correlated with altered electrophysiological properties in organoids expressing the archaic variant. Our results suggest that the human-specific substitution in NOVA1, which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species' evolution.

RevDate: 2021-07-27

Reinscheid RK, Mafessoni F, Lüttjohann A, et al (2021)

Neandertal introgression and accumulation of hypomorphic mutations in the neuropeptide S (NPS) system promote attenuated functionality.

Peptides, 138:170506.

The neuropeptide S (NPS) system plays an important role in fear and fear memory processing but has also been associated with allergic and inflammatory diseases. Genes for NPS and its receptor NPSR1 are found in all tetrapods. Compared to non-human primates, several non-synonymous single-nucleotide polymorphisms (SNPs) occur in both human genes that collectively result in functional attenuation, suggesting adaptive mechanisms in a human context. To investigate historic and geographic origins of these hypomorphic mutations and explore genetic signs of selection, we analyzed ancient genomes and worldwide genotype frequencies of four prototypic SNPs in the NPS system. Neandertal and Denisovan genomes contain exclusively ancestral alleles for NPSR1 while all derived alleles occur in ancient genomes of anatomically modern humans, indicating that they arose in modern Homo sapiens. Worldwide genotype frequencies for three hypomorphic NPSR1 SNPs show significant regional homogeneity but follow a gradient towards increasing derived allele frequencies that supports an out-of-Africa scenario. Increased density of high-frequency polymorphisms around the three NPSR1 loci suggests weak or possibly balancing selection. A hypomorphic mutation in the NPS precursor, however, was detected at high frequency in Eurasian Neandertal genomes and shows genetic signatures indicating that it was introgressed into the human gene pool, particularly in Southern Europe, by interbreeding with Neandertals. We discuss potential evolutionary scenarios including behavior and immune-based natural selection.

RevDate: 2021-04-13

Bonfante B, Faux P, Navarro N, et al (2021)

A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation.

Science advances, 7(6):.

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.

RevDate: 2021-01-20
CmpDate: 2021-01-20

Kondratieva EA, Kondratev SA, Denisova AA, et al (2020)

[Results of treatment with intravenous amantadine sulfate (PK-Merz) patients with chronic disorders of consciousness].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 120(12):102-108.

The article presents literature review of the recent publications devoted to the drugs with dopaminergic, antiglutamatergic and GABA-ergic effects in the treatment of patients with vegetative state/areactive wakefulness syndrome (VS/AWS). The authors analyzed their own results of the effects of intravenous form of amantadine sulfate (PK Merz) in 142 VS/AWS patients caused by different etiological factors. Depending on the dominant neurological symptoms, patients were divided into three main groups: areactive type of course (group 1 - 61 patients), predominance of primitive limbic reactions (group 2 - 35 patients) and predominance of extrapyramidal symptoms (group 3 - 46 patients). Therapy results were evaluated one month later by CRS-R scale, which showed that the most distinct positive dynamics was observed in group 3.

RevDate: 2021-05-28
CmpDate: 2021-05-28

Greer C, Bhakta H, Ghanem L, et al (2021)

Deleterious variants in genes regulating mammalian reproduction in Neanderthals, Denisovans and extant humans.

Human reproduction (Oxford, England), 36(3):734-755.

STUDY QUESTION: Were Neanderthals and Denisovans (referred here also as extinct hominidae) carrying deleterious variants in genes regulating reproduction?

SUMMARY ANSWER: The majority of extinct hominidae analyzed here, presented a considerable number of deleterious variants per individual in proteins regulating different aspects of reproduction, including gonad and uterine function, and gametogenesis.

WHAT IS KNOWN ALREADY: Neanderthals, Denisovans and extant humans were interfertile and hybridized while occupying geographically overlapping areas in Europe and Asia. This is evidenced by the small archaic genome component (average ∼2%) present in non-African extant humans.

STUDY DESIGN, SIZE, DURATION: The genome of eight extinct hominidae, together with five human genome databases, plus 44 mothers and 48 fathers (fertile controls), were screened to look for deleterious variants in 1734 protein-coding genes regulating reproduction.

