Miracle-dz/UniFAR-FTUs huggingface dataset:
Sensory neuron-associated macrophages proliferate in the sensory ganglia after peripheral nerve injury in a CX3CR1 signaling dependent manner

Resident macrophages are distributed across all tissues and are highly heterogeneous as a consequence of adaptation to different tissue-specific environments. The resident macrophages of the sensory ganglia (sensory neuron-associated macrophages, sNAMs) are in close contact with the cell body of primary sensory neurons and might play physiological and pathophysiological roles. After peripheral nerve injury, there is an increase in the population of macrophages in the sensory ganglia which have been involved in different conditions, especially in neuropathic pain development and nerve regeneration. However, it is still under debate whether macrophages accumulation in the sensor ganglia after peripheral nerve injury is due to the local proliferation of resident macrophages or as a result of blood monocytes infiltration. Here, we confirmed that the number of macrophages increased in the DRGs after spared nerve injury (SNI) model in mice. By using different approaches, we found that the increase in the number of macrophages in the DRGs after SNI is mainly in consequence of the proliferation of resident CX3CR1+ macrophages but not due to infiltration of CCR2+ blood monocytes. These proliferating macrophages are the source of the production of pro-inflammatory cytokines such as TNF and IL-1b. In addition, we found that CX3CR1 signaling is involved in the sNAMs proliferation after peripheral nerve injury. In summary, these results indicated that peripheral nerve injury leads to sNAMs proliferation in the sensory ganglia in a CX3CR1-dependent manner. In conclusion, sNAMs proliferation could be modulated to change pathophysiological conditions such as chronic neuropathic pain and/or nerve regeneration.
Cellular mechanisms underlying central sensitization in a mouse model of chronic muscle pain

Chronic pain disorders are often associated with psychiatric symptoms. The central nucleus of the amygdala (CeA) has emerged as an integrative hub for nociceptive and affective components during the development of central pain. Although the exact cause for this process remains unknown, prior adverse injuries are precipitating factors and thought to transform nociceptors into a primed state for chronic pain. However, the cellular basis underlying the primed state and the subsequent pain chronification remains unknown. Here, we investigated cellular and synaptic alterations of the CeA in a mouse model of chronic muscle pain. In these mice, local infusion of pregabalin, a clinically approved drug for fibromyalgia and other chronic pain disorders, into the CeA or selective inactivation of somatostatin-expressing CeA (CeA-SST) neurons during the priming phase prevented pain chronification. Further, electrophysiological recording revealed that CeA-SST neurons received increased excitatory transmission and showed enhanced excitability in chronic pain states. In line with the possible role of CeA-SST neurons in central sensitization, chemogenetic inactivation of CeA-SST neurons or pharmacological suppression of nociceptive afferents from the brainstem to CeA-SST neurons by pregabalin after the development of chronic muscle pain alleviated pain and negative emotions.
The genomics and physiology of abiotic stressors associated with global elevation gradients in Arabidopsis thaliana

Arabidopsis thaliana has a wide elevational range and much of its diversity may be associated with local adaptation to elevation. We took a multi-regional view of the genomics and physiology of elevational adaptation in Arabidopsis, with >200 ecotypes, including 17 newly collected from Africa. We measured plant responses to potential high elevation stressors: low pCO 2 , high light, and night freezing and conducted genome-wide association studies (GWAS). We found evidence of an adaptive cline in the western Mediterranean with low δ 13 C/early flowering at low elevations to high δ 13 C/late flowering at high elevations. By contrast, central Asian high elevation ecotypes flowered earlier. Antioxidants and pigmentation under high light and freezing showed regional differentiation but not elevational clines and may be associated with maladaptive plasticity. We found natural variation in non-photochemical quenching (NPQ) kinetics in response to chilling and fluctuating light, though with an unclear role in local adaptation. There were several candidate genetic loci mapped, including the ascorbate transporter PHT4;4 (associated with antioxidants) that influences the xanthophyll cycle, and may be involved in local adaptation to Morocco. Our study shows how the ecological strategies and genetic loci causing local adaptation to elevation change across regions and contribute to diversity in Arabidopsis. climatic gradients and tested for adaptive elevational clines in four geographic regions: the western Mediterranean, Europe, central Asia, and eastern Africa (including previously unstudied populations). We performed genome-wide association studies (GWAS) to map loci causing trait variation and tested if selection maintains trait variation. We tested the following hypotheses: Statistical analysis Data were tested with the Brown–Forsythe test for homogeneity of variance and the Shapiro–Wilk test for normality. If either test discarded the null hypothesis, data were transformed, or a Wilcoxon non-parametric test was applied followed by a Kruskal-Wallis test. One-way analysis of variance was applied to gas exchange and fluorescence data, photosynthesis-related pigments, and biomass. light intensity of 50 and 500 μmol m -2 s -1 , respectively (unit less); R d - mitochondrial respiration rate in the light estimated from intercept of the A / Q response (μmol m -2 s -1 ); Φ CO 2max – maximum quantum efficiency of leaf net CO 2 assimilation estimated from initial slope of A / Q curve (CO 2 / photon); Φ PSII max – maximum quantum efficiency of linear electron transport estimated from the initial linear part of the J / Q curves (e - / photon).
Pin1-promoted SUMOylation of RNF168 restrains its chromatin accumulation

