Miracle-dz/UniFAR-FTUs huggingface dataset:
Plasticity after cortical stroke involves potentiating responses of pre-existing circuits but not functional remapping to new circuits

Functional recovery after stroke is thought to be mediated by adaptive circuit plasticity, whereby surviving neurons assume the roles of those that died. This “remapping” hypothesis is based on human brain mapping studies showing apparent reorganization of cortical sensorimotor maps and animal studies documenting molecular and structural changes that could support circuit rewiring. However, definitive evidence of remapping is lacking, and other studies have suggested that maladaptive plasticity mechanisms, such as enhanced inhibition in peri-infarct cortex, might actually limit plasticity after stroke. Here we sought to directly test whether neurons can change their response selectivity after a stroke that destroys a single barrel (C1) within mouse primary somatosensory cortex. Using multimodal in vivo imaging approaches, including two-photon calcium imaging to longitudinally record sensory-evoked activity in peri-infarct cortex before and after stroke, we found no evidence to support the remapping hypothesis. In an attempt to promote plasticity via rehabilitation, we also tested the effects of forced use therapy by plucking all whiskers except the C1 whisker. Again, we failed to detect an increase in the number of C1 whisker-responsive neurons in surrounding barrels even 2 months after stroke. Instead, we found that forced use therapy potentiated sensory-evoked responses in a pool of surviving neurons that were already C1 whisker responsive by significantly increasing the reliability of their responses. Together, our results argue against the long-held theory of functional remapping after stroke, but support a plausible circuit-based mechanism for how rehabilitation may improve recovery of function.
Antibiotic resistance among Escherichia coli and Salmonella isolated from dairy cattle feces in Texas

This study was conducted to develop and field-test a low cost protocol to estimate the isolate- and sample-level prevalence of resistance to critically important antibiotic drugs among Escherichia coli and Salmonella isolated from dairy cattle feces. E. coli and Salmonella were isolated from and screened on selective media, with and without antibiotics respectively. Bacterial isolates were further tested for susceptibility to a suite of antibiotics using disk diffusion. Molecular methods were performed on select bacterial isolates to identify and distinguish genetic determinants associated with the observed phenotypes. Among 85 non-type-specific E. coli randomly isolated from MacConkey agar without antibiotics, the isolate-level prevalence of resistance to tetracycline was the highest (8.2%), there was no isolate resistant to third-generation cephalosporin (0.0%) and one isolate was resistant to nalidixic acid (1.2%). Among 37 E. coli recovered from MacConkey agar with cefotaxime at 1. 0µg/ml, 100% were resistant to ampicillin and 56.8% were resistant to a third-generation cephalosporin (ceftriaxone). Among 22 E. coli isolates recovered from MacConkey agar with ciprofloxacin at 0. 5µg/ml, 90.9% were resistant to tetracycline whereas 77.3% and 54.5% were resistant to nalidixic acid and ciprofloxacin respectively. Sixteen Salmonella were isolated and only one demonstrated any resistance (i.e., single resistance to streptomycin). Among E. coli isolates that were either resistant or intermediate to ceftriaxone, an AmpC phenotype was more common than an extended spectrum beta-lactamase (ESBL) phenotype (29 versus 10 isolates, respectively). Among 24 E. coli isolates that were whole genome sequenced, phenotypic profiles of antibiotic resistance detected were generally substantiated by genotypic profiles. For instance, all isolates with an AmpC phenotype carried a blaCMY2 gene. The protocol used in this study is suited to detecting and estimating prevalence of antimicrobial resistance in bacteria isolated from food animal feces in resource-limited laboratories in the developing world.
Gain-of-function assay for SARS-CoV-2 Mpro inhibition in living cells

The main protease, Mpro, of SARS-CoV-2 is required to cleave the viral polyprotein into precise functional units for virus replication and pathogenesis. Here we demonstrate a quantitative reporter for Mpro function in living cells, in which protease inhibition by genetic or chemical methods results in strong eGFP fluorescence. This robust gain-of-function system readily distinguishes between inhibitor potencies and can be scaled-up to high-throughput platforms for drug testing.
The Worldwide Invasion of Drosophila suzukii Is Accompanied by a Large Increase of Transposable Element Load and a Small Number of Putatively Adaptive Insertions

