Miracle-dz/UniFAR-FTUs huggingface dataset:
SNPC-1.3 is a sex-specific transcription factor that drives male piRNA expression in C. elegans

Piwi-interacting RNAs (piRNAs) play essential roles in silencing repetitive elements to promote fertility in metazoans. Studies in worms, flies, and mammals reveal that piRNAs are expressed in a sex-specific manner. However, the mechanisms underlying this sex-specific regulation are unknown. Here we identify SNPC-1.3, a variant of a conserved subunit of the snRNA activating protein complex, as a male-specific piRNA transcription factor in C. elegans. Binding of SNPC-1.3 at male piRNA loci drives spermatogenic piRNA transcription and requires the core piRNA transcription factor SNPC-4. Loss of snpc-1.3 leads to depletion of male piRNAs and defects in male-dependent fertility. Furthermore, TRA-1, a master regulator of sex determination, binds to the snpc-1.3 promoter and represses its expression during oogenesis. Loss of TRA-1 targeting causes ectopic expression of snpc-1.3 and male piRNAs during oogenesis. Thus, sexual dimorphic regulation of snpc-1.3 coordinates male and female piRNA expression during germline development.
Evaluating geographic variation within molecular operational taxonomic units (OTUs) using network analyses in Scandinavian lakes

Operational taxonomic units (OTUs) are usually treated as if they are internally uniform in environmental metabarcoding studies of microbial and macrobial eukaryotes, even when the OTUs are being used to infer biogeographic patterns. The OTUs constructed by the program Swarm have underlying network topologies in which nodes represent amplicons and edges represent 1 nucleotide differences between nodes. Such networks can be exploited to search for biogeographic patterns within each OTU. To do this, here we used an available protistan metabarcoding dataset consisting of the hypervariable V4 region of the 18S rRNA locus amplified from 77 lakes collected across Norway and Sweden. The 82 most abundant and wide-spread OTUs constructed by Swarm were evaluated using shortest path, assortativity, and geographical analyses. We found that while pairs of amplicons from the same lake were usually connected directly to each other within the OTUs, these pairs of amplicons from the same lake did not form assortative clusters within the OTUs, and amplicons were not more connected with other amplicons occurring in neighboring lakes than expected by chance. This new approach to looking at within-OTU is applicable to other metabarcoding datasets and we provide code to perform these analyses.
Effect of Handedness on Learned Controllers and Sensorimotor Noise During Trajectory-Tracking

In human-in-the-loop control systems, operators can learn to manually control dynamic machines with either hand using a combination of reactive (feedback) and predictive (feedforward) control. This paper studies the effect of handedness on learned controllers and performance during a continuous trajectory-tracking task. In an experiment with 18 participants, subjects perform an assay of unimanual trajectory-tracking and disturbance-rejection tasks through second-order machine dynamics, first with one hand then the other. To assess how hand preference (or dominance) affects learned controllers, we extend, validate, and apply a non-parametric modeling method to estimate the concurrent feedback and feedforward elements of subjects’ controllers. We find that handedness does not affect the learned controller and that controllers transfer between hands. Observed improvements in time-domain tracking performance may be attributed to adaptation of feedback to reject disturbances arising exogenously (i.e. applied by the experimenter) and endogenously (i.e. generated by sensorimotor noise).
Characterization of a Sex-Determining Region and Its Genomic Context via Statistical Estimates of Haplotype Frequencies in Daughters and Sons Sequenced in Pools

