Miracle-dz/UniFAR-FTUs huggingface dataset:
Spatio‐temporal variation in the strength and mode of selection acting on major histocompatibility complex diversity in water vole (Arvicola terrestris) metapopulations

Patterns of spatio‐temporal genetic variation at a class II major histocompatibility complex (MHC) locus and multiple microsatellite loci were analysed within and between three water vole metapopulations in Scotland, UK. Comparisons of MHC and microsatellite spatial genetic differentiation, based on standardised tests between two demographically asynchronous zones within a metapopulation, suggested that spatial MHC variation was affected by balancing selection, directional selection and random genetic drift, but that the relative effects of these microevolutionary forces vary temporally. At the metapopulation level, between‐year differentiation for MHC loci was significantly correlated with that of microsatellites, signifying that neutral factors such as migration and drift were primarily responsible for overall temporal genetic change at the metapopulation scale. Between metapopulations, patterns of genetic differentiation implied that, at large spatial scales, MHC variation was primarily affected by directional selection and drift. Levels of MHC heterozygosity in excess of Hardy–Weinberg expectations were consistent with overdominant balancing selection operating on MHC variation within metapopulations. However, this effect was not constant among all samples, indicating temporal variation in the strength of selection relative to other factors. The results highlight the benefit of contrasting variation at MHC with neutral markers to separate the effects of stochastic and deterministic microevolutionary forces, and add to a growing body of evidence showing that the mode and relative strength of selection acting on MHC diversity varies both spatially and temporally.
Telomerase Activity and Telomere Length in Male Germ Cells

ABSTRACT Telomeres are located at the outermost ends of all eukaryotic chromosomes and provide for the maintenance of genomic stability and integrity during the life span of organisms. The length of telomeres shortens due to each round of DNA replication, genotoxic insults, and/or reactive oxygen species. To counteract this shortening, certain types of cells, including stem cells, male/female germline cells, granulosa cells, early embryos, and most cancerous cells, express an enzyme known as telomerase, which has the potential of restoring the shortened telomeres. Presence of telomerase activity in the male germ cells ensures maintenance of telomere length at maximum levels during spermatogenesis despite telomere attrition due to DNA replication or other genotoxic factors. In this review, telomerase activity and telomere length in mammalian male germ cells during spermatogenesis are evaluated in detail based on the studies in this field. Also, the relationship between telomerase activity/telomere length and development of male infertility is comprehensively discussed.
DNA barcoding of flowering plants in Sumatra, Indonesia

Abstract The rapid conversion of Southeast Asian lowland rainforests into monocultures calls for the development of rapid methods for species identification to support ecological research and sustainable land‐use management. Here, we investigated the utilization of DNA barcodes for identifying flowering plants from Sumatra, Indonesia. A total of 1,207 matK barcodes (441 species) and 2,376 rbcL barcodes (750 species) were successfully generated. The barcode effectiveness is assessed using four approaches: (a) comparison between morphological and molecular identification results, (b) best‐close match analysis with TaxonDNA, (c) barcoding gap analysis, and (d) formation of monophyletic groups. Results show that rbcL has a much higher level of sequence recoverability than matK (95% and 66%). The comparison between morphological and molecular identifications revealed that matK and rbcL worked best assigning a plant specimen to the genus level. Estimates of identification success using best‐close match analysis showed that >70% of the investigated species were correctly identified when using single barcode. The use of two‐loci barcodes was able to increase the identification success up to 80%. The barcoding gap analysis revealed that neither matK nor rbcL succeeded to create a clear gap between the intraspecific and interspecific divergences. However, these two barcodes were able to discriminate at least 70% of the species from each other. Fifteen genera and twenty‐one species were found to be nonmonophyletic with both markers. The two‐loci barcodes were sufficient to reconstruct evolutionary relationships among the plant taxa in the study area that are congruent with the broadly accepted APG III phylogeny.
A Character-Level Approach to the Text Normalization Problem Based on a New Causal Encoder

Text normalization is a ubiquitous process that appears as the first step of many Natural Language Processing problems. However, previous Deep Learning approaches have suffered from so-called silly errors, which are undetectable on unsupervised frameworks, making those models unsuitable for deployment. In this work, we make use of an attention-based encoder-decoder architecture that overcomes these undetectable errors by using a fine-grained character-level approach rather than a word-level one. Furthermore, our new general-purpose encoder based on causal convolutions, called Causal Feature Extractor (CFE), is introduced and compared to other common encoders. The experimental results show the feasibility of this encoder, which leverages the attention mechanisms the most and obtains better results in terms of accuracy, number of parameters and convergence time. While our method results in a slightly worse initial accuracy (92.74%), errors can be automatically detected and, thus, more readily solved, obtaining a more robust model for deployment. Furthermore, there is still plenty of room for future improvements that will push even further these advantages.
The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD)*

