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The availability of public genomic resources can greatly assist biodiversity assessment, conservation, and restoration efforts by providing evidence for scientifically informed management decisions. Here we survey the main approaches and applications in biodiversity and conservation genomics, considering practical factors, such as cost, time, prerequisite skills, and current shortcomings of applications. Most approaches perform best in combination with reference genomes from the target species or closely related species. We review case studies to illustrate how reference genomes can facilitate biodiversity research and conservation across the tree of life. We conclude that the time is ripe to view reference genomes as fundamental resources and to integrate their use as a best practice in conservation genomics., Trends in Genetics, 39 (7), ISSN:0168-9525

Background: Experimental and epidemiological studies indicate an association between exposure to particulate matter (PM) air pollution and increased risk of type 2 diabetes. In view of the high and increasing prevalence of diabetes, we aimed to quantify the burden of type 2 diabetes attributable to PM2·5 originating from ambient and household air pollution.Methods: We systematically compiled all relevant cohort and case-control studies assessing the effect of exposure to household and ambient fine particulate matter (PM2·5) air pollution on type 2 diabetes incidence and mortality. We derived an exposure–response curve from the extracted relative risk estimates using the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. The estimated curve was linked to ambient and household PM2·5 exposures from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019, and estimates of the attributable burden (population attributable fractions and rates per 100 000 population of deaths and disability-adjusted life-years) for 204 countries from 1990 to 2019 were calculated. We also assessed the role of changes in exposure, population size, age, and type 2 diabetes incidence in the observed trend in PM2·5-attributable type 2 diabetes burden. All estimates are presented with 95% uncertainty intervals.Findings: In 2019, approximately a fifth of the global burden of type 2 diabetes was attributable to PM2·5 exposure, with an estimated 3·78 (95% uncertainty interval 2·68–4·83) deaths per 100 000 population and 167 (117–223) disability-adjusted life-years (DALYs) per 100 000 population. Approximately 13·4% (9·49–17·5) of deaths and 13·6% (9·73–17·9) of DALYs due to type 2 diabetes were contributed by ambient PM2·5, and 6·50% (4·22–9·53) of deaths and 5·92% (3·81–8·64) of DALYs by household air pollution. High burdens, in terms of numbers as well as rates, were estimated in Asia, sub-Saharan Africa, and South America. Since 1990, the attributable burden has increased by 50%, driven largely by population growth and ageing. Globally, the impact of reductions in household air pollution was largely offset by increased ambient PM2·5.Interpretation: Air pollution is a major risk factor for diabetes. We estimated that about a fifth of the global burden of type 2 diabetes is attributable PM2·5 pollution. Air pollution mitigation therefore might have an essential role in reducing the global disease burden resulting from type 2 diabetes.Funding: Bill & Melinda Gates Foundation.

BackgroundCancer somatic mutations are the product of multiple mutational and repair processes, which are tightly associated with DNA replication. Distinctive patterns of somatic mutations accumulation in tumors, termed mutational signatures, are indicative of processes the tumors underwent. While tumor mutational load is correlated with late replicating regions and spatial genome organization, much is unknown about the association of many different mutational processes and replication timing, and the interplay with chromatin structure remains an open question.MethodsWe systematically analyzed the mutational landscape of 2,787 WGS tumors from 32 different tumor types separately for early and late replicating regions. We used sequence context normalization and chromatin data to account for sequence and chromatin accessibility differences between early and late replicating regions. Moreover, we expanded the signature analyses to doublet base substitutions and small insertions and deletions by developing an artificial genomes-based approach to account for sequence differences between various genomic regions.ResultsWe revealed the replication timing (RT) association of single base, doublet base and small insertions and deletions mutational signatures. The association is signature specific: some are associated with early or late replication (such as UV-exposure signatures SBS7b and SBS7a, respectively) and others have no association. Most associations exist even after normalizing for genome accessibility. We further developed a focused mutational signature identification approach, which uses RT information to improve signature identification, and found that SBS16, which is biased towards early replication, is strongly associated with better survival rates in liver cancer.ConclusionsOur comprehensive analyses enabled a more robust classification of RT association of single base, doublet base and indels signatures. By doing so, we demonstrated a variation in the association with RT, as many mutational processes biased towards either early or late replication timing, and others have an equal RT distribution. These associations were independent from chromatin accessibility in most cases. This work highlights that restricting signatures analyses to concise genomic regions improves identification of signatures, such as SBS16, and demonstrates its clinically relevance as a predictor of improved survival of liver cancer patients.

Progress in genome sequencing now enables the large-scale generation of reference genomes. Various international initiatives aim to generate reference genomes representing global biodiversity. These genomes provide unique insights into genomic diversity and architecture, thereby enabling comprehensive analyses of population and functional genomics, and are expected to revolutionize conservation genomics., Trends in Ecology & Evolution, 37 (3), ISSN:0169-5347, ISSN:1872-8383

The growing human population is currently facing an unprecedented challenge on global food production and sustainability. Despite recognizing poultry as one of the most successful and rapidly growing food industries to address this challenge; poultry health and safety remain major issues that entail immediate attention. Bacterial diseases including colibacillosis, salmonellosis, and necrotic enteritis have become increasingly prevalent during poultry production. Likewise, outbreaks caused by consumption of undercooked poultry products contaminated with zoonotic bacterial pathogens such as Salmonella, Campylobacter and Listeria, are a serious public health concern. With antimicrobial resistance problem and restricted use of antibiotics in food producing animals, bacteriophages are increasingly recognized as an attractive natural antibacterial alternative. Bacteriophages have recently shown promising results to treat diseases in poultry, reduce contamination of carcasses, and enhance the safety of poultry products. Omics technologies have been successfully employed to accurately characterize bacteriophages and their genes/proteins important for interaction with bacterial hosts. In this review, the potential of using lytic bacteriophages to mitigate the risk of major poultry-associated bacterial pathogens are explored. This study also explores challenges associated with the adoption of this technology by industries. Furthermore, the impact of omics approaches on studying bacteriophages, their host interaction and applications is discussed.