Sex chromosomes are generally derived from a pair of autosomes that have acquired a locus controlling sex. Sex chromosomes usually evolve reduced recombination around this locus and undergo a long process of molecular divergence. Although sex chromosomes have been intensively studied in several model taxa, the actual loci controlling sex are difficult to identify in highly diverged sex chromosomes, hence they are known in relatively few species. Taxa with evolutionarily young sex chromosomes can help fill this gap in knowledge. Here we aimed at pinpointing the sex-determining region (SDR) of Armadillidium vulgare, a terrestrial isopod with female heterogamety (ZW females and ZZ males) and which presumably presents evolutionarily young sex chromosomes. To locate the SDR, we assessed SNP allele frequencies in F1 daughters and sons sequenced in pools (pool-seq) in several families. We developed a Bayesian method that uses the SNP genotypes of individually sequenced parents and poolseq data from F1 siblings to estimate the genetic distance between a given genomic region (contig) and the SDR. This allowed us to assign more than 43 Megabases of contigs to sex chromosomes. By taking advantage of the several F1 families, we delineated a very short genomic region (~65 kilobases) that did not show evidence for recombination with the SDR. In this region, the comparison of sequencing depths between sexes outlined female-specific genes that may be involved in sex determination. Overall, our results provide strong evidence for an extremely low divergence of sex chromosomes in A. vulgare.
MeCP2 deficiency exacerbates the neuroinflammatory setting and autoreactive response during an autoimmune challenge: implications for Rett Syndrome

Background Rett syndrome is a severe and progressive neurological disorder linked to mutations in the MeCP2 gene located on the X chromosome. So far it has not been established how the presence of a mutant form of MeCP2 can maintain essential regulation of immune responses to support the normal homeostasis of individuals. Since MeCP2 is mostly expressed as a “partially functional” protein in humans with RTT, the aim of our work was to evaluate whether a mutation in MeCP2 interferes with the induction of neuroinflammatory responses in real time. Methods We used MeCP2308/y mouse model (MUT) and exposed it to an autoimmune challenge, experimental autoimmune encephalomyelitis (EAE). WT and MUT mice were immunized with CFA-MOG or CFA alone (control) and clinical scores were evaluated daily. Animals were sacrificed at either 12 days post-induction (dpi, acute stage) or 30 dpi (chronic stage) and spleen and spinal cord were collected from individual mice for further studies. Cellular infiltration and microgliosis was evaluated by IHC. Cytokine production was assessed in spinal cord and in cultured splenocytes after MOG activation ex-vivo by cytometry and real time RT-PCR. Results Our results showed that MeCP2 deficiency increased the susceptibility to develop EAE, along with a defective induction of anti-inflammatory responses and an exacerbated MOG-specific reactivity with high IFNγ expression in peripheral immune sites. During the chronic stage, an increase in gene expression of pro-inflammatory cytokines (IFNγ, TNFα and IL-1β) and downregulation of genes relevant for immune regulation (IL-10, FoxP3 and CX3CR1) was found in MUT-EAE spinal cords. Conclusions This is the first study performed in a MeCP2 mutant mouse model that explores the pathophysiology and neuroinflammation in the context of an autoimmune challenge. We could establish that an MeCP2 mutation act intrinsically affecting neuroimmune interactions by promoting an inflammatory environment and a deficient immune regulatory setting. These results are relevant for understanding the consequences of MeCP2 mutations on immune homeostasis in MeCP2-related disorders, as well as setting the bases for further therapeutic interventions that consider the immune status in patients.
Towards A 3D Chromosome Shape Alphabet

The study of the 3-dimensional (3D) structure of chromosomes – the largest macromolecules in biology – is one of the most challenging to date in structural biology. Here, we develop a novel representation of chromosomes, as sequences of shape letters from a finite shape alphabet, which provides a compact and efficient way to analyze ensembles of chromosome shape data, akin to the analysis of texts in a language by using letters. We construct a Chromosome Shape Alphabet (CSA) from an ensemble of chromosome 3D structures inferred from Hi-C data – via SIMBA3D or other methods – by segmenting curves based on topologically associating domains (TADs) boundaries, and by clustering all TADs’ 3D structures into groups of similar shapes. The median shapes of these groups, with some pruning and processing, form the Chromosome Shape Letters (CSLs) of the alphabet. We provide a proof-of-concept for these CSLs by reconstructing independent test curves using only CSLs (and corresponding transformations) and comparing these reconstructions with the original curves. Finally, we demonstrate how CSLs can be used to summarize the variability of shapes in an ensemble of chromosome 3D structures using generalized sequence logos.
Short sequence motif dynamics in the SARS-CoV-2 genome suggest a role for cytosine deamination in CpG reduction