Regulatory T (Treg) cells expressing the transcription factor FOXP3 play a pivotal role in maintaining immunologic self-tolerance. We and others have shown previously that EZH2 is recruited to the FOXP3 promoter and its targets in Treg cells. To further address the role for EZH2 in Treg cellular function, we have now generated mice that lack EZH2 specifically in Treg cells (EZH2Δ/ΔFOXP3+). We find that EZH2 deficiency in FOXP3+ T cells results in lethal multiorgan autoimmunity. We further demonstrate that EZH2Δ/ΔFOXP3+ T cells lack a regulatory phenotype in vitro and secrete proinflammatory cytokines. Of special interest, EZH2Δ/ΔFOXP3+ mice develop spontaneous inflammatory bowel disease. Guided by these results, we assessed the FOXP3 and EZH2 gene networks by RNA sequencing in isolated intestinal CD4+ T cells from patients with Crohn's disease. Gene network analysis demonstrates that these CD4+ T cells display a Th1/Th17-like phenotype with an enrichment of gene targets shared by FOXP3 and EZH2. Combined, these results suggest that the inflammatory milieu found in Crohn's disease could lead to or result from deregulation of FOXP3/EZH2-enforced T cell gene networks contributing to the underlying intestinal inflammation.
Multilocus assignment analyses reveal multiple units and rare migration events in the recently expanded yellow‐eyed penguin (Megadyptes antipodes)

The identification of demographically independent populations and the recognition of management units have been greatly facilitated by the continuing advances in genetic tools. Managements units now play a key role in short‐term conservation management programmes of declining species, but their importance in expanding populations receives comparatively little attention. The endangered yellow‐eyed penguin (Megadyptes antipodes) expanded its range from the subantarctic to New Zealand's South Island a few hundred years ago and this new population now represents almost half of the species’ total census size. This dramatic expansion attests to M. antipodes’ high dispersal abilities and suggests the species is likely to constitute a single demographic population. Here we test this hypothesis of panmixia by investigating genetic differentiation and levels of gene flow among penguin breeding areas using 12 autosomal microsatellite loci along with mitochondrial control region sequence analyses for 350 individuals. Contrary to our hypothesis, however, the analyses reveal two genetically and geographically distinct assemblages: South Island vs. subantarctic populations. Using assignment tests, we recognize just two first‐generation migrants between these populations (corresponding to a migration rate of < 2%), indicating that ongoing levels of long‐distance migration are low. Furthermore, the South Island population has low genetic variability compared to the subantarctic population. These results suggest that the South Island population was founded by only a small number of individuals, and that subsequent levels of gene flow have remained low. The demographic independence of the two populations warrants their designation as distinct management units and conservation efforts should be adjusted accordingly to protect both populations.
Evidence Supporting a Role for SMAD2/3 in Bovine Early Embryonic Development: Potential Implications for Embryotropic Actions of Follistatin1

ABSTRACT The TGF-beta-SMAD signaling pathway is involved in regulation of various aspects of female reproduction. However, the intrinsic functional role of SMADs in early embryogenesis remains poorly understood. Previously, we demonstrated that treatment with follistatin, an activin (TGF-beta superfamily ligand)-binding protein, is beneficial for bovine early embryogenesis and specific embryotropic actions of follistatin are dependent on SMAD4. Because SMAD4 is a common SMAD that can bind both SMAD2/3 and SMAD1/5, the objective of this study was to further determine the intrinsic role of SMAD2/3 in the control of early embryogenesis and delineate if embryotropic actions of follistatin in early embryos are SMAD2/3 dependent. By using a combination of pharmacological and small interfering RNA-mediated inhibition of SMAD2/3 signaling in the presence or absence of follistatin treatment, our results indicate that SMAD2 and SMAD3 are both required for bovine early embryonic development and stimulatory actions of follistatin on 8- to 16-cell and that blastocyst rates, but not early cleavage, are muted when SMAD2/3 signaling is inhibited. SMAD2 deficiency also results in reduced expression of the bovine trophectoderm cell-specific gene CTGF. In conclusion, the present work provides evidence supporting a functional role of SMAD2/3 in bovine early embryogenesis and that specific stimulatory actions of follistatin are not observed in the absence of SMAD2/3 signaling.
The Family Secrets of Avian Egg-Specific Ovalbumin and Its Related Proteins Y and X