Vascular dysfunction is entwined with aging and in the pathogenesis of Alzheimer's disease (AD) and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects using two-photon live animal imaging, behavioral tasks, and biochemical and histological analysis. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of Aß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia. Motivated by these findings, we exposed elderly patients with significant memory loss at baseline to HBOT and observed an increase in CBF and improvement in cognitive performances. This study demonstrates HBOT efficacy in hypoxia-related neurological conditions, particularly in AD and aging.

Body size evolution on islands is widely studied and hotly debated. Gigantism and dwarfism are thought to evolve under strong natural selection, especially on small remote islands. We report a curious co-occurrence of both dwarf and giant lizards on the same small, remote island (Plakida): the largest Podarcis erhardii (Lacertidae) and smallest Mediodactylus kotschyi sensu lato; Gekkonidae — the two commonest insular reptiles in the Aegean Sea. The geckos of Plakida have a peculiar tail-waving behavior, documented here for the first time in this genus. We suspect that P. erhardii evolved large size to consume geckos and the geckos evolved a unique tail-waving behavior as a defensive mechanism.

The skink genus Lobulia is endemic to New Guinea, the largest and highest tropical island in the world. Lobulia and its related genera represent an important component of the montane herpetofauna of New Guinea, but it remains understudied and poorly known. We here provide the first, large-scale, systematic revision of Lobulia, using molecular phylogenetic and morphological comparisons to assess the monophyly of the genus and the diversity of species within it. We find that Lobulia, as currently defined, is polyphyletic. The eight species currently assigned to it form three clades. Furthermore, many specimens from New Guinea of unknown specific affinity are genetically and morphologically distinct from each other. Based on these data, we re-diagnose Lobulia and two of its closely related genera, Prasinohaema and Papuascincus. We erect four new genera (Alpinoscincus gen. nov., Nubeoscincus gen. nov., Ornithuroscincus gen. nov. and Palaia gen. nov.) to address the problem of polyphyly and describe nine new species Lobulia fortis sp. nov., Lobulia huonensis sp. nov., Loublia marmorata sp. nov., Lobulia vogelkopensis sp. nov., Ornithuroscincus bengaun sp. nov., Ornithuroscincus inornatus sp. nov., Ornithuroscincus pterophilus sp. nov., Ornithuroscincus shearmani sp. nov. and Ornithuroscincus viridis sp. nov. We supplement this taxonomic revision by investigating the biogeographic history of Lobulia s.l. and find evidence for a large radiation in the accreted terranes of New Guinea, with multiple independent colonizations of montane habitats and subsequent recolonization of lowland habitats. Our study reinforces the uniqueness and richness of the montane herpetofauna of New Guinea and the importance of mountains to biodiversity in the Tropics., This work was supported by a Binational Science Foundation grant 2012143 to S.M. and A.A., a Naomi Foundation through the Tel Aviv University GRTF programme grant 064181317 to A.S., National Science Foundation grants DEB-0103794 and DEB-0743890 to F.K. and A.A. A.S. is supported by a Royal Society grant RGF\EA\181082.

The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein–coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ–activated eosinophils facilitated CD4+ and CD8+ T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics. Significance: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.

ObjectiveAnti-drug antibodies (ADA) to anti-tumour necrosis factor (anti-TNF) therapy drive treatment loss of response. An association between intestinal microbial composition and response to anti-TNF therapy was noted. We therefore aimed to assess the implications of antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD).DesignWe analysed data from the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all patients with IBD in Israel. We included all patients treated with anti-TNF who had available ADA levels. Survival analysis with drug use as time varying covariates were used to assess the association between antibiotic use and ADA development. Next, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days.ResultsAmong 1946 eligible patients, with a median follow-up of 651 days from initiation of therapy, 363 had positive ADA. Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with β-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35). In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA.ConclusionADA production is associated with the microbial composition. The risk of ADA development during anti-TNF therapy can possibly be reduced by avoidance of cephalosporins and penicillin-BLIs, or by treatment with fluoroquinolones or macrolides.

We make magnitude-related decisions every day, for example, to choose the shortest queue at the grocery store. When making such decisions, which magnitudes do we consider? The dominant theory suggests that our focus is on numerical quantity, i.e., the number of items in a set. This theory leads to quantity-focused research suggesting that discriminating quantities is automatic, innate, and is the basis for mathematical abilities in humans. Another theory suggests, instead, that non-numerical magnitudes, such as the total area of the compared items, are usually what humans rely on, and numerical quantity is used only when required. Since wild animals must make quick magnitude-related decisions to eat, seek shelter, survive, and procreate, studying which magnitudes animals spontaneously use in magnitude-related decisions is a good way to study the relative primacy of numerical quantity versus non-numerical magnitudes. We asked whether, in an animal model, the influence of non-numerical magnitudes on performance in a spontaneous magnitude comparison task is modulated by the number of non-numerical magnitudes that positively correlate with numerical quantity. Our animal model was the Archerfish, a fish that, in the wild, hunts insects by shooting a jet of water at them. These fish were trained to shoot water at artificial targets presented on a computer screen above the water tank. We tested the Archerfish's performance in spontaneous, untrained two-choice magnitude decisions. We found that the fish tended to select the group containing larger non-numerical magnitudes and smaller quantities of dots. The fish selected the group containing more dots mostly when the quantity of the dots was positively correlated with all five different non-numerical magnitudes. The current study adds to the body of studies providing direct evidence that in some cases animals’ magnitude-related decisions are more affected by non-numerical magnitudes than by numerical quantity, putting doubt on the claims that numerical quantity perception is the most basic building block of mathematical abilities.