RNA viruses use CpG reduction to evade the host cell defense, but the driving mechanisms are still largely unknown. In an attempt to address this we used a rapidly growing genomic dataset of SARS-CoV-2 with relevant metadata information. Remarkably, by simply ordering SARS-CoV-2 genomes by their date of collection, we find a progressive increase of C-to-U substitutions resulting in 5’-UCG-3’ motif reduction that in turn have reduced the CpG frequency over just a few months of observation. This is consistent with APOBEC-mediated RNA editing resulting in CpG reduction, thus allowing the virus to escape ZAP-mediated RNA degradation. Our results thus link the dynamics of target sequences in the viral genome for two known host molecular defense mechanisms, mediated by the APOBEC and ZAP proteins.
Genome diversity in Ukraine

The main goal of this collaborative effort is to provide genome wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for the public data release. DNBSEQ-G50 sequences, and genotypes by an Illumina GWAS chip were cross-validated on multiple samples, and additionally referenced to one sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. The genome data has been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, CNVs, SNPs and microsatellites. This study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for historic and medical research in a large understudied population. While most of the common variation is shared with other European populations, this survey of population variation contributes a number of novel SNPs and structural variants that have not been reported in the gnomAD/1KG databases representing global distribution of genomic variation. These endemic variants will become a valuable resource for designing future population and clinical studies, help address questions about ancestry and admixture, and will fill a missing place in the puzzle characterizing human population diversity in Eastern Europe. Our results indicate that genetic diversity of the Ukrainian population is uniquely shaped by the evolutionary and demographic forces, and cannot be ignored in the future genetic and biomedical studies. This data will contribute a wealth of new information bringing forth different risk and/or protective alleles. The newly discovered low frequency and local variants can be added to the current genotyping arrays for genome wide association studies, clinical trials, and in genome assessment of proliferating cancer cells.
Emerging fungal pathogen on an invasive grass differentially affects native species

Infectious diseases and invasive species are strong drivers of biological systems that may interact to shift plant community composition. Disease and invasion can each directly suppress native populations, but variation in responses among native species to disease, invasion, and their combined effects are not well characterized. Here, we quantified the responses of three native North American grass species to experimental inoculation with the fungal pathogen Bipolaris gigantea, which has recently emerged in populations of the invasive grass Microstegium vimineum, causing leaf spot disease. In a greenhouse experiment, we examined the direct effects of disease on the native species and the indirect effects of disease on the native species through altered competition with M. vimineum, which was planted at a range of densities. Pathogen inoculation directly affected each of the three native species in unique ways, by increasing, decreasing, or not changing their biomass relative to mock inoculation. Higher M. vimineum densities, however, reduced the biomass of all three native species, regardless of inoculation treatment, suggesting that disease had no indirect effects through altered competition. In addition, competition with M. vimineum suppressed native plant biomass to a greater extent than disease. The differential impacts of B. gigantea and the consistent impacts of M. vimineum on native species biomass suggest that disease may modify native plant community composition while plant invasion may suppress multiple native plant species in systems where these drivers co-occur.
Sex and estrogen receptor β have modest effects on gene expression in the mouse brain posterior cortex