ABSTRACT The ovalbumin gene family in Gallus gallus is composed of three homologous genes located within a 46 kb locus on chromosome 2: ovalbumin, ovalbumin-related protein Y (OVAY), and ovalbumin-related protein X (OVAX) genes. The expression of these genes in hen oviduct is under estrogen control, but their relative hormonal responsiveness and subsequent protein concentration in egg, is distinctive. Interestingly, all three proteins lack the classical signal peptide for secretion. Ovalbumin, OVAX, and OVAY belong to the serine protease inhibitor (serpin) family whose members share a common tertiary structure. Ovalbumin and OVAX are one of the few members of this family that do not express any protease inhibition activity whereas OVAY has been predicted to be inhibitory, by comparison with the consensus sequence for inhibitory serpins. In contrast to ovalbumin and OVAY, OVAX interacts with heparin, a negatively charged glycosaminoglycan, via a positively charged domain exposed at the surface of the molecule. Ovalbumin is the major egg white protein and might be a source of amino acids for the developing embryo. The physiological function of OVAY is not known, but recent data have revealed a possible role of this protein in early embryonic development. Considering the antibacterial activities of OVAX, this protein might play a role in egg defense. This review sheds light on the expression, biochemistry, and structural specificities of these three highly similar paralogs. It gives new clues in favor of diverging functions, which are likely to have arisen by duplication events from a common ancestral gene.
Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development*

Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFα signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells.
Microarray analysis reveals transcriptional plasticity in the reef building coral Acropora millepora

We investigated variation in transcript abundance in the scleractinian coral, Acropora millepora, within and between populations characteristically exposed to different turbidity regimes and hence different levels of light and suspended particulate matter. We examined phenotypic plasticity by comparing levels of gene expression between source populations and following 10 days of acclimatization to a laboratory environment. Analyses of variance revealed that 0.05% of genes were differentially expressed between source populations, 1.32% following translocation into a common laboratory and 0.07% in the interaction (source population‐dependent responses to translocation). Functional analyses identified an over‐representation of differentially expressed genes associated with metabolism and fluorescence categories (primarily downregulated), and environmental information processing (primarily upregulated) following translocation to a lower light and turbidity environment. Such metabolic downregulation may indicate nonoxidative stress, hibernation or caloric restriction associated with the changed environmental conditions. Green fluorescent protein‐related genes were the most differentially expressed and were exclusively downregulated; however, green fluorescent protein levels remained unchanged following translocation. Photophysiological responses of corals from both locations were characterized by a decline when introduced to the common laboratory environment but remained healthy (Fv/Fm > 0.6). Declines in total lipid content following translocation were the greatest for inshore corals, suggesting that turbid water corals have a strong reliance on heterotrophic feeding.
Differentially Expressed Genes in Endometrium and Corpus Luteum of Holstein Cows Selected for High and Low Fertility Are Enriched for Sequence Variants Associated with Fertility1

ABSTRACT Despite the importance of fertility in humans and livestock, there has been little success dissecting the genetic basis of fertility. Our hypothesis was that genes differentially expressed in the endometrium and corpus luteum on Day 13 of the estrous cycle between cows with either good or poor genetic merit for fertility would be enriched for genetic variants associated with fertility. We combined a unique genetic model of fertility (cattle that have been selected for high and low fertility and show substantial difference in fertility) with gene expression data from these cattle and genome-wide association study (GWAS) results in ∼20 000 cattle to identify quantitative trait loci (QTL) regions and sequence variants associated with genetic variation in fertility. Two hundred and forty-five QTL regions and 17 sequence variants associated primarily with prostaglandin F2alpha, steroidogenesis, mRNA processing, energy status, and immune-related processes were identified. Ninety-three of the QTL regions were validated by two independent GWAS, with signals for fertility detected primarily on chromosomes 18, 5, 7, 8, and 29. Plausible causative mutations were identified, including one missense variant significantly associated with fertility and predicted to affect the protein function of EIF4EBP3. The results of this study enhance our understanding of 1) the contribution of the endometrium and corpus luteum transcriptome to phenotypic fertility differences and 2) the genetic architecture of fertility in dairy cattle. Including these variants in predictions of genomic breeding values may improve the rate of genetic gain for this critical trait.
Phosphoinositide-dependent Kinase 1 Integrates T Cell Receptor and Cd28 Co-receptor Signaling to Effect Nf-κb Induction and T Cell Activation

In addition to T cell receptor (TCR) ligation, activation of CD28 coreceptor by costimulatory molecule B7 is required for transcription factor NF-κB induction and robust T cell activation, though exactly how CD28 contributes to this remains incompletely understood. We demonstrated here that phosphoinositide-dependent kinase 1 (PDK1) plays an essential role in integrating TCR and CD28 signals. Upon deletion of PDK1 in T cells, TCR-CD28 signals failed to induce NF-κB activation or protein kinase C θ (PKC-θ) phosphorylation, although T cell survival and pathways dependent on p38 and Jnk kinases or transcription factor NF-AT were unaffected. CD28 facilitated NF-κB activation by regulating PDK1 recruitment and phosphorylation, which are necessary for efficient binding of PDK1 to PKC-θ and CARMA1, and thus for NF-κB induction.
High-Yield Superovulation in Adult Mice by Anti-Inhibin Serum Treatment Combined with Estrous Cycle Synchronization1