Rensch's rule relates to a pattern whereby sexual size dimorphism (SSD) is more female-biased in small-sized species and more male-biased in large-sized ones. We collected literature and museum data on the body size of males and females belonging to 4,032 lizard species, as well as data on their reproductive modes and clutch sizes. We used phylogenetic comparative analyses, and general linear mixed models, to test Rensch's rule and examined how reproductive mode and clutch size affect sexual size dimorphism. Sexual size dimorphism was independent of clutch size in lizard species with variable clutch sizes and in oviparous lizards. Large litters were associated with female-biased sexual dimorphism in viviparous and in scincomorph lizards. Inference regarding Rensch's rule depended on the analytical method used to identify it. The widely used, but less conservative, reduced major axis regression usually support Rensch's rule while ordinary least squares regressions mostly show isometric relationships. The rule tended to apply more to oviparous than viviparous lizards. We infer that Rensch's rule is, at best, a weak pattern in lizards. This is especially true in viviparous lineages, where females reproduce infrequently, therefore evolve large sizes to maximise fecundity, resulting in female-biased dimorphism. This article is protected by copyright. All rights reserved.

Late onset neutropenia (LON) after rituximab is a previously described complication. We aimed to assess and characterize LON after obinutuzumab, a novel anti-CD20 antibody, in the real-world setting and compare it to LON after rituximab therapy. We retrospectively analyzed 330 consecutive patients with lymphoproliferative neoplasms (rituximab-treated n = 283; obinutuzumab-treated n = 47). LON occurred in 23% patients with similar incidence in rituximab (n = 66, 23%) or obinutuzumab (n = 10, 21%) groups (p = 0.853). Patients treated for CLL and post-transplantation lymphoproliferative disease (PTLD) were at higher risk to develop LON (multivariate analysis: HR for CLL - 6.62 CI 95% 1.33-32.92; HR for PTLD 15.82 CI 95% 2.04-122.4). Febrile neutropenia was uncommon during LON and occurred in 15 patients (4.5%; rituximab (n = 14) and obinutuzumab (n = 1).These data suggest that LON after obinutuzumab treatment is as common as with rituximab. The similarities in LON after rituximab and obinutuzumab argue for a possible class effect for anti-CD20 monoclonal antibodies.

The coronavirus disease 2019 (COVID-19) pandemic affected people at all ages. Whereas pregnant women seemed to have a worse course of disease than age-matched non-pregnant women, the risk of feto-placental infection is low. Using a cohort of 66 COVID-19-positive women in late pregnancy, we correlated clinical parameters with disease severity, placental histopathology, and the expression of viral entry and Interferon-induced transmembrane (IFITM) antiviral transcripts. All newborns were negative for SARS-CoV-2. None of the demographic parameters or placental histopathological characteristics were associated with disease severity. The fetal-maternal transfer ratio for IgG against the N or S viral proteins was commonly less than one, as recently reported. We found that the expression level of placentalACE2,but notTMPRSS2orFurin,was higher in women with severe COVID-19. Placental expression of IFITM1 and IFITM3, which have been implicated in antiviral response, was higher in participants with severe disease. We also showed that IFITM3 protein expression, which localized to early and late endosomes, was enhanced in severe COVID-19. Our data suggest an association between disease severity and placental SARS-CoV-2 processing and antiviral pathways, implying a role for these proteins in placental response to SARS-CoV-2.

Purpose We previously developed Haploseek, a method for comprehensive preimplantation genetic testing (PGT). However, some key features were missing, and the method has not yet been systematically validated. Methods We extended Haploseek to incorporate DNA from embryo grandparents and to allow testing of variants on chromosome X or in regions where parents share common haplotypes. We then validated Haploseek on 151 embryo biopsies from 27 clinical PGT cases. We sequenced all biopsies to low coverage (0.2×), and performed single-nucleotide polymorphism (SNP) microarray genotyping on the embryos' parents and siblings/grandparents. We used the extended Haploseek to predict chromosome copy-number variants (CNVs) and relevant variant-flanking haplotypes in each embryo. We validated haplotype predictions for each clinical sample against polymerase chain reaction (PCR)-based PGT case results, and CNV predictions against established commercial kits. Results For each of the 151 embryo biopsies, all Haploseek-derived haplotypes and CNVs were concordant with clinical PGT results. The cases included 17 autosomal dominant, 5 autosomal recessive, and 3 X-linked monogenic disorders. In addition, we evaluated 1 Robertsonian and 2 reciprocal translocations, and 17 cases of chromosome copy-number counting were performed. Conclusion Our results demonstrate that Haploseek is clinically accurate and fit for all standard clinical PGT applications.