Ancient DNA from six Neanderthals and two Denisovans dated between ∼82 000 and 43 000 calibrated years was retrieved from the public European Nucleotide Archive. The hominins analyzed include Altai, Vindija 33.15, 33.19, 33.25 and 33.26, El Sidron 1253, Denisova 3 and 11. Their DNA was analyzed using the CLC Genomics Workbench 12, by mapping overlapping paired-end reads (Illumina, FASTQ files) to the human genome assembly GRCh37 (hg19) (Vindija 33.19, 33.25, 33.26, Denisova 3 and Denisova 11) or by analyzing BAM files (Altai, El Sidron 1253 and Vindija 33.15) (human genome reference, GRCh37 (hg19)). Non-synonymous reproductive variants were classified as deleterious or tolerated (PolyPhen-2 and SIFT analyses) and were compared to deleterious variants obtained from extant human genome databases (Genome Aggregation Database (GnomAD), 1000 Genomes, the Haplotype Map (HapMap), Single Nucleotide Polymorphism Database (dbSNPs)) across different populations. A genetic intersection between extant or extinct DNA variants and other genetic disorders was evaluated by annotating the obtained variants with the Clinical Variant (ClinVar) database.

Among the eight extinct hominidae analyzed, a total of 9650 non-synonymous variants (only coverage ≥20 reads included; frameshift mutations were excluded) in 1734 reproductive protein-coding genes were found, 24% of which were classified as deleterious. The majority (73%) of the deleterious alleles present in extant humans that are shared between extant humans and extinct hominidae were found to be rare (<1%) in extant human populations. A set of 8044 variants were found uniquely in extinct hominidae. At the single-gene level, no extinct individual was found to be homozygous for deleterious variants in genes necessary for gamete recognition and fusion, and no higher chance of embryo-lethality (calculated by Mendelian Genetics) was found upon simulated mating between extant human and extinct hominidae compared to extant human-extant human. However, three of the eight extinct hominidae were found to be homozygous for 48-69 deleterious variants in 55 genes controlling ovarian and uterine functions, or oogenesis (AKAP1, BUB1B, CCDC141, CDC73, DUSP6, ESR1, ESR2, PATL2, PSMC3IP, SEMA3A, WT1 and WNT4). Moreover, we report the distribution of nine Neanderthal variants in genes associated with a human fertility phenotype found in extant human populations, one of which has been associated with polycystic ovarian syndrome and primary congenital glaucoma.

While analyzing archaic DNA, stringent filtering criteria were adopted to screen for deleterious variants in Neanderthals and Denisovans, which could result in missing a number of variants. Such restraints preserve the potential for detection of additional deleterious variants in reproductive proteins in extinct hominidae.

This study provides a comprehensive overview of putatively deleterious variants in extant human populations and extinct individuals occurring in 1734 protein-coding genes controlling reproduction and provides the fundaments for future functional studies of extinct variants in human reproduction.

This study was supported by the Department of Biological Science and by the Office of Research and Sponsored Programs at the University of Tulsa (Faculty Research Grant and Faculty Research Summer Fellowship) to M.A. and the University of Tulsa, Tulsa Undergraduate Research Challenge (TURC) program to E.L.; no conflict of interest to declare.

TRIAL REGISTRATION NUMBER: N/A.

RevDate: 2021-01-11

Alexeeva E, Horneff G, Dvoryakovskaya T, et al (2021)

Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial.

Pediatric rheumatology online journal, 19(1):5.

BACKGROUND: Remission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease.

METHODS: A multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit.

RESULTS: By intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/-IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14-32) and 32 (24-40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients.

CONCLUSIONS: Early combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.

RevDate: 2021-03-12

Bentzon AK, Panteleev A, Mitsura V, et al (2021)

Healthcare delivery for HIV-positive people with tuberculosis in Europe.

HIV medicine, 22(4):283-293.

BACKGROUND: In a 2013 survey, we reported distinct discrepancies in delivery of tuberculosis (TB) and HIV services in eastern Europe (EE) vs. western Europe (WE).

OBJECTIVES: To verify the differences in TB and HIV services in EE vs. WE.

METHODS: Twenty-three sites completed a survey in 2018 (EE, 14; WE, nine; 88% response rate). Results were compared across as well as within the two regions. When possible, results were compared with the 2013 survey.