The E3 ubiquitin ligase RNF168 is a rate-limiting component of DNA double-strand break signalling that acts to amplify histone ubiquitylation. The confining of RNF168 chromatin spreading around DNA break sites has been related to constraining its expression levels and to the removal of ubiquitin-conjugates to which it binds. Here we identify a new mechanism that suppresses RNF168 amplification at chromatin. We show that depletion of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) or mutation of the Pin1-binding site of RNF168 increases DNA-damage site accumulation of RNF168 to supraphysiological levels without impacting RNF168 expression levels. Pin1 promotes SUMOylation of RNF168 by SUMO2/3, and a SUMO conjugation site on RNF168 is required to restrict RNF168 accumulations. We find Pin1-SUMO mediated-regulation of RNF168 is associated with cellular radioresistance. These data demonstrate that the regulation of chromatin ubiquitylation is actively suppressed by modification of RNF168 to counteract excessive RNF168-ubiquitin spreading.
Ontology-Aware Biomedical Relation Extraction

Motivation Automatically extracting relationships from biomedical texts among multiple sorts of entities is an essential task in biomedical natural language processing with numerous applications, such as drug development or repurposing, precision medicine, and other biomedical tasks requiring knowledge discovery. Current Relation Extraction (RE) systems mostly use one set of features, either as text, or more recently, as graph structures. The state-of-the-art systems often use resource-intensive hence slow algorithms and largely work for a particular type of relationship. However, a simple yet agile system that learns from different sets of features has the advantage of adaptability over different relationship types without an extra burden required for system re-design. Results We model RE as a classification task and propose a new multi-channel deep neural network designed to process textual and graph structures in separate input channels. We extend a Recurrent Neural Network (RNN) with a Convolutional Neural Network (CNN) to process three sets of features, namely, tokens, types, and graphs. We demonstrate that entity type and ontology graph structure provide better representations than simple token-based representations for RE. We also experiment with various sources of knowledge, including data resources in the Unified Medical Language System (UMLS) to test our hypothesis. Extensive experiments on four well-studied biomedical benchmarks with different relationship types show that our system outperforms earlier ones. Thus, our system has state-of-the-art performance and allows processing millions of full-text scientific articles in a few days on one typical machine.
B cell receptor repertoire analysis unveils dynamic antibody response and severity markers in COVID-19 patients

