Miracle-dz/UniFAR-FTUs huggingface dataset:
The discovery of gene mutations making SARS-CoV-2 well adapted for humans: host-genome similarity analysis of 2594 genomes from China, the USA and Europe

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded virus approximately 30 kb in length, causes the ongoing novel coronavirus disease-2019 (COVID-19). Studies confirmed significant genome differences between SARS-CoV-2 and SARS-CoV, suggesting that the distinctions in pathogenicity might be related to genomic diversity. However, the relationship between genomic differences and SARS-CoV-2 fitness has not been fully explained, especially for open reading frame (ORF)-encoded accessory proteins. RNA viruses have a high mutation rate, but how SARS-CoV-2 mutations accelerate adaptation is not clear. This study shows that the host-genome similarity (HGS) of SARS-CoV-2 is significantly higher than that of SARS-CoV, especially in the ORF6 and ORF8 genes encoding proteins antagonizing innate immunity in vivo. A power law relationship was discovered between the HGS of ORF3b, ORF6, and N and the expression of interferon (IFN)-sensitive response element (ISRE)-containing promoters. This finding implies that high HGS of SARS-CoV-2 genome may further inhibit IFN I synthesis and cause delayed host innate immunity. An ORF1ab mutation, 10818G>T, which occurred in virus populations with high HGS but rarely in low-HGS populations, was identified in 2594 genomes with geolocations of China, the USA and Europe. The 10818G>T caused the amino acid mutation M37F in the transmembrane protein nsp6. The results suggest that the ORF6 and ORF8 genes and the mutation M37F may play important roles in causing COVID-19. The findings demonstrate that HGS analysis is a promising way to identify important genes and mutations in adaptive strains, which may help in searching potential targets for pharmaceutical agents.
Geometricus Represents Protein Structures as Shape-mers Derived from Moment Invariants

Motivation As the number of experimentally solved protein structures rises, it becomes increasingly appealing to use structural information for predictive tasks involving proteins. Due to the large variation in protein sizes, folds, and topologies, an attractive approach is to embed protein structures into fixed-length vectors, which can be used in machine learning algorithms aimed at predicting and understanding functional and physical properties. Many existing embedding approaches are alignment-based, which is both time-consuming and ineffective for distantly related proteins. On the other hand, library- or model-based approaches depend on a small library of fragments or require the use of a trained model, both of which may not generalize well. Results We present Geometricus, a novel and universally applicable approach to embedding proteins in a fixed-dimensional space. The approach is fast, accurate, and interpretable. Geometricus uses a set of 3D moment invariants to discretize fragments of protein structures into shape-mers, which are then counted to describe the full structure as a vector of counts. We demonstrate the applicability of this approach in various tasks, ranging from fast structure similarity search, unsupervised clustering, and structure classification across proteins from different superfamilies as well as within the same family. Availability Python code available at https://git.wur.nl/durai001/geometricus Contact aaltjan.vandijk@wur.nl, janani.durairaj@wur.nl
Hepatoprotective Activity of Melittin on Isoniazid and Rifampicin Induced Liver Damage in Male Albino Rats

Objective The present study aimed to investigate the ameliorative effect of melittin, a major polypeptide in the venom of honeybee (Apis mellifera) on isoniazid (INH) and rifampicin (RIF) induced hepatotoxicity in male albino rats. Method: The rats (140-200g) were divided into five groups (n=6): normal control (NC); toxic (T) group treated with INH+RIF (100 mg/kg, p.o.); melittin-treated (Mel15, Mel30) group (15 or 30 µg/kg s.c); and normal recovery (NR) group. Blood and liver samples were collected for biochemical, hematological and histopathological studies respectively. Results The administration of melittin was found to prevent the antitubercular drug-induced alterations in the diagnostic markers; reduced glutathione (GSH), direct bilirubin (DB), total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and total serum protein (TSP). Besides, hematological alterations were significantly high (P<0.0001) in Mel-treated groups when compared to the toxic control. The NR group exhibited lower levels of DB, TB, ALP, LDH and TSP. In addition, treatment with melittin offered protection in the NR group with respect to MDA levels. Conclusion Evidence from this study indicate that melittin is beneficial for the prevention of acute hepatic failure in antitubercular drug-induced hepatoxicity.
Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition

PARP-1 is a key early responder to DNA damage in eukaryotic cells. An allosteric mechanism links initial sensing of DNA single-strand breaks by PARP-1’s F1 and F2 domains via a process of further domain assembly to activation of the catalytic domain (CAT); synthesis and attachment of poly(ADP-ribose) (PAR) chains to protein sidechains then signals for assembly of DNA repair components. A key component in transmission of the allosteric signal is the HD subdomain of CAT, which alone bridges between the assembled DNA-binding domains and the active site in the ART subdomain of CAT. Here we present a study of isolated CAT domain from human PARP-1, using NMR-based dynamics experiments to analyse WT apo-protein as well as a set of inhibitor complexes (with veliparib, olaparib, talazoparib and EB-47) and point mutants (L713F, L765A and L765F), together with new crystal structures of the free CAT domain and inhibitor complexes. Variations in both dynamics and structures amongst these species point to a model for full-length PARP-1 activation where first DNA binding and then substrate interaction successively destabilise the folded structure of the HD subdomain to the point where its steric blockade of the active site is released and PAR synthesis can proceed.
VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis

The prokaryotic ubiquitous Toxin-antitoxin (TA) modules encodes for a stable toxin and an unstable antitoxin. VapBC subfamily is the most abundant Type II TA system in M. tuberculosis genome. However, the exact physiological role for most of these Type II TA systems are still unknown. Here, we have comprehensively characterized the VapBC21 TA locus from M. tuberculosis. The overexpression of VapC21 inhibited mycobacterial growth in a bacteriostatic manner and as expected, growth inhibition was abrogated upon co-expression of the cognate antitoxin, VapB21. We observed that the deletion of vapC21 had no noticeable influence on the in vitro and in vivo growth of M. tuberculosis. Using co-expression and biophysical studies, we observed that in addition to VapB21, VapC21 is also able to interact with non-cognate antitoxin, VapB32. The strength of interaction varied between the cognate and non-cognate TA pairs. The overexpression of VapC21 resulted in differential expression of approximately 435 transcripts in M. tuberculosis. The transcriptional profiles obtained upon ectopic expression of VapC21 was similar to those reported in M. tuberculosis upon exposure to stress conditions such as nutrient starvation and enduring hypoxic response. Further, VapC21 overexpression also led to increased expression of WhiB7 regulon and bacterial tolerance to aminoglycosides and ethambutol. Taken together, these results indicate that a complex network of interactions exists between non-cognate TA pairs and VapC21 contributes to drug tolerance in vitro.
Mitochondrial, cell cycle control and neuritogenesis alterations in an iPSC-based neurodevelopmental model for schizophrenia

Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world’s population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients and do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls. Our results revealed differentially regulated proteins in pathways related to mitochondrial function, oxidative phosphorylation, cell cycle control, DNA repair, and neuritogenesis. Moreover, metabolic analysis of NSCs revealed alterations in mitochondrial function in schizophrenia-derived cells. Hence, this study shows that changes in important cellular processes are present during neurodevelopment and could be involved with the establishment of schizophrenia, as well as the phenotypic traits observed in adult patients.
Lamin A/C functions independently from mechanical signaling during adipogenesis

Mesenchymal stem cells (MSC) maintain the musculoskeletal system by differentiating into multiple cell types including osteocytes and adipocytes. Mechanical signals, including strain and low intensity vibration (LIV), are important regulators of MSC differentiation. Lamin A/C is a vital protein for nuclear architecture that supports chromatin organization, as well as mechanical integrity and mechano-sensitivity of the nucleus in MSCs. Here, we investigated whether Lamin A/C and mechano-responsiveness are functionally coupled during adipogenesis. Lamin depletion in MSCs using siRNA increased nuclear area, height and volume and decreased circularity and stiffness, while phosphorylation of focal adhesions and dynamic substrate strain in response to LIV remained intact. Lamin A/C depletion decelerates adipogenesis as reflected by delayed appearance of key biomarkers (e.g., adiponectin/ADIPOQ). Based on RNA-seq data, reduced Lamin A/C levels decrease the activation of the adipocyte transcriptome that is normally observed in response to adipogenic cues mediating differentiation of MSCs. Mechanical stimulation via daily LIV application reduced the expression levels of ADIPOQ in both control and Lamin A/C depleted cells. Yet, treatment with LIV did not induce major transcriptome changes in either control or Lamin A/C depleted MSCs, suggesting that the biological effects of LIV on adipogenesis may not occur at the transcriptional level. We conclude that while Lamin A/C activation is essential for normal adipogenesis, it is dispensible for activation of focal adhesions by dynamic vibration induced mechanical signals.
Pilot Suppression trial of Aedes albopictus mosquitoes through an Integrated Vector Management strategy including the Sterile Insect Technique in Mauritius