This work investigates how bovine serum albumin (BSA), a commonly used protein in the fabrication of electrochemical immunosensors, can impact on the sensitivity of detection when integrated with antibody (Ab) pre-encapsulated with (i) insulating polyacrylonitrile (PAN) fibre (i.e., GCE-PAN-Ab-BSA immunosensor) or (ii) conducting PAN-grafted iron (II) phthalocyanine (FePc) (i.e., GCE-PAN@FePc-Ab-BSA immunosensor), using Vibrio cholerae toxin as a case study bioanalyte. Both immunosensors show different charge-transfer kinetics that strongly impact on their immunosensitive detection. From the electrochemical data, GCE-PAN-Ab-BSA is more insulating with the presence of BSA, while the GCE-PAN@FePc-Ab-BSA is more conducting with BSA. The CV of the GCE-PAN-Ab-BSA is dominated by radial diffusion process, while that of the GCE-PAN@FePc-Ab-BSA is planar diffusion process. The behaviour of GCE-PAN@FePc-Ab-BSA has been associated with the facile coordination of BSA and FePc that permits co-operative charge-transport of the redox probe, while that of the GCE-PAN-Ab-BSA is related to the interaction-induced PAN-BSA insulating state that suppresses charge-transport. As a consequence of these different interaction processes, GCE-PAN-Ab-BSA immunosensor provides higher electroanalytical performance for the detection of Vibrio cholerae toxin (with sensitivity of 16.12 Ω/log [VCT, g/mL] and limit of detection (LoD) of 3.20 × 10−13 g/mL compared to those of the GCE-PAN@FePc-Ab-BSA (4.16 Ω/log (VCT, g mL−1) and 2.00 × 10−12 g/mL). The study confirms the need for a thorough understanding of the physico-chemistries of the electrode platforms for the construction of immunosensors. Although this work is on immunosensors for cholera infection, it may well apply to other immunosensors.

During their life, crustaceans undergo several molts, which if theoretically compared to the human body would be equivalent to replacing all bones at a single event. Such a dramatic repetitive event is coupled to unique molecular mechanisms of mineralization so far mostly unknown. Unlike human bone mineralized with calcium phosphate, the crustacean exoskeleton is mineralized mainly by calcium carbonate. Crustacean growth thus necessitates well-timed mobilization of bicarbonate to specific extracellular sites of biomineralization at distinct molt cycle stages. Here, by looking at the crayfish Cherax quadricarinatus at different molting stages, we suggest that the mechanisms of bicarbonate ion transport for mineralization in crustaceans involve the SLC4 family of transporters and that these proteins play a key role in the tight coupling between molt cycle events and mineral deposition. This discovery of putative bicarbonate transporters in a pancrustacean with functional genomic evidence from genes encoding the SLC4 family—mostly known for their role in pH control—is discussed in the context of the evolution of calcium carbonate biomineralization.

Pumpkin leaves (Cucurbita moschata) were subjected to different household cooking methods (boiling, microwaving, steaming, and stir-frying) to evaluate their effect on antinutrients, phenolic compounds, antioxidant properties (ABTS, and DPPH) and in vitro α-glucosidase activity. All cooking methods studied significantly reduced the antinutrients and antioxidant activities, whilst phenolic compounds p-coumaric and ferulic acids significantly increased. The cooking methods reduced the oxalates by more than 50%, tannins by 47% and phytates by 79.22%. Steaming and boiling resulted in highest concentrations of p-coumaric (195.40 mg kg(−1)) and ferulic acids (103.90 mg kg(−1)) compared to other methods. Overall, boiled leaves retained the highest total phenolic compounds, whilst steamed leaves retained the highest antioxidant capacity. Raw pumpkin leaf extracts showed higher in vitro α-glucosidase inhibitory effects than the cooked leaves. Thus, cooking affected the inhibitory effect of in vitro α-glucosidase activity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10068-021-00916-w.

A hallmark of meiosis is chromosomal pairing, which requires telomere tethering and rotation on the nuclear envelope through microtubules, driving chromosome homology searches. Telomere pulling toward the centrosome forms the “zygotene chromosomal bouquet.” Here, we identified the “zygotene cilium” in oocytes. This cilium provides a cable system for the bouquet machinery and extends throughout the germline cyst. Using zebrafish mutants and live manipulations, we demonstrate that the cilium anchors the centrosome to counterbalance telomere pulling. The cilium is essential for bouquet and synaptonemal complex formation, oogenesis, ovarian development, and fertility. Thus, a cilium represents a conserved player in zebrafish and mouse meiosis, which sheds light on reproductive aspects in ciliopathies and suggests that cilia can control chromosomal dynamics.

Fanconi anemia is an inherited genome instability syndrome characterized by interstrand cross-link hypersensitivity, congenital defects, bone marrow failure, and cancer predisposition. Although DNA repair mediated by Fanconi anemia genes has been extensively studied, how inactivation of these genes leads to specific cellular phenotypic consequences associated with Fanconi anemia is not well understood. Here we report that Fanconi anemia stem cells in the C. elegans germline and in murine embryos display marked nonhomologous end joining (NHEJ)–dependent radiation resistance, leading to survival of progeny cells carrying genetic lesions. In contrast, DNA cross-linking does not induce generational genomic instability in Fanconi anemia stem cells, as widely accepted, but rather drives NHEJ-dependent apoptosis in both species. These findings suggest that Fanconi anemia is a stem cell disease reflecting inappropriate NHEJ, which is mutagenic and carcinogenic as a result of DNA misrepair, while marrow failure represents hematopoietic stem cell apoptosis. Significance: This study finds that Fanconi anemia stem cells preferentially activate error-prone NHEJ-dependent DNA repair to survive irradiation, thereby conferring generational genomic instability that is instrumental in carcinogenesis.