Introduction Sex differences in brain cortical function affect cognition, behavior, and susceptibility to neural diseases, but the molecular basis of sexual dimorphism in cortical function is still largely unknown. Estrogen and estrogen receptors (ERs), specifically ERβ, the most abundant ER in the cortex, may play a role in determining sex differences in gene expression, which could underlie functional sex differences. However, further investigation is needed to address brain region specificity of the effects of sex and ERβ on gene expression. The goal of this study was to investigate sex differences in gene expression in the mouse posterior cortex, where sex differences in transcription have never been examined, and to determine how genetic ablation of ERβ affects transcription. Methods In this study, we performed unbiased transcriptomics on RNA from the posterior cortex of adult wild-type and ERβ knockout mice (n=4/sex/genotype). We used unbiased clustering to analyze whole-transcriptome changes between the groups. We also performed differential expression analysis on the data using DESeq2 to identify specific changes in gene expression. Results We found only 27 significantly differentially expressed genes (DEGs) in wild-type (WT) males vs females, of which 17 were autosomal genes. Interestingly, in ERβKO males vs females all the autosomal DEGs were lost. Gene Ontology analysis of the subset of DEGs with sex differences only in the WT cortex revealed a significant enrichment of genes annotated with the function ‘cation channel activity’. Moreover, within each sex we found only a few DEGs in ERβKO vs WT mice (8 and 5 in males and females, respectively). Conclusions Overall, our results suggest that in the adult mouse posterior cortex there are surprisingly few sex differences in gene expression, and those that exist are mainly related to cation channel activity. Additionally, they indicate that brain region-specific functional effects of ERβ may be largely post-transcriptional.
The influence of eye movements and their retinal consequences on bistable motion perception

Eye related movements such as blinks and microsaccades are modulated during bistable perceptual tasks, however, the role of such movements in these purely internal perceptual switches is not known. We conducted two experiments involving an ambiguous plaid stimulus, wherein participants had to continuously report their motion percept. To dissociate the effect of blinks and microsaccades from the visual consequences of such eye movements, we added external blanks and microshifts. Our results showed that while blanks facilitated a switch to the coherent motion percept, this was not the case for a switch to component percept. A similar difference was found with respect to blinks. While both types of perceptual switches were preceded by a decrease in blinks, only the switch to coherent percept was followed by an increase in blinks. These blink related findings, which we largely replicated and refined in a second study, indicate distinct internal processes underlying the two perceptual switches. Microsaccade rates, on the other hand, only showed a weak relation with perceptual switches but their direction was modulated by the perceived motion direction. Additionally, our data showed that microsaccades are differently modulated around internal (blinks) and external events (blanks, microshifts), indicating an interaction between different eye related movements. This study shows that eye movements such as blinks and microsaccades are modulated by purely internal perceptual events independent of task related motor or attentional demands. Eye movements therefore can uncover distinct internal perceptual processes that might otherwise be hard to dissociate.
Gene-Editing Technologies Paired With Viral Vectors for Translational Research Into Neurodegenerative Diseases

Diseases of the central nervous system (CNS) have historically been among the most difficult to treat using conventional pharmacological approaches. This is due to a confluence of factors, including the limited regenerative capacity and overall complexity of the brain, problems associated with repeated drug administration, and difficulties delivering drugs across the blood-brain barrier (BBB). Viral-mediated gene transfer represents an attractive alternative for the delivery of therapeutic cargo to the nervous system. Crucially, it usually requires only a single injection, whether that be a gene replacement strategy for an inherited disorder or the delivery of a genome- or epigenome-modifying construct for treatment of CNS diseases and disorders. It is thus understandable that considerable effort has been put towards the development of improved vector systems for gene transfer into the CNS. Different viral vectors are of course tailored to their specific applications, but they generally should share several key properties. The ideal viral vector incorporates a high-packaging capacity, efficient gene transfer paired with robust and sustained expression, lack of oncogenicity, toxicity and pathogenicity, and scalable manufacturing for clinical applications. In this review, we will devote attention to viral vectors derived from human immunodeficiency virus type 1 (lentiviral vectors; LVs) and adeno-associated virus (AAVs). The high interest in these viral delivery systems vectors is due to: (i) robust delivery and long-lasting expression; (ii) efficient transduction into postmitotic cells, including the brain; (iii) low immunogenicity and toxicity; and (iv) compatibility with advanced manufacturing techniques. Here, we will outline basic aspects of LV and AAV biology, particularly focusing on approaches and techniques aiming to enhance viral safety. We will also allocate a significant portion of this review to the development and use of LVs and AAVs for delivery into the CNS, with a focus on the genome and epigenome-editing tools based on clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas 9) and the development of novel strategies for the treatment of neurodegenerative diseases (NDDs).
An ancient, conserved gene regulatory network led to the rise of oral venom systems