It is often difficult to control the vector mosquito Aedes albopictus using conventional chemical control methods alone at an operational level mainly because of (1) the ability of the species to lay eggs in a variety of places which are often difficult to detect or access by larviciding operators, (2) the inherent tendency of adults to live and feed outdoor which makes them unlikely targets of Insecticide Residual Spraying and (3) the development of resistance to insecticides by the species. It is therefore necessary for countries to investigate alternative control methods (such as the Sterile Insect Technique (SIT)) that can be integrated in their national vector control programme in order to address those limitations. In this field trial, mass-produced, radio-sterilized Ae. albopictus males could successfully compete with wild males in a small village in Mauritius. Our study also demonstrated that within specific eco-climatic conditions, SIT can be used as a suppression tool against Ae. albopictus and, unlike numerous chemical control methods, effectively maintain the suppression level when the latter is found at low densities. Finally, the need for mosquito SIT programmes to develop contingency plans against increasingly frequent extreme weather occurrences was also highlighted.
Predictors of Long-Term Improvement Following Cognitive Remediation in a Sample With Elevated Depressive Symptoms

Objective Cognitive remediation (CR) techniques (interventions to enhance cognitive functioning) have proven moderately effective in improving cognition and daily functioning in major depressive disorder (MDD). However, baseline predictors of treatment response are lacking. The present study aimed to identify factors influencing long-term CR outcomes in a sample with current or previous, mild or moderate MDD and with self-reported cognitive deficits. Methods Forty-two completers of group-based CR (strategy learning or drill-and-practice), were pooled into one sample. Based on change scores from baseline to 6-month follow-up, participants were categorized as “improvers” or “non-improvers” using reliable change index calculations. Measures included a questionnaire of everyday executive functioning and a neuropsychological test of attention. Finally, improvers and non-improvers were compared in terms of various sociodemographic, psychological, illness-related, and neuropsychological baseline variables. Results Seventeen participants improved reliably in everyday executive functioning, and fourteen demonstrated a reliable improvement in attention. No statistically significant differences emerged between improvers and non-improvers. Conclusion No major predictors of CR were identified. Importantly, the current findings are insufficient to guide clinical decision-making. Large-scale studies with a priori hypotheses are needed to make advances in the future.
CyDAP–A fluorescent probe for cytosolic dopamine detection

Dopamine (DA) is an essential neurotransmitter modulating motor and cognitive functions. Several neurological disorders, including Parkinson’s disease (PD) and drug addiction, are the result of DA system dysfunction; however, it remains incomplete understood of why DA neuron is selectively more vulnerable than other neurons. Here we utilize the spectral feature of human MAO B (monoamine oxidase B) to design a genetic-amenable, GFP-based fluorescent probe CyDAP. Upon genetic and pharmacological manipulations to elevate the cytosolic DA levels in cells and Drosophila models, CyDAP shows enhanced GFP emission, suggesting this probe is feasible for DA detection. Furthermore, we observe that expressing human α-Synuclein in Drosophila elicited GFP emission from CyDAP, suggesting a link between cytosolic DA imbalance and regional vulnerability in PD context. Importantly, CyDAP can detect the change of cytosolic DA in live Drosophila brains, as demonstrated by time-lapse and the 4D light-sheet confocal recording. CyDAP may serve as a tool for evaluating metabolic deregulation of DA in brain models of PD and other DA system-related psychiatric disorders.
Micro-XRF study of the troodontid dinosaur Jianianhualong tengi reveals new biological and taphonomical signals