Transposable Elements (TEs) are ubiquitous and mobile repeated sequences. They are major determinants of host fitness. Here, we portrayed the TE content of the spotted wing fly Drosophila suzukii. Using a recently improved genome assembly, we reconstructed TE sequences de novo, and found that TEs occupy 47% of the genome and are mostly located in gene poor regions. The majority of TE insertions segregate at low frequencies, indicating a recent and probably ongoing TE activity. To explore TE dynamics in the context of biological invasions, we studied variation of TE abundance in genomic data from 16 invasive and six native populations (of D. suzukii). We found a large increase of the TE load in invasive populations correlated with a reduced Watterson estimate of genetic diversity a proxy of effective population size. We did not find any correlation between TE contents and bio-climatic variables, indicating a minor effect of environmentally induced TE activity. A genome-wide association study revealed that ca. 5,000 genomic regions are associated with TE abundance. We did not find, however, any evidence in such regions of an enrichment for genes known to interact with TE activity (e.g. transcription factor encoding genes or genes of the piRNA pathway). Finally, the study of TE insertion frequencies revealed 15 putatively adaptive TE insertions, six of them being likely associated with the recent invasion history of the species.
African Swine Fever Virus CD2v protein promotes β-Interferon expression and apoptosis in swine cells

African swine fever (ASF) is a disease of swine characterized by massive lymphocyte depletion in lymphatic tissues due to apoptosis of B and T cells, most likely triggered by proteins or factors secreted by infected adjacent macrophages. Here we describe a role for the ASF virus (ASFV) protein CD2v in apoptosis induction in lymphocytes. CD2v is a viral homolog of host CD2 that has been implicated in viral virulence and immunomodulation in vitro; however, its actual function remains unknown. We show that CD2v is secreted into culture medium of CD2v-expressing swine cells; and expression of-or treatment with CD2v led to significant induction of IFN-β/ISGs transcription and antiviral state. CD2v expression led to enhanced NF-κB-p65 nuclear translocation in these cultures and incubation with a NF-κB inhibitor reduced CD2v-induced NF-κB-p65 nuclear translocation and IFN-β transcription. We show that CD2v binds CD58, the natural CD2 ligand, and that CD58 siRNA knock-down results in significant reduction in NF-κB-p65 nuclear translocation and IFN-β transcription. Treatment of swine PBMC with purified CD2v led to enhanced NF-κB-p65 nuclear translocation and induction of IFN-β transcription. Further, induction of caspase-3 and PARP1 cleavage was observed in these swine PBMC at later times, providing a mechanism for CD2v-induced apoptosis of lymphocytes. Finally, IFN-β induction and NF-κB activation was inhibited in swine PBMC treated with purified CD2v pre-incubated with antibodies against CD2v. Overall, our results indicate that ASFV CD2v is an immunomodulatory protein that, by promoting lymphocyte apoptosis, may contribute to bystander lymphocyte depletion observed during ASFV infection in pigs. IMPORTANCE ASF, a severe hemorrhagic disease of domestic swine, represents a significant economic threat to swine industry worldwide. One critical pathological event observed in pigs infected with virulent isolates is an extensive destruction of lymphoid tissue and massive lymphocyte depletion. However, viral factor/s involved in this event are yet to be identified. Here we show that, by inducing NF-κB-dependent IFN signaling, ASFV CD2v is able to promote apoptosis in swine PBMC. We propose that CD2v released by ASFV-infected macrophages contributes to the massive depletion of lymphocytes observed in lymphoid tissues of infected pigs. Results here improve our understanding of ASFV pathogenesis and will encourage novel intervention approaches.
Interpretation of network-based integration from multi-omics longitudinal data

Cost reduction of high-throughput technologies has enabled the monitoring of the same biological sample across multiple omics studies and multiple timepoints. The goal is to combine longitudinal multi-omics data to detect temporal relationships between molecules and interactions between omics layers. This can finally lead to uncover new regulation mechanisms and interactions that could be responsible for causing complex phenotype or disease. However multi-omics integration of diverse omics data is still challenging due to heterogeneous data and designs. Moreover, interpretation of multi-omics models is the key to understand biological systems. We propose a generic analytic and integration framework for multi-omics longitudinal datasets that consists of multi-omics kinetic clustering and multi-layer network-based analysis. This frame-work was successfully applied to two case studies with different experimental designs and omics data collected. The first case studied transcriptomic and proteomic changes during cell cycle in human HeLa cells, while the second focused on maize transcriptomic and metabolomic response to aphid feeding. Propagation analysis on multi-layer networks identifies regulatory mechanisms and function prediction for both case studies. Our framework has led to the identification of new multi-layer interactions involved in key biological functions that cannot be revealed with single omics analysis and interplay in the kinetics that could help identify novel biological mechanisms.
Theta rhythmicity governs the timing of behavioral and hippocampal responses in humans specifically during memory-dependent tasks

Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding or retrieval of cue-object associative memories. We found no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz), while responses from later forgotten trials do not lock to the behavioral oscillation. Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but only for correctly remembered trials, providing a mechanistic underpinning for the theta oscillations found in behavioral responses.
Water-immersion finger-wrinkling improves grip efficiency in handling wet objects

For most people, immersing their hands in water leads to wrinkling of the skin of the fingertips. This phenomenon is very striking, yet we know little about why it occurs. It has been proposed that the wrinkles act to distribute water away from the contact surfaces of the fingertip, meaning that wet objects can be grasped more readily. This study examined the coordination between the grip force used to hold an object and the load force exerted on it, when participants used dry or wrinkly fingers, or fingers that were wet but not wrinkly. The results showed that wrinkly fingers reduce the grip force needed to grip a wet object, bringing that force in line with what is needed for handling a dry object. The results suggest that enhancing grip force efficiency in watery environments is a possible adaptive reason for the development of wrinkly fingers.
A Mycobacterium tuberculosis effector protein attacks host innate immunity by acting as an unusual ubiquitinating enzyme

Protein kinase G (PknG), a eukaryotic type serine-threonine protein kinase (STPK) in Mycobacterium tuberculosis (Mtb), is secreted into the cytosol of infected macrophages to promote intracellular survival of mycobacteria and has been considered as a promising therapeutic target for tuberculosis (TB) treatment. However, the molecular details of Mtb PknG-host intracellular interactions remain obscure. Here, we demonstrate that PknG serves as both the ubiquitin-activating enzyme (E1) and the ubiquitin ligase (E3) to promote ubiquitination and degradation of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TGF–β-activated kinase 1 (TAK1), and thus inhibits the NF-κB-mediated host innate immune responses. Surprisingly, PknG promotes the attachment of ubiquitin (Ub) to ubiquitin-conjugating enzyme (E2) UbcH7 via an isopeptide bond (UbcH7 K82-Ub), instead of a usual C86-Ub thiol-ester bond, and then promotes the discharge of Ub from UbcH7 by acting as an isopeptidase before attaching Ub to its substrates TRAF2 and TAK1. These results demonstrate that Mtb PknG promotes ubiquitination of the key components of the host innate immunity by acting as an unusual ubiquitinating enzyme to suppress innate immunity. Our findings provide a potential TB treatment via targeting unconventional ubiquitinating activities of PknG. Significance Mycobacterium tuberculosis (Mtb) protein kinase G (PknG), which is critical for Mtb intracellular survival, is a promising target for tuberculosis (TB) treatment. However, the molecular mechanisms underlying PknG-host interactions remain largely unclear. Here we demonstrate that PknG serves as both the ubiquitin-activating enzyme and the ubiquitin ligase to promote the ubiquitination and degradation of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TGF-β-activated kinase 1 (TAK1), thus inhibiting NF-κB signaling activation. PknG promotes the attachment of ubiquitin to ubiquitin-conjugating enzyme UbcH7 via an isopeptide bond, instead of a usual thiol-ester bond, and releases the ubiquitin from UbcH7 by acting as an isopeptidase. These findings provide important information for rational development of TB treatment via targeting unconventional ubiquitinating activity of PknG.
Neutrophil Extracellular Traps Induce the Epithelial-Mesenchymal Transition: Implications in Post-COVID-19 Fibrosis

The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19. Neutrophils activated with PMA (PMA-Neu), a stimulus known to induce NETs formation, induce both EMT and cell death in the lung epithelial cell line, A549. Notably, NETs isolated from PMA-Neu induce EMT without cell damage. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs. Thus, we tested in an in vitro alveolar model the hypothesis that virus-induced NET may drive EMT. Co-culturing A549 at air-liquid interface with alveolar macrophages, neutrophils and SARS-CoV2, we demonstrated a significant induction of the EMT in A549 together with high concentration of NETs, IL8 and IL1β, best-known inducers of NETosis. Lung tissues of COVID-19 deceased patients showed that epithelial cells are characterized by increased mesenchymal markers. These results show for the first time that NETosis plays a major role in triggering lung fibrosis in COVID-19 patients.
Evaluating and Improving SSU rRNA PCR Primer Coverage via Metagenomes from Global Ocean Surveys