Significance Although oral venom systems are ecologically important characters, how they originated is still unclear. In this study, we show that oral venom systems likely originated from a gene regulatory network conserved across amniotes. This network, which we term the “metavenom network,” comprises over 3,000 housekeeping genes coexpressed with venom and play a role in protein folding and modification. Comparative transcriptomics revealed that the network is conserved between venom glands of snakes and salivary glands of mammals. This suggests that while these tissues have evolved different functions, they share a common regulatory core, that persisted since their common ancestor. We propose several evolutionary mechanisms that can utilize this common regulatory core to give rise to venomous animals from their nonvenomous ancestors. Oral venom systems evolved multiple times in numerous vertebrates enabling the exploitation of unique predatory niches. Yet how and when they evolved remains poorly understood. Up to now, most research on venom evolution has focused strictly on the toxins. However, using toxins present in modern day animals to trace the origin of the venom system is difficult, since they tend to evolve rapidly, show complex patterns of expression, and were incorporated into the venom arsenal relatively recently. Here we focus on gene regulatory networks associated with the production of toxins in snakes, rather than the toxins themselves. We found that overall venom gland gene expression was surprisingly well conserved when compared to salivary glands of other amniotes. We characterized the “metavenom network,” a network of ∼3,000 nonsecreted housekeeping genes that are strongly coexpressed with the toxins, and are primarily involved in protein folding and modification. Conserved across amniotes, this network was coopted for venom evolution by exaptation of existing members and the recruitment of new toxin genes. For instance, starting from this common molecular foundation, Heloderma lizards, shrews, and solenodon, evolved venoms in parallel by overexpression of kallikreins, which were common in ancestral saliva and induce vasodilation when injected, causing circulatory shock. Derived venoms, such as those of snakes, incorporated novel toxins, though still rely on hypotension for prey immobilization. These similarities suggest repeated cooption of shared molecular machinery for the evolution of oral venom in mammals and reptiles, blurring the line between truly venomous animals and their ancestors.
Hsa-miR-155-5p Up-Regulation in Breast Cancer and Its Relevance for Treatment With Poly[ADP-Ribose] Polymerase 1 (PARP-1) Inhibitors

miR-155-5p is a well-known oncogenic microRNA, showing frequent overexpression in human malignancies, including breast cancer. Here, we show that high miR-155-5p levels are associated with unfavorable prognostic factors in two independent breast cancer cohorts (CSS cohort, n = 283; and TCGA-BRCA dataset, n = 1,095). Consistently, miR-155-5p results as differentially expressed in the breast cancer subgroups identified by the surrogate molecular classification in the CSS cohort and the PAM50 classifier in TCGA-BRCA dataset, with the TNBC and HER2-amplified tumors carrying the highest levels. Since the analysis of TCGA-BC dataset also demonstrated a significant association between miR-155-5p levels and the presence of mutations in homologous recombination (HR) genes, we hypothesized that miR-155-5p might affect cell response to the PARP-1 inhibitor Olaparib. As expected, miR-155-5p ectopic overexpression followed by Olaparib administration resulted in a greater reduction of cell viability as compared to Olaparib administration alone, suggesting that miR-155-5p might induce a synthetic lethal effect in cancer cells when coupled with PARP-1-inhibition. Overall, our data point to a role of miR-155-5p in homologous recombination deficiency and suggest miR-155-5p might be useful in predicting response to PARP1 inhibitors in the clinical setting.