RESULTS: Delivery of healthcare was significantly less integrated in EE: provision of TB and HIV services at one site (36% in EE vs. 89% in WE; P = 0.034), and continued TB follow-up in one location (42% vs. 100%; P = 0.007). Although access to TB diagnostics, standard TB and HIV drugs was generally good, fewer sites in EE reported unlimited access to rifabutin/multi-drug-resistant TB (MDR-TB) drugs, HIV integrase inhibitors and opioid substitution therapy (OST). Compared with 2013, routine usage of GeneXpert was more common in EE in 2018 (54% vs. 92%; P = 0.073), as was access to moxifloxacin (46% vs. 91%; P = 0.033), linezolid (31% vs. 64%; P = 0.217), and bedaquiline (0% vs. 25%; P = 0.217). Integration of TB and HIV services (46% vs. 39%; P = 1.000) and provision of OST to patients with opioid dependency (54% vs. 46%; P = 0.695) remained unchanged.

CONCLUSION: Delivery of TB and HIV healthcare, including integration of TB and HIV care and access to MDR-TB drugs, still differs between WE and EE, as well as between individual EE sites.

RevDate: 2021-02-10
CmpDate: 2021-02-10

Cook S, Kudryavtsev AV, Bobrova N, et al (2020)

Prevalence of symptoms, ever having received a diagnosis and treatment of depression and anxiety, and associations with health service use amongst the general population in two Russian cities.

BMC psychiatry, 20(1):537.

BACKGROUND: Little is known about the burden of common mental disorders in Russia despite high levels of suicide and alcohol-related mortality. Here we investigated levels of symptoms, self-reports of ever having received a diagnosis and treatment of anxiety and depression in two Russian cities.

METHODS: The study population was men and women aged 35-69 years old participating in cross-sectional population-based studies in the cities of Arkhangelsk and Novosibirsk (2015-18). Participants completed an interview which included the PHQ-9 and GAD-7 scales, questions on whether participants had ever received a diagnosis of depression or anxiety, and health service use in the past year. Participants also reported current medication use and medications were coded in line with the WHO anatomical therapeutic classification (ATC). Depression was defined as PHQ-9 ≥ 10 and Anxiety as GAD-7 ≥ 10.

RESULTS: Age-standardised prevalence of PHQ-9 ≥ 10 was 10.7% in women and 5.4% in men (GAD-7 ≥ 10 6.2% in women; 3.0% in men). Among those with PHQ-9 ≥ 10 17% reported ever having been diagnosed with depression (equivalent finding for anxiety 29%). Only 1.5% of those with PHQ-9 ≥ 10 reported using anti-depressants and 0.6% of those with GAD-7 ≥ 10 reported using anxiolytics. No men with PHQ-9 ≥ 10 and/or GAD-7 ≥ 10 reported use of anti-depressants or anxiolytics. Use of health services increased with increasing severity of both depression and anxiety.

CONCLUSION: There was a large gap between symptoms and reporting of past diagnosis and treatment of common mental disorders in two Russian cities. Interventions aimed at improving mental health literacy and reducing stigma could be of benefit in closing this substantial treatment gap.

RevDate: 2021-01-10

Aston S, Denisova K, Hurlbert A, et al (2020)

Exploring the Determinants of Color Perception Using #Thedress and Its Variants: The Role of Spatio-Chromatic Context, Chromatic Illumination, and Material-Light Interaction.

Perception, 49(11):1235-1251.

The colors that people see depend not only on the surface properties of objects but also on how these properties interact with light as well as on how light reflected from objects interacts with an individual's visual system. Because individual visual systems vary, the same visual stimulus may elicit different perceptions from different individuals. #thedress phenomenon drove home this point: different individuals viewed the same image and reported it to be widely different colors: blue and black versus white and gold. This phenomenon inspired a collection of demonstrations presented at the Vision Sciences Society 2015 Meeting which showed how spatial and temporal manipulations of light spectra affect people's perceptions of material colors and illustrated the variability in individual color perception. The demonstrations also explored the effects of temporal alterations in metameric lights, including Maxwell's Spot, an entoptic phenomenon. Crucially, the demonstrations established that #thedress phenomenon occurs not only for images of the dress but also for the real dress under real light sources of different spectral composition and spatial configurations.