Jianianhualong tengi is a key taxon for understanding the evolution of pennaceous feathers as well as troodontid theropods, and it is known by only the holotype, which was recovered from the Lower Cretaceous Yixian Formation of western Liaoning, China. Here, we carried out a large-area micro-X-Ray fluorescence (micro-XRF) analysis on the holotypic specimen of Jianianhualong tengi via a Brucker M6 Jetstream mobile XRF scanner. The elemental distribution measurements of the specimen show an enrichment of typical bones couponing elements such as S, P and Ca allowing to visualize the fossil structure. Additionally, to this, the bones are enriched in several heavier elements such as Sr, Th, Y and Ce over the surrounding rocks. The enrichment is most likely associated to secondary mineralization and the phosphates from the bones. Interestingly the plumage shape correlates with an enrichment in elements such as Cu, Ni and Ti, consistent with a previous study [1] on Archaeopteryx using synchrotron imaging. The analysis presented here provide new biological and taphonomic information of this fossil. An in-situ and nondestructive micro-XRF analysis is currently the most ideal way to map the chemistry of fossils, so far this is manly restricted to small samples. Larger samples usually required a synchrotron facility for analysis. Our study demonstrated that laboratory-based large-area micro-XRF scanner can provides a practical tool for the study of large large-sized specimens allowing collect full chemical data for a better understanding of evolutionary and taphonomic processes.
Formation of a Key Intermediate Complex Species in Catalytic Hydrolysis of NH3BH3 by Bimetal Clusters: Metal-Dihydride and Boron-Multihydroxy

The hydrolysis of AB (AB, NH3BH3) with the help of transition metal catalysts has been identified as one of the promising strategies for the dehydrogenation in numerous experiments. Although great progress has been achieved in experiments, evaluation of the B-N bond cleavage channel as well as the hydrogen transfer channel has not been performed to gain a deep understanding of the kinetic route. Based on the density functional theory (DFT) calculation, we presented a clear mechanistic study on the hydrolytic reaction of AB by choosing the smallest NiCu cluster as a catalyst model. Two attacking types of water molecules were considered for the hydrolytic reaction of AB: stepwise and simultaneous adsorption on the catalyst. The Ni and Cu metal atoms play the distinctive roles in catalytic activity, i.e., Ni atom takes reactions for the H2O decomposition with the formation of [OH]− group whereas Cu atom takes reactions for the hydride transfer with the formation of metal-dihydride complex. The formation of Cu-dihydride and B-multihydroxy complex is the prerequisite for the effectively hydrolytic dehydrogenation of AB. By analyzing the maximum barrier height of the pathways which determines the kinetic rates, we found that the hydride hydrogen transferring rather than the N-B bond breaking is responsible to the experimentally measured activation energy barrier.
Visual speech differentially modulates beta, theta, and high gamma bands in auditory cortex

Speech perception is a central component of social communication. While speech perception is primarily driven by sounds, accurate perception in everyday settings is also supported by meaningful information extracted from visual cues (e.g., speech content, timing, and speaker identity). Previous research has shown that visual speech modulates activity in cortical areas subserving auditory speech perception, including the superior temporal gyrus (STG), likely through feedback connections from the multisensory posterior superior temporal sulcus (pSTS). However, it is unknown whether visual modulation of auditory processing in the STG is a unitary phenomenon or, rather, consists of multiple temporally, spatially, or functionally discrete processes. To explore these questions, we examined neural responses to audiovisual speech in electrodes implanted intracranially in the temporal cortex of 21 patients undergoing clinical monitoring for epilepsy. We found that visual speech modulates auditory processes in the STG in multiple ways, eliciting temporally and spatially distinct patterns of activity that differ across theta, beta, and high-gamma frequency bands. Before speech onset, visual information increased high-gamma power in the posterior STG and suppressed beta power in mid-STG regions, suggesting crossmodal prediction of speech signals in these areas. After sound onset, visual speech decreased theta power in the middle and posterior STG, potentially reflecting a decrease in sustained feedforward auditory activity. These results are consistent with models that posit multiple distinct mechanisms supporting audiovisual speech perception. Significance Statement Visual speech cues are often needed to disambiguate distorted speech sounds in the natural environment. However, understanding how the brain encodes and transmits visual information for usage by the auditory system remains a challenge. One persistent question is whether visual signals have a unitary effect on auditory processing or elicit multiple distinct effects throughout auditory cortex. To better understand how vision modulates speech processing, we measured neural activity produced by audiovisual speech from electrodes surgically implanted in auditory areas of 21 patients with epilepsy. Group-