Humoral and cell mediated immunity are critical against viral infections. The knowledge of composition, diversity, gene usage of the B cell repertoires helps in determining the immune response to SARS-CoV-2 infection. Examining B cell response provides insights on therapeutic antibodies, disease severity markers and aids in predicting vaccine response. We have analyzed public domain immunoglobulin sequencing data from PBMCs of SARS-CoV-2 infected individuals to gain a better understanding of B cell repertoire in patients. Public clonotypes showed increased usage of IGHV3, IGHV4, IGKV1, IGKV3, IGLV3 and IGLV2 family genes during the acute phase infection. Identical CDR3 sequences were identified for heavy (H), kappa (K) and lambda (L) chains across individuals, indicating the convergence of B cell selection during SARS-CoV-2 infection. While the immune repertoire dynamically changed over the course of convalescence, there were persistent clones across early and late timepoints. The diversity of antibody repertoire, measured by Shannon-Weiner diversity index for H and K chains, reduced during the acute phase of infection. In addition, the repertoire diversity was low in severe patients compared to patients with mild or moderate symptoms. Increased usage of IGHV4-59 gene was observed in COVID-19 patients with severe symptoms requiring ventilator support at 2 weeks and 3 weeks post symptom onset. IGHV4-59 is reported to have rheumatoid factor (RF) activity with high affinity for IgG and the elevated level of IGHV4-59 provides a potential mechanism for the increased autoimmune responses in severe patients. Correlation of the clinical features with the B cell receptor repertoire dynamics elucidated public antibody clonotypes and disease severity markers for COVID-19.
Particle-Swarm Based Modelling Reveals Two Distinct Classes of CRHPVN Neurons

Electrophysiological recordings can provide detailed information of single neurons’ dynamical features and shed light into their response to stimuli. Unfortunately, rapidly modeling electrophysiological data for inferring network-level behaviours remains challenging. Here, we investigate how modeled single neuron dynamics lead to network-level responses in the paraventricular nucleus of the hypothalamus (PVN), a critical nucleus for the mammalian stress response. Recordings of corticotropinreleasing hormone neurons from the PVN (CRHPVN) were performed using whole-cell current-clamp. These, neurons, which initiate the endocrine response to stress, were rapidly and automatically fit to a modified Adaptive Exponential Integrate and Fire model (AdEx) with Particle Swarm Optimization (PSO). All CRHPVN neurons were accurately fit by the AdEx model with PSO. Multiple sets of parameters were found that reliably reproduced current-clamp traces for any single neuron. Despite multiple solutions, the dynamical features of the models such as the rheobase current levels, fixed points, and bifurcations, were shown to be stable across fits. We found that CRHPVN neurons can be divided into two sub-types according to their bifurcation at the onset of firing: saddles (integrators) and sub-critical Hopf (resonators). We constructed networks of these fit CRHPVN model neurons to investigate the network level responses of CRHPVN neurons. We found that CRHPVN-resonators maintain baseline firing in networks even when all inputs are inhibitory. The dynamics of a small subset of CRHPVN neurons may be critical to maintaining a baseline firing tone in the PVN. Key Points Corticotropin-releasing hormone neurons (CRHPVN) in the paraventricular nucleus of the hypothalamus act as the final neural controllers of the stress response. We developed a rapid computational modeling platform that uses Particle-Swarm Optimization to rapidly and accurately fit biophysical neuron models. A model was fit to each patched neuron without the use of dynamic clamping, or other procedures requiring sophisticated inputs and fitting procedures. Any neuron undergoing standard current clamping for a few minutes can be fit by this procedure The dynamical analysis of the modeled neurons shows thatCRHPVN comes in two specific ‘flavours’: CRHPVN-resonators and CRHPVN-integrators. Network simulations show thatCRHPVN-resonators are critical to retaining the baseline firing rate of the entire network of CRHPVN neurons as these cells can fire rebound spikes and bursts in the presence of strong inhibitory synaptic input.
IsarPipeline: Combining MMseqs2 and PSI-BLAST to Quickly Generate Extensive Protein Sequence Alignment Profiles

Many of the machine learning (ML) models used in the field of bioinformatics and computational biology to predict either function or structure of proteins rely on the evolutionary information as summarized in multiple-sequence alignments (MSAs) or the resulting position-specific scoring matrices (PSSMs), as generated by PSI-BLAST. The current procedure used in protein structure and function prediction is computationally exhaustive and time-consuming. The main issue relies on the PSI-BLAST software being forced to load the current database of sequences (about 220 GB) in batches and search for similar sequence alignments to a query sequence. This leads to an average runtime of about 40-60 min for a medium-sized (450 Amino Acids) query protein. This average runtime is strictly dependent on the hardware used to run the software. The issue is becoming more problematic since the bio-sequence data pools are increasing in size exponentially over time, hence raising PSI-BLAST runtime as well. A prominent solution claims to speed up the current process by 100 folds. The MMseqs2 method, given enough memory, will load the whole database in memory and apply certain heuristics to retrieve the relevant set of aligned sequences. However, this solution cannot be used directly to generate the final output in the desired PSI-BLAST alignment and PSSM profile data format. In this research project, we analyzed the runtime performance of each tool separately. Furthermore, we built a pipeline that combines both MMseqs2 and PSI-BLAST to obtain a robust, optimized and very fast hybrid alignment tool, faster than PSI-BLAST by two orders of magnitude. It is implemented in C++ and is freely available under the MIT license at https://github.com/issararab/IsarPipeline. The output of our pipeline was evaluated on two previously built predictive models.
Recognition of copy-back defective interfering rabies virus genomes by RIG-I triggers the antiviral response against vaccine strains