Small subunit ribosomal RNA (SSU rRNA) amplicon sequencing comprehensively profiles microbiomes, but results will only be accurate if PCR primers perfectly match environmental sequences. To evaluate whether primers commonly used in microbial oceanography match naturally-occurring organisms, we compared primers with > 300 million rRNA sequences retrieved from globally-distributed metagenomes. The best-performing 16S primers were 515Y/926R and 515Y/806RB which perfectly matched most sequences (~0.95). Considering Cyanobacteria/Chloroplast 16S, 515Y/926R had the highest coverage (0.99), making it ideal for quantifying phytoplankton. For 18S sequences, 515Y/926R performed best (0.88), followed by V4R/V4RB (18S-specific; 0.82). Using Atlantic and Pacific BioGEOTRACES field samples, we demonstrate high correspondence between 515Y/926R amplicons (generated as part of this study) and metagenomic 16S rRNA (median R2=0.98, n=272), indicating amplicons can produce equally accurate community composition data versus shotgun metagenomics. Since our pipeline identifies missed taxa, we suggest modifications to improve coverage of biogeochemically-important oceanic microorganisms - a strategy applicable to any environment with metagenomic data. Significance Statement Quantification of taxonomically-informative marker genes using PCR amplification and high-throughput sequencing is a low-cost technique for monitoring distributions and changes of microbial communities across space and time. In order to maximize this procedure’s effectiveness, it is essential that environmental organisms match PCR primer sequences exactly. In this study, we developed a software pipeline to evaluate how well commonly-used primers match primer-binding regions from globally-distributed short-read oceanic metagenomes. Our results demonstrate common primer sets vary widely in performance, and that including additional degenerate bases is a simple strategy to maximize environmental coverage. Written in the reproducible snakemake workflow language and publicly accessible, our pipeline provides a general-purpose tool to guide rational design of PCR primers for any environment with metagenomic data.
emiRIT: a text-mining-based resource for microRNA information

Motivation microRNAs (miRNAs) are essential gene regulators and their dysregulation often leads to diseases. Easy access to miRNA information is crucial for interpreting generated experimental data, connecting facts across publications, and developing new hypotheses built on previous knowledge. Here, we present emiRIT, a text mining-based resource, which presents miRNA information mined from the literature through a user-friendly interface. Results We collected 149,233 miRNA-PubMed ID pairs from Medline between January 1997 to May 2020. emiRIT currently contains miRNA-gene regulation (60,491 relations); miRNA-disease (cancer) (12,300 relations); miRNA-biological process and pathways (23,390 relations); and circulatory miRNAs in extracellular locations (3,782 relations). Biological entities and their relation to miRNAs were extracted from Medline abstracts using publicly available and in-house developed text mining tools, and the entities were normalized to facilitate querying and integration. We built a database and an interface to store and access the integrated data, respectively. Conclusion We provide an up-to-date and user-friendly resource to facilitate access to comprehensive miRNA information from the literature on a large-scale, enabling users to navigate through different roles of miRNA and examine them in a context specific to their information needs. To assess our resource’s information coverage, in the absence of gold standards, we have conducted two case studies focusing on the target and differential expression information of miRNAs in the context of diseases. Database URL: https://research.bioinformatics. udel.edu/emirit/
Age-dependent contribution of domain-general network interactions to semantic cognition

Aging is characterized by a decline of cognitive control. In semantic cognition, this leads to the paradox that older adults usually show poorer task performance than young adults despite their greater semantic knowledge. So far, the underlying neural changes of these behavioral differences are poorly understood. In the current neuroimaging study, we investigated the interplay of domain-specific and domain-general networks in young and older adults during a verbal semantic fluency task. In both age groups, task processing was characterized by a strong interaction between the domain-general multiple-demand and the default mode system during semantic fluency. However, the behavioral relevance of strengthened connectivity differed between groups: While within- and between-network functional connectivity predicted better performance in young adults, these increases were associated with a performance decline in older adults. Our findings lend novel support to the notion of reduced efficiency in the aging brain, due to neural dedifferentiation in semantic cognition.
Dilp8 controls a time window for tissue size adjustment in Drosophila

The control of organ size mainly relies on precise autonomous growth programs. However, organ development is subject to random variations, called developmental noise, best revealed by the fluctuating asymmetry observed between bilateral organs. The developmental mechanisms ensuring bilateral symmetry in organ size are mostly unknown. In Drosophila, null mutations for the relaxin-like hormone Dilp8 increase wing fluctuating asymmetry, suggesting that Dilp8 plays a role in buffering developmental noise. Here we show that size adjustment of the wing primordia involves a peak of Dilp8 expression that takes place sharply at the end of juvenile growth. Wing size adjustment relies on a crossorgan communication involving the epidermis as the source of Dilp8. We identify ecdysone signaling as both the trigger for epidermal dilp8 expression and its downstream target in the wing primordia, thereby establishing reciprocal feedback between the two hormones as a systemic mechanism controlling organ size precision. Our results reveal a hormone-based time window ensuring fine-tuning of organ size and bilateral symmetry.