RevDate: 2021-01-08
CmpDate: 2021-01-08

Vorobieva NV, Makunin AI, Druzhkova AS, et al (2020)

High genetic diversity of ancient horses from the Ukok Plateau.

PloS one, 15(11):e0241997.

A growing number of researchers studying horse domestication come to a conclusion that this process happened in multiple locations and involved multiple wild maternal lines. The most promising approach to address this problem involves mitochondrial haplotype comparison of wild and domestic horses from various locations coupled with studies of possible migration routes of the ancient shepherds. Here, we sequenced complete mitochondrial genomes of six horses from burials of the Ukok plateau (Russia, Altai Mountains) dated from 2.7 to 1.4 thousand years before present and a single late Pleistocene wild horse from the neighboring region (Denisova cave). Sequencing data indicates that the wild horse belongs to an extinct pre-domestication lineage. Integration of the domestic horse data with known Eurasian haplotypes of a similar age revealed two distinct groups: the first one widely distributed in Europe and presumably imported to Altai, and the second one specific for Altai Mountains and surrounding area.

RevDate: 2021-09-18
CmpDate: 2021-07-13

Nesterenko MA, Starunov VV, Shchenkov SV, et al (2020)

Molecular signatures of the rediae, cercariae and adult stages in the complex life cycles of parasitic flatworms (Digenea: Psilostomatidae).

Parasites & vectors, 13(1):559.

BACKGROUND: Parasitic flatworms (Trematoda: Digenea) represent one of the most remarkable examples of drastic morphological diversity among the stages within a life cycle. Which genes are responsible for extreme differences in anatomy, physiology, behavior, and ecology among the stages? Here we report a comparative transcriptomic analysis of parthenogenetic and amphimictic generations in two evolutionary informative species of Digenea belonging to the family Psilostomatidae.

METHODS: In this study the transcriptomes of rediae, cercariae and adult worm stages of Psilotrema simillimum and Sphaeridiotrema pseudoglobulus, were sequenced and analyzed. High-quality transcriptomes were generated, and the reference sets of protein-coding genes were used for differential expression analysis in order to identify stage-specific genes. Comparative analysis of gene sets, their expression dynamics and Gene Ontology enrichment analysis were performed for three life stages within each species and between the two species.

RESULTS: Reference transcriptomes for P. simillimum and S. pseudoglobulus include 21,433 and 46,424 sequences, respectively. Among 14,051 orthologous groups (OGs), 1354 are common and specific for two analyzed psilostomatid species, whereas 13 and 43 OGs were unique for P. simillimum and S. pseudoglobulus, respectively. In contrast to P. simillimum, where more than 60% of analyzed genes were active in the redia, cercaria and adult worm stages, in S. pseudoglobulus less than 40% of genes had such a ubiquitous expression pattern. In general, 7805 (36.41%) and 30,622 (65.96%) of genes were preferentially expressed in one of the analyzed stages of P. simillimum and S. pseudoglobulus, respectively. In both species 12 clusters of co-expressed genes were identified, and more than a half of the genes belonging to the reference sets were included into these clusters. Functional specialization of the life cycle stages was clearly supported by Gene Ontology enrichment analysis.

CONCLUSIONS: During the life cycles of the two species studied, most of the genes change their expression levels considerably, consequently the molecular signature of a stage is not only a unique set of expressed genes, but also the specific levels of their expression. Our results indicate unexpectedly high level of plasticity in gene regulation between closely related species. Transcriptomes of P. simillimum and S. pseudoglobulus provide high quality reference resource for future evolutionary studies and comparative analyses.

RevDate: 2020-11-06

Mahesh S, Denisova T, Gerasimova L, et al (2020)

Multimorbidity After Surgical Menopause Treated with Individualized Classical Homeopathy: A Case Report.

Clinical medicine insights. Case reports, 13:1179547620965560.

Classical homeopathy was shown to be beneficial in climacteric syndrome in many studies, but the clinical effect is unclear. To inspect if individualized classical homeopathy has a role in treating complaints after surgical menopause through real world case, we present a case of a 54-year-old Russian woman treated with individualized classical homeopathy for multimorbid conditions after surgical menopause examined for changes from homeopathic treatment. We assessed changes in climacteric symptoms, changes in comorbidities, and the general well-being of the patient. The woman had severe climacteric syndrome, pelvic inflammatory disease, dyslipidemia, obesity, hepatic steatosis, pancreatic lipomatosis, gall bladder disease, and mild subclinical hypothyroidism to begin with. She was treated with individualized classical homeopathy and followed up for 31 months. She was relieved of the vasomotor symptoms and psychological disturbances of climacteric syndrome, her weight reduced, the ultrasound scan showed absence of lipomatosis/gall bladder disease/hepatic steatosis. Blood tests showed reduction of thyroid stimulating hormone and a balance in the lipid status. Individualized classical homeopathy may have a role in the climacteric syndrome and comorbidities after surgical menopause. The efficacy of homeopathic therapy in climacteric problems must be scientifically investigated further.

RevDate: 2020-11-03

Chernyshev VM, Denisova EA, Eremin DB, et al (2020)

The key role of R-NHC coupling (R = C, H, heteroatom) and M-NHC bond cleavage in the evolution of M/NHC complexes and formation of catalytically active species.

Chemical science, 11(27):6957-6977.

Complexes of metals with N-heterocyclic carbene ligands (M/NHC) are typically considered the systems of choice in homogeneous catalysis due to their stable metal-ligand framework. However, it becomes obvious that even metal species with a strong M-NHC bond can undergo evolution in catalytic systems, and processes of M-NHC bond cleavage are common for different metals and NHC ligands. This review is focused on the main types of the M-NHC bond cleavage reactions and their impact on activity and stability of M/NHC catalytic systems. For the first time, we consider these processes in terms of NHC-connected and NHC-disconnected active species derived from M/NHC precatalysts and classify them as fundamentally different types of catalysts. Problems of rational catalyst design and sustainability issues are discussed in the context of the two different types of M/NHC catalysis mechanisms.

RevDate: 2020-12-21
CmpDate: 2020-12-21

Zhang D, Xia H, Chen F, et al (2020)

Denisovan DNA in Late Pleistocene sediments from Baishiya Karst Cave on the Tibetan Plateau.

Science (New York, N.Y.), 370(6516):584-587.

A late Middle Pleistocene mandible from Baishiya Karst Cave (BKC) on the Tibetan Plateau has been inferred to be from a Denisovan, an Asian hominin related to Neanderthals, on the basis of an amino acid substitution in its collagen. Here we describe the stratigraphy, chronology, and mitochondrial DNA extracted from the sediments in BKC. We recover Denisovan mitochondrial DNA from sediments deposited ~100 thousand and ~60 thousand years ago (ka) and possibly as recently as ~45 ka. The long-term occupation of BKC by Denisovans suggests that they may have adapted to life at high altitudes and may have contributed such adaptations to modern humans on the Tibetan Plateau.

RevDate: 2021-09-24
CmpDate: 2020-12-21

Massilani D, Skov L, Hajdinjak M, et al (2020)

Denisovan ancestry and population history of early East Asians.

Science (New York, N.Y.), 370(6516):579-583.

We present analyses of the genome of a ~34,000-year-old hominin skull cap discovered in the Salkhit Valley in northeastern Mongolia. We show that this individual was a female member of a modern human population that, following the split between East and West Eurasians, experienced substantial gene flow from West Eurasians. Both she and a 40,000-year-old individual from Tianyuan outside Beijing carried genomic segments of Denisovan ancestry. These segments derive from the same Denisovan admixture event(s) that contributed to present-day mainland Asians but are distinct from the Denisovan DNA segments in present-day Papuans and Aboriginal Australians.

RevDate: 2020-12-21
CmpDate: 2020-12-21

Gibbons A (2020)

Denisovan DNA found in cave on Tibetan Plateau.

Science (New York, N.Y.), 370(6516):512-513.

RevDate: 2020-10-20

Pan L, Dumoncel J, Mazurier A, et al (2020)

Hominin diversity in East Asia during the Middle Pleistocene: A premolar endostructural perspective.

Journal of human evolution, 148:102888 pii:S0047-2484(20)30149-4 [Epub ahead of print].