ABSTRACT Producing many mature oocytes is of great importance for assisted reproductive technologies. In mice, superovulation by consecutive injections of equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) has been the gold standard for oocyte collection. However, the yield of mature oocytes by this regimen can fluctuate according to the stage of the estrous cycle, strain, and age. Therefore, our objective was to develop a high-yield superovulation protocol to collect higher numbers of oocytes from adult female mice of different strains and ages. First, we aimed to synchronize the estrous cycle using C57BL/6 (B6) female mice. Most (93%) were synchronized to metestrus after two daily injections of progesterone. Second, we found that with the injection of anti-inhibin serum (AIS) instead of eCG, the mean number of ovulated oocytes almost doubled (21 vs. 41 per mouse). Third, by combining estrous cycle synchronization with two AIS injections, we obtained 62 oocytes per mouse, about three times that with the eCG-hCG protocol. Importantly, this approach increased the proportion of mice that ovulated >25 oocytes from about 40% (eCG-hCG) to 90%. The same protocol was also effective in other inbred (BALB/cA), outbred (ICR), and hybrid (B6D2F1) strains. In addition, B6 female mice aged over 1 yr ovulated 1.8-fold more oocytes by this protocol. Thus, estrous cycle synchronization followed by AIS-hCG yielded a broadly applicable, highly efficient superovulation. This protocol should promote the effective use of invaluable female mouse strains and decrease the numbers of animals euthanized.
Learning to Speak and Act in a Fantasy Text Adventure Game

We introduce a large-scale crowdsourced text adventure game as a research platform for studying grounded dialogue. In it, agents can perceive, emote, and act whilst conducting dialogue with other agents. Models and humans can both act as characters within the game. We describe the results of training state-of-the-art generative and retrieval models in this setting. We show that in addition to using past dialogue, these models are able to effectively use the state of the underlying world to condition their predictions. In particular, we show that grounding on the details of the local environment, including location descriptions, and the objects (and their affordances) and characters (and their previous actions) present within it allows better predictions of agent behavior and dialogue. We analyze the ingredients necessary for successful grounding in this setting, and how each of these factors relate to agents that can talk and act successfully.
Repulsive Guidance Molecule b (RGMb) Is Dispensable for Normal Gonadal Function in Mice1

ABSTRACT Bone morphogenetic protein (BMP) signaling plays an important role in spermatogenesis and follicle development. Our previous studies have shown that repulsive guidance molecule b (RGMb, also known as Dragon) is a coreceptor that enhances BMP2 and BMP4 signaling in several cell types and that RGMb is expressed in spermatocytes and spermatids in the testis and in oocytes of the secondary follicles in the ovary. Here, we demonstrated that specific deletion of Rgmb in germ cells in the testis and ovary did not alter Smad1/5/8 phosphorylation, gonadal structures, and fertility. In addition, ovaries from postnatal global Rgmb knockout mice showed similar structures to the wild-type ovaries. Our results suggest that RGMb is not essential for normal gonadal function.
Interaction of amyloid-β (Aβ) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice

Brain accumulation of the amyloid-β protein (Aβ) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). Aβ oligomers (AβOs) are synaptotoxins that build up in the brains of patients and are thought to contribute to memory impairment in AD. Thus, identification of novel synaptic components that are targeted by AβOs may contribute to the elucidation of disease-relevant mechanisms. Trans-synaptic interactions between neurexins (Nrxs) and neuroligins (NLs) are essential for synapse structure, stability, and function, and reduced NL levels have been associated recently with AD. Here we investigated whether the interaction of AβOs with Nrxs or NLs mediates synapse damage and cognitive impairment in AD models. We found that AβOs interact with different isoforms of Nrx and NL, including Nrx2α and NL1. Anti-Nrx2α and anti-NL1 antibodies reduced AβO binding to hippocampal neurons and prevented AβO-induced neuronal oxidative stress and synapse loss. Anti-Nrx2α and anti-NL1 antibodies further blocked memory impairment induced by AβOs in mice. The results indicate that Nrx2α and NL1 are targets of AβOs and that prevention of this interaction reduces the deleterious impact of AβOs on synapses and cognition. Identification of Nrx2α and NL1 as synaptic components that interact with AβOs may pave the way for development of novel approaches aimed at halting synapse failure and cognitive loss in AD.