The Levant represents one of the most important reptile diversity hotspots and centers of endemism in the Western Palearctic. The region harbored numerous taxa in glacial refugia during the Pleistocene climatic oscillations. Due to the hostile arid conditions in the warmer periods they were not always able to spread or come into contact with populations from more distant regions. One large and conspicuous member of the Levantine herpetofauna is the legless anguid lizardPseudopus apodus. This species is distributed from the Balkans to Central Asia with a portion of its range running along the eastern Mediterranean coast. Mitochondrial and nuclear DNA sequences, microsatellite genotypes, and morphology show that populations in this region differ from the two named subspecies and presumably had a long independent evolutionary history during the Quaternary. Here we describe the Levantine population as a new subspecies and present biogeographic scenarios for its origin and diversification. The new subspecies is genetically highly diverse, and it forms a sister lineage toPseudopusfrom the remaining parts of the range according to mtDNA. It is the largest-bodied of the three subspecies, but occupies the smallest range.

In this study we tested the hypothesis that pharmacological modulation of glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. Using a battery of social behavioral tasks, we found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with a single dose of PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.

The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6447 exome-sequences of healthy, genetically-unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal recessive (AR) genes, and that 0.8-1% of European couples are at-risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins, but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.

Background Surveillance of antimicrobial resistance (AMR) is critical to reducing its wide-reaching impact. Its reliance on sample size invites solutions to longstanding constraints regarding scalability. A robotic platform (RASP) was developed for high-throughput AMR surveillance in accordance with internationally recognized standards (CLSI and ISO 20776-1:2019) and validated through a series of experiments. Methods Experiment A compared RASP’s ability to achieve consistent MICs with that of a human technician across eight replicates for four Escherichia coli isolates. Experiment B assessed RASP’s agreement with human-performed MICs across 91 E. coli isolates with a diverse range of AMR profiles. Additionally, to demonstrate its real-world applicability, the RASP workflow was then applied to five faecal samples where a minimum of 47 E. coli per animal (239 total) were evaluated using an AMR indexing framework. Results For each drug–rater–isolate combination in Experiment A, there was a clear consensus of the MIC and deviation from the consensus remained within one doubling dilution (the exception being gentamicin at two dilutions). Experiment B revealed a concordance correlation coefficient of 0.9670 (95% CI: 0.9670–0.9670) between the robot- and human-performed MICs. RASP’s application to the five faecal samples highlighted the intra-animal diversity of gut commensal E. coli, identifying between five and nine unique isolate AMR phenotypes per sample. Conclusions While adhering to internationally accepted guidelines, RASP was superior in throughput, cost and data resolution when compared with an experienced human technician. Integration of robotics platforms in the microbiology laboratory is a necessary advancement for future One Health AMR endeavours.

Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer’s patients. To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In addition, we traced these differences in human and mouse samples of Alzheimer’s and Parkinson’s diseases, healthy aging and calorie restriction (CR). Our results define four gene expression categories that change with age in a pathological or non-pathological manner, which are either reversed or not by CR. We found that each of these gene expression categories is associated with specific transcription factors, thus serving as potential candidates for their category-specific regulation. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.

Amniote vertebrates share a suite of extra-embryonic membranes that distinguish them from anamniotes. Other than that, however, their reproductive characteristics could not be more different. They differ in basic ectothermic vs endothermic physiology, in that two clades evolved powered flight, and one clade evolved a protective shell. In terms of reproductive strategies, some produce eggs and others give birth to live young, at various degrees of development. Crucially, endotherms provide lengthy parental care, including thermal and food provisioning—whereas ectotherms seldom do. These differences could be expected to manifest themselves in major differences between clades in quantitative reproductive traits. We review the reproductive characteristics, and the distributions of brood sizes, breeding frequencies, offspring sizes and their derivatives (yearly fecundity and biomass production rates) of the four major amniote clades (mammals, birds, turtles and squamates), and several major subclades (birds: Palaeognathae, Galloanserae, Neoaves; mammals: Metatheria and Eutheria). While there are differences between these clades in some of these traits, they generally show similar ranges, distribution shapes and central tendencies across birds, placental mammals and squamates. Marsupials and turtles, however, differ in having smaller offspring, a strategy which subsequently influences other traits.

The effect of cranberry pomace (CP) incorporation on S. enterica serovars inactivation, starter culture population, and physicochemical properties of sausages during the manufacture of dry fermented sausages (DFS) was studied. Sausages containing a five-strain cocktail of S. enterica serovars at 7-log CFU/g, with different levels of CP (control, 0%; low, 0.55%; medium, 1.70%; high, 2.25% wt/wt), or liquid lactic acid (0.33% vol/wt, LA) were subjected to typical fermentation and drying conditions. A significant (P

BACKGROUND Most studies on architectural rules in corals have focused on the branch and the colony level, unveiling a variety of allometric rules. Working on the branching coral Stylophora pistillata, here we further extend the astogenic directives of this species at the polyp level, to reveal allometric and morphometric rules dictating polyps' arrangement. RESULTS We identified a basic morphometric landscape as a six-polyp circlet developed around a founder polyp, with established distances between polyps (six equilateral triangles), reflecting a strong genetic-based background vs high plasticity on the population level. Testing these rules in regular and chimeric S. pistillata colonies, we revealed similar morphometric/allometric rules developed via a single astogenic pathway. In regular colonies, this pathway was driven by the presence/absence of intra-circlet budding polyps, while in chimeras, by the distances between the two founder polyps. In addition, we identified the intra-circlet budding as the origin of first branching, if BPC distances are kept

The N-methyl-D-aspartate receptors (NMDARs; GluNRS) are glutamate receptors, commonly located at excitatory synapses. Mutations affecting receptor function often lead to devastating neurodevelopmental disorders. We have identified two toddlers with different heterozygous missense mutations of the same, and highly conserved, glycine residue located in the ligand-binding-domain of GRIN2B: G689C and G689S. Structure simulations suggest severely impaired glutamate binding, which we confirm by functional analysis. Both variants show three orders of magnitude reductions in glutamate EC50, with G689S exhibiting the largest reductions observed for GRIN2B (~2000-fold). Moreover, variants multimerize with, and upregulate, GluN2Bwt-subunits, thus engendering a strong dominant-negative effect on mixed channels. In neurons, overexpression of the variants instigates suppression of synaptic GluNRs. Lastly, while exploring spermine potentiation as a potential treatment, we discovered that the variants fail to respond due to G689’s novel role in proton-sensing. Together, we describe two unique variants with extreme effects on channel function. We employ protein-stability measures to explain why current (and future) LBD mutations in GluN2B primarily instigate Loss-of-Function.

The majority of lizard clades are ancestrally and predominantly diurnal. The only major taxon in which most species are nocturnal is the Gekkota (geckos and pygopodids). As ectothermic thermoregulators, lizard metabolic rates are highly temperature dependent, and diurnal lizards therefore demonstrate higher metabolic rates than nocturnal ones. Furthermore, exposure to solar radiation is thought to reduce ectothermic longevity by increasing both metabolic costs and the rate of accumulating harmful mutations through UV radiation (UVC specifically). In being nocturnal, ectothermic species may reduce their intrinsic mortality rates and thus live longer. To test this hypothesis, we collected literature data on the maximum longevities of 740 lizard species, of which 185 are geckos. We examined whether geckos live longer than other lizards, and whether activity time affects gecko longevity. While geckos live relatively long for lizards of their size, their activity time was found to be unrelated to longevity, contradicting our predictions. We suggest that diurnal species may have evolved higher resistance to UV radiation via thicker, more keratinized skin. Elevated metabolic rates do not automatically equate with faster aging. Mortality through extrinsic causes (e.g., predation) may impose much stronger selective pressures than intrinsic causes.

1935 gecko species (and 224 subspecies) were known in December 2019 in seven families and 124 genera. These nearly 2000 species were described by ~950 individuals of whom more than 100 described more than 10 gecko species each. Most gecko species were discovered during the past 40 years. The primary type specimens of all currently recognized geckos (including subspecies) are distributed over 161 collections worldwide, with 20 collections having about two thirds of all primary types. The primary type specimens of about 40 gecko taxa have been lost or unknown. The phylogeny of geckos is well studied, with DNA sequences being available for ~76% of all geckos (compared to ~63% in other reptiles) and morphological characters now being collected in databases. Geographically, geckos occur on five continents and many islands but are most species-rich in Australasia (which also houses the greatest diversity of family-level taxa), Southeast Asia, Africa, Madagascar, and the West Indies. Among countries, Australia has the highest number of geckos (241 species), with India, Madagascar, and Malaysia being the only other countries with more than 100 described species each. As expected, when correcting for land area, countries outside the tropics have fewer geckos.

As a heritable sequence-specific adaptive immune system, CRISPR-Cas is a powerful force shaping strain diversity in host-virus systems. While the diversity of CRISPR alleles has been explored, the associated structure and dynamics of host-virus interactions have not. We explore the role of CRISPR in mediating the interplay between host-virus interaction structure and eco-evolutionary dynamics in a computational model and compare results with three empirical datasets from natural systems. We show that the structure of the networks describing who infects whom and the degree to which strains are immune, are respectively modular (containing groups of hosts and viruses that interact strongly) and weighted-nested (specialist hosts are more susceptible to subsets of viruses that in turn also infect the more generalist hosts with many spacers matching many viruses). The dynamic interplay between these networks influences transitions between dynamical regimes of virus diversification and host control. The three empirical systems exhibit weighted-nested protection networks, a pattern our theory shows is indicative of hosts able to suppress virus diversification. Previously missing from studies of microbial host-pathogen systems, the protection network plays a key role in the coevolutionary dynamics.

Objective Higher serum alkaline phosphatase (sALP) levels associate with a poor prognosis in maintenance hemodialysis patients. However, little is known about the meaning of lower sALP in this population. We hypothesized that lower sALP concentrations may express nutritional status and survival accordingly. Methods A retrospective, longitudinal cohort study of a clinical database containing the medical records of 554 patients (367 men and 187 women, mean age 67.6 ± 14.2 years) receiving maintenance hemodialysis from November 2007 to July 2018 in a single center was conducted. sALP, nutritional, bone turnover, and inflammatory marker levels were recorded at 0, 6, 12, 18, 24, 30,and 36 months followed by 58 additional months of clinical observations. Results The median sALP level was 90.0 (71.0-125.8) U/L. In a linear mixed effects model adjusted for baseline demographics and clinical parameters, each 1.0 U/L increase above the mean sALP at baseline was associated with 0.7% slower rate of decline in geriatric nutritional risk index per 3 years (P = .02 for sALP × time interaction). sALP remained associated with the rate of change in geriatric nutritional risk index, even after controlling for C-reactive protein and intact parathyroid hormone levels. For each 1.0 U/L increase in sALP over time, the fully adjusted all-cause mortality hazard ratio using Cox models with the time-varying risk effect was 0.996 (95% confidence interval 0.993-1.000, P = .04). Conclusions Increasing longitudinal levels of sALP associate with improved nutritional status and lower mortality rates. sALP can be used as an integrated marker, combining the properties of the nutritional marker, the marker of mineral-bone disease and inflammation, according to its levels.

The number of shrew species in Israel has been and still is the subject of debate. In this work we used for the first time a molecular marker, the cytochrome b gene, to investigate the number and identity of shrew species in Israel. Our molecular results confirmed the presence of four species: Crocidura leucodon, Crocidura suaveolens gueldenstaedtii, Crocidura ramona, and Suncus etruscus. The C. ramona sequences were found to differ from all other Crocidura species sequenced to date, supporting its status as a distinct species. Whether it is conspecific with Crocidura portali (described in 1920 from Israel and usually synonymized with C. suaveolens), will require additional study. The sequences of Israeli C. suaveolens were found to be very similar to those of Iran, Turkey, and Georgia (i.e., C. suaveolens gueldenstaedtii), in agreement with previous studies. The Israeli C. leucodon sequences, however, formed a distinct clade among C. leucodon. Finally, the S. etruscus sequences clustered with sequences from France, Italy, and Iran.

Recent developments in near-infrared (NIR) dyes and imaging modalities enable tumor fluorescent images in preclinical and clinical settings. However, NIR dyes have several drawbacks, and therefore,...

Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. This document also covers advice and best practice in the design and conduct of animal studies to support researchers in improving standards from the start of the experimental design process through to publication., The NC3Rs developed the ARRIVE guidelines in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. This article explains the rationale behind each item in the revised and updated ARRIVE guidelines 2019, clarifying key concepts and providing illustrative examples.

Gene drives based on CRISPR/Cas9 have the potential to reduce the enormous harm inflicted by crop pests and insect vectors of human disease, as well as to bolster valued species. In contrast with extensive empirical and theoretical studies in diploid organisms, little is known about CRISPR gene drive in haplodiploids, despite their immense global impacts as pollinators, pests, natural enemies of pests, and invasive species in native habitats. Here, we analyze mathematical models demonstrating that, in principle, CRISPR homing gene drive can work in haplodiploids, as well as at sex‐linked loci in diploids. However, relative to diploids, conditions favoring the spread of alleles deleterious to haplodiploid pests by CRISPR gene drive are narrower, the spread is slower, and resistance to the drive evolves faster. By contrast, the spread of alleles that impose little fitness cost or boost fitness was not greatly hindered in haplodiploids relative to diploids. Therefore, altering traits to minimize damage caused by harmful haplodiploids, such as interfering with transmission of plant pathogens, may be more likely to succeed than control efforts based on introducing traits that reduce pest fitness. Enhancing fitness of beneficial haplodiploids with CRISPR gene drive is also promising.

Measurements of agronomic and fruit quality traits in a multi-environment trial using a multi-parental advanced generation intercross population identify QTLs for plasticity and QTL × environment interactions in response to abiotic stresses in tomato., Deciphering the genetic basis of phenotypic plasticity and genotype × environment interactions (G×E) is of primary importance for plant breeding in the context of global climate change. Tomato (Solanum lycopersicum) is a widely cultivated crop that can grow in different geographical habitats and that displays a great capacity for expressing phenotypic plasticity. We used a multi-parental advanced generation intercross (MAGIC) tomato population to explore G×E and plasticity for multiple traits measured in a multi-environment trial (MET) comprising optimal cultural conditions together with water deficit, salinity, and heat stress over 12 environments. Substantial G×E was observed for all the traits measured. Different plasticity parameters were estimated by employing Finlay–Wilkinson and factorial regression models and these were used together with genotypic means for quantitative trait loci (QTL) mapping analyses. In addition, mixed linear models were also used to investigate the presence of QTL × environment interactions. The results highlighted a complex genetic architecture of tomato plasticity and G×E. Candidate genes that might be involved in the occurrence of G×E are proposed, paving the way for functional characterization of stress response genes in tomato and for breeding climate-adapted cultivars.

Polyploid giant cancer cells (PGCC) represent a poorly understood, small subpopulation of tumor cells that are increasingly being recognized for their critical role in therapy resistance, metastasis, and cancer recurrence. PGCC have the potential to generate progeny through primitive or cleavage‐like division, which allows them to evade antimitotic insults. We recently demonstrated that the sphingolipid enzyme acid ceramidase (ASAH1) is required for this process. Since specific ASAH1 inhibitors are not clinically available, we investigated whether tamoxifen, which interferes with ASAH1 function via off‐target effects, has a potential clinical benefit independent of estrogen signaling. Our results show that tamoxifen inhibits generation of PGCC offspring in prostate cancer, glioblastoma, and melanoma cells. Analysis of two state‐level cancer registries revealed that tamoxifen improves survival outcomes for second, nonbreast cancers that develop in women with early stage breast cancer. Our results suggest that tamoxifen may have a clinical benefit in a variety of cancers that is independent of estrogen signaling and could be due to its inhibition of acid ceramidase. Thus the distinct application of tamoxifen as potentially a first‐in‐class therapeutic that inhibits the generation of PGCC offspring should be considered in future clinical trials., This study suggests that tamoxifen has an estrogen‐signaling independent clinical benefit in a variety of cancers that could be due to acid ceramidase inhibition. This would make tamoxifen a first‐in‐class therapeutic against formation of PGCC progeny.

Most species remain unknown to science and might go extinct before we recognize their existence. Although specimens belonging to many of these unknown taxa may already be housed in scientific collections, they can remain ‘shelved’ for years bearing the wrong name or without a formal name. We investigate factors underlying variation in time lag between collection and description dates for 2356 reptile species described worldwide between 1992 and 2017. We modelled the time to description using biological and sociological variables in a time-to-event analysis. Time lag between collection and description varied from zero to 155 years (median = 5). More than one-quarter of species involved specimens ‘shelved’ for 12 years or more. The time lag was shorter when the collector of the holotype – specimen serving as the name-bearer of the species – was an author of the description, while taxonomic revisions uncovered species with longer time lags. Unknown species collected by non-taxonomists and ‘shelved’ in scientific collections remained incorrectly identified for a much longer time. Taxonomic revisions are crucial to reverse this trend and improve benefits of the collecting performed by non-taxonomists. Our findings reveal the kinds of preserved reptile specimens that most likely represent unknown species in scientific collections.

Previous studies have suggested that crude plant extracts of the anti-diabetic medicinal plant, Momordica balsamina (MB) may exert their anti-diabetic effect through either enhancement of insulin sensitivity or inhibition of intestinal glucose absorption. However, the effects of these MB extracts on insulin synthesis and secretion are not well documented in the literature. Therefore, a main purpose of the current research was to examine in vitro effects of MB crude fruit extracts on selected aspects of the insulin synthesis and secretion pathway. The study results indicated that ethanol, ethyl acetate and hexane MB crude extracts had the significantly enhanced the uptake of glucose by RIN-m5F β-cells in a manner depending on concentration. Furthermore, these same MB fruit extracts significantly increased the quantities of synthesized and secreted insulin by RIN-m5F β-cells. In addition, significant upregulation of the pre-proinsulin gene levels by the same MB fruit extracts was detected by the conventional end-point Polymerase Chain Reaction (RT-PCR), whereas a significant upregulation of gene expression levels of the two pancreatic glucose sensors (glucokinase enzyme and Glucose Transporter 2 (GLUT2)) as well as the two insulin gene transcription factors Musculoaponeurotic Fibrosarcoma homolog A (MafA) and Pancreatic Duodenal Homeobox-1 (PDX-1) were detected by means of quantitative reverse transcriptase PCR. In conclusion, the outcomes of this research propose that MB fruit extracts may, in addition to their effects on sensitivity of insulin and inhibition of intestinal glucose absorption, exert their anti-diabetic effects through stimulation of both the insulin synthesis and secretion.

Based on a comprehensive literature survey, we determined the sources of the terrestrial vertebrate species on Christmas Island, asking where they originated relative to Wallace’s Line (the southern end of the divide lies 1100 km to the east, where the Lombok Strait adjoins the eastern Indian Ocean). The two bats, Pipistrellus murrayi and Pteropus natalis, are from the west. Concerning the endemic and ‘resident’ bird species, one is from the west (Collocalia natalis), four are from the east (Accipiter fasciatus, Egretta novaehollandiae, Falco cenchroides and Ninox natalis) and the other 15 are ambiguous or indeterminate. Most of the land-locked species are also from the east: rodents Rattus macleari and Rattus nativitatis, and squamates Cryptoblepharus egeriae, Emoia nativitatis and Lepidodactylus listeria. Additionally, two have westerly origins (Crocidura trichura and Cyrtodactylus sadleiri), one is ambiguous (Emoia atrocostata) and another is unknown (Ramphotyphlops exocoeti). West-directed surface currents that flow across the eastern Indian Ocean towards Christmas Island would have facilitated most of the land-animal colonizations. We therefore suggest that Wallace’s Line be redrawn such that the landmass is placed on the Australasian side of this fundamental biogeographical boundary.

Insular animals are thought to be under weak predation pressure and increased intraspecific competition compared with those on the mainland. Thus, insular populations are predicted to evolve ‘slow’ life histories characterized by fewer and smaller clutches of larger eggs, a pattern called the ‘island syndrome’. To test this pattern, we collected data on egg volume, clutch size and laying frequency of 31 Aegean Island populations of the closely related geckos of the Mediodactylus kotschyi species complex. We tested how predation pressure, resource abundance, island area and isolation influenced reproductive traits. Isolation and predation were the main drivers of variation in life-history traits. Higher predator richness seemed to promote faster life histories, perhaps owing to predation on adults, whereas the presence of boas promoted slower life histories, perhaps owing to release from predation by rats on the eggs of geckos. Insular geckos followed only some of the predictions of the ‘island syndrome’. Predation pressure seemed to be more complex than expected and drove life histories of species in two opposing directions. Our results highlight the importance of considering the identity of specific predators in ecological studies., The study was funded by an Israel Science Foundation (ISF) grant #1005/12.

The present study reported the effects of Sclerocarya birrea stem-bark (SBSB) extracts on glucose uptake, insulin synthesis and the expression of glucose transporter 2 (GLUT2), glucokinase, pancreatic duodenal homeobox-1 (PDX-1), musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) and pre-proinsulin genes in rat insulinoma (RIN)-m5F pancreatic beta cells. The amount of glucose takenup by RIN-m5F cells was measured using a glucose oxidase-based assay kit. Intracellular and secreted insulin were measured using an enzyme linked immunoassay kit. Pre-proinsulin gene expression was determined using the conventional polymerase chain reaction (PCR) technique, while the expressions of GLUT2, glucokinase, PDX-1 and MafA genes were evaluated using quantitative real-time PCR technique. Of the four SBSB extracts investigated in the study, only the SBSB hexane extract positively affected all the study variables in RIN-m5F cells compared with the DMSO control. Thus, the SBSB hexane extract contains phytochemicals capable of enhancing insulin synthesis partly through up-regulation of the expression of GLUT2, glucokinase, PDX-1, MafA and pre-proinsulin genes.