Following the recent studies of East Asian mid-Middle to early Late Pleistocene hominin material, a large spectrum of morphological diversity has been recognized and the coexistence of archaic ('Homo erectus-like') and derived ('modern-like') dental morphological patterns has been highlighted. In fact, for most of these Chinese fossils, generally categorized as 'archaic Homo sapiens' or 'post-H. erectus Homo', the taxonomic attribution is a matter of contention. With the help of μCT techniques and a deformation-based 3D geometric morphometric approach, we focused on the morphological variation in the enamel-dentine junction (EDJ) of 18 upper and lower premolars from Chinese Middle Pleistocene hominins. We then compared our results with a number of fossil and modern human groups, including Early Pleistocene H. erectus from Sangiran; late Early Pleistocene hominins from Tighenif, Algeria; classic Neanderthals; and modern humans. Our results highlight an evolutionary/chronological trend of crown base reduction, elevation of EDJ topography, and EDJ surface simplification in the hominin groups studied here. Moreover, this study brings insights to the taxonomy/phylogeny of 6 late Middle Pleistocene specimens whose evolutionary placement has been debated for decades. Among these specimens, Changyang premolars show features that can be aligned with the Asian H. erectus hypodigm, whereas Panxian Dadong and Tongzi premolars are more similar to Late Pleistocene Homo. Compared with early to mid-Middle Pleistocene hominins in East Asia, late Middle Pleistocene hominins evince an enlarged morphological variation. A persistence of archaic morphotypes and possible admixture among populations during the late Middle Pleistocene are discussed.

RevDate: 2020-12-14
CmpDate: 2020-12-04

Petr M, Hajdinjak M, Fu Q, et al (2020)

The evolutionary history of Neanderthal and Denisovan Y chromosomes.

Science (New York, N.Y.), 369(6511):1653-1656.

Ancient DNA has provided new insights into many aspects of human history. However, we lack comprehensive studies of the Y chromosomes of Denisovans and Neanderthals because the majority of specimens that have been sequenced to sufficient coverage are female. Sequencing Y chromosomes from two Denisovans and three Neanderthals shows that the Y chromosomes of Denisovans split around 700 thousand years ago from a lineage shared by Neanderthals and modern human Y chromosomes, which diverged from each other around 370 thousand years ago. The phylogenetic relationships of archaic and modern human Y chromosomes differ from the population relationships inferred from the autosomal genomes and mirror mitochondrial DNA phylogenies, indicating replacement of both the mitochondrial and Y chromosomal gene pools in late Neanderthals. This replacement is plausible if the low effective population size of Neanderthals resulted in an increased genetic load in Neanderthals relative to modern humans.

RevDate: 2020-09-28

Merisaari J, Denisova OV, Doroszko M, et al (2020)

Monotherapy efficacy of blood-brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma.

Brain communications, 2(1):fcaa002.

Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood-brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood-brain barrier-permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies.

RevDate: 2020-12-07

Eremin DB, Boiko DA, Kostyukovich AY, et al (2020)

Mechanistic Study of Pd/NHC-Catalyzed Sonogashira Reaction: Discovery of NHC-Ethynyl Coupling Process.

Chemistry (Weinheim an der Bergstrasse, Germany), 26(67):15672-15681.

The product of a revealed transformation-NHC-ethynyl coupling-was observed as a catalyst transformation pathway in the Sonogashira cross-coupling, catalyzed by Pd/NHC complexes. The 2-ethynylated azolium salt was isolated in individual form and fully characterized, including X-ray analysis. A number of possible intermediates of this transformation with common formulae (NHC)n Pd(C2 Ph) (n=1,2) were observed and subjected to collision-induced dissociation (CID) and infrared multiphoton dissociation (IRMPD) experiments to elucidate their structure. Measured bond dissociation energies (BDEs) and IRMPD spectra were in an excellent agreement with quantum calculations for coupling product π-complexes with Pd0 . Molecular dynamics simulations confirmed the observed multiple CID fragmentation pathways. An unconventional methodology to study catalyst evolution suggests the reported transformation to be considered in the development of new catalytic systems for alkyne functionalization reactions.

RevDate: 2021-07-20
CmpDate: 2020-12-17

Telis N, Aguilar R, K Harris (2020)

Selection against archaic hominin genetic variation in regulatory regions.

Nature ecology & evolution, 4(11):1558-1566.

Traces of Neandertal and Denisovan DNA persist in the modern human gene pool, but have been systematically purged by natural selection from genes and other functionally important regions. This implies that many archaic alleles harmed the fitness of hybrid individuals, but the nature of this harm is poorly understood. Here, we show that enhancers contain less Neandertal and Denisovan variation than expected given the background selection they experience, suggesting that selection acted to purge these regions of archaic alleles that disrupted their gene regulatory functions. We infer that selection acted mainly on young archaic variation that arose in Neandertals or Denisovans shortly before their contact with humans; enhancers are not depleted of older variants found in both archaic species. Some types of enhancer appear to have tolerated introgression better than others; compared with tissue-specific enhancers, pleiotropic enhancers show stronger depletion of archaic single-nucleotide polymorphisms. To some extent, evolutionary constraint is predictive of introgression depletion, but certain tissues' enhancers are more depleted of Neandertal and Denisovan alleles than expected given their comparative tolerance to new mutations. Foetal brain and muscle are the tissues whose enhancers show the strongest depletion of archaic alleles, but only brain enhancers show evidence of unusually stringent purifying selection. We conclude that epistatic incompatibilities between human and archaic alleles are needed to explain the degree of archaic variant depletion from foetal muscle enhancers, perhaps due to divergent selection for higher muscle mass in archaic hominins compared with humans.

RevDate: 2021-03-05
CmpDate: 2021-03-01

Quartier P, Alexeeva E, Constantin T, et al (2021)

Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open-Label, Randomized Study.

Arthritis & rheumatology (Hoboken, N.J.), 73(2):336-346.

OBJECTIVE: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA).

METHODS: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study.

RESULTS: In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified.

CONCLUSION: Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consistent interleukin-1 inhibition appears necessary to maintain this response.

RevDate: 2020-09-23
CmpDate: 2020-09-23

Hubisz MJ, Williams AL, A Siepel (2020)

Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph.

PLoS genetics, 16(8):e1008895.

The sequencing of Neanderthal and Denisovan genomes has yielded many new insights about interbreeding events between extinct hominins and the ancestors of modern humans. While much attention has been paid to the relatively recent gene flow from Neanderthals and Denisovans into modern humans, other instances of introgression leave more subtle genomic evidence and have received less attention. Here, we present a major extension of the ARGweaver algorithm, called ARGweaver-D, which can infer local genetic relationships under a user-defined demographic model that includes population splits and migration events. This Bayesian algorithm probabilistically samples ancestral recombination graphs (ARGs) that specify not only tree topologies and branch lengths along the genome, but also indicate migrant lineages. The sampled ARGs can therefore be parsed to produce probabilities of introgression along the genome. We show that this method is well powered to detect the archaic migration into modern humans, even with only a few samples. We then show that the method can also detect introgressed regions stemming from older migration events, or from unsampled populations. We apply it to human, Neanderthal, and Denisovan genomes, looking for signatures of older proposed migration events, including ancient humans into Neanderthal, and unknown archaic hominins into Denisovans. We identify 3% of the Neanderthal genome that is putatively introgressed from ancient humans, and estimate that the gene flow occurred between 200-300kya. We find no convincing evidence that negative selection acted against these regions. Finally, we predict that 1% of the Denisovan genome was introgressed from an unsequenced, but highly diverged, archaic hominin ancestor. About 15% of these "super-archaic" regions-comprising at least about 4Mb-were, in turn, introgressed into modern humans and continue to exist in the genomes of people alive today.

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In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

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In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

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Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

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In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

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Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

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When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

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Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

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With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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One of the most intriguing, and philosophically suggestive, recent scientific findings has been the discovery that the human lineage included several branches at the species level in which each species had developed culture (tool making, mastery of fire, burial of the dead). Before the Chicxulub impact that ended the realm of the dinosaurs, sentience and culture had not occurred in any lineage, despite several hundred million years of evolution. However, in the mammalian radiation that occurred afterwards, several primate lineages occurred. In just the last few million years, one of those lineages diverged into several sentient, culture-developing species. This book explores how only one of those species (ours) survived, while the others went extinct. Recommended. R. Robbins

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

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Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

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Selected Bibliographies

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