Rabies virus (RABV) is a lethal neurotropic virus that causes 60,000 human deaths every year around the world. A typical feature of RABV infection is the suppression of type I and III interferon (IFN)-mediated antiviral response. However, molecular mechanisms leading to RABV sensing by RIG-I-like receptors (RLR) to initiate IFN signaling remain elusive. Here, we showed that RABV RNAs are recognized by RIG-I (retinoic acid-inducible gene I) sensor resulting in an IFN response of the infected cells but that this global feature was differently modulated according to the type of RABV used. RNAs from pathogenic RABV strain, THA, were poorly detected in the cytosol by RIG-I and therefore mediated a weak antiviral response. On the opposite, we revealed a strong interferon activity triggered by the RNAs of the attenuated RABV vaccine SAD strain mediated by RIG-I. Using next-generation sequencing (NGS) combined with bioinformatics tools, we characterized two major 5’copy-back defective interfering (5’cb DI) genomes generated during SAD replication. Furthermore, we identified a specific interaction of 5’cb DI genomes and RIG-I that correlated with a high stimulation of the type I IFN signaling. This study indicates that RNAs from a wild-type RABV poorly activate the RIG-I pathway, while the presence of 5’cb DIs in vaccine SAD strain serves as an intrinsic adjuvant that strengthens its efficiency by enhancing RIG-I detection and therefore strongly stimulates the IFN response. Highlights RABV pathogenic strain replication in vitro is characterized by the absence of defective interfering genomes thus induces a weak RLR-mediated innate immunity antiviral response. RABV vaccine attenuated strain shows a high release of 5’ copy-back defective interfering genomes during replication in vitro and therefore enhances a strong antiviral response upon infection. RIG-I is the main sensor for RABV RNA detection within cells.
Ubiquitin ligase TRAIP plays an essential role during the S-phase of unperturbed cell cycle in the resolution of DNA replication – transcription conflicts

Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, for the first time, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We find that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.
Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes

Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. Consequently, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated. We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion channel families. We collected and curated 3,049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12,546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures. We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our novel 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis center and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and fucntional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate (NMDA) receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1,422 neurodevelopmental disorder pathogenic patient variants, and 679 electrophysiological experiments that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain vs. loss-of-channel function. In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional read-outs and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.
Controlled Synthesis of Small Water-Soluble Hybrid Gold Nanoparticles: An Optimized Strategy for Stable Nano-Dispersion and Towards Cellular Uptake

The development of effective drug delivery systems is one of the major challenges in the fight against cancer. Gold nanoparticles could effectively harness cancer therapies by improving their potency while reducing toxic side effects. In this work, we describe a high-yield one-step synthesis of small water-soluble gold nanoparticles (AuNPs). Efficient purification was monitored, and discrete structure was fully characterized by combining molecular analytical technics (UV-visible and NMR spectroscopies) and solid-state analyses (thermal gravimetric analysis and transmission electron microscopy). These AuNPs have good dispersibility in various biocompatible media and can be used without any additives. Preliminary study with in vitro treatment of IB115 human cancer cells showed massive cellular uptake associated to moderate intrinsic cytotoxicity. The high control of the synthesis and the small size of these AuNPs are offering fine surface properties control, crucial for challenging biological nano-dispersion issues. Thus, limitation of the agglomeration of nanoparticles and improvement of interaction with the surface of cell should open new leads for vectorization of drugs or imaging probes for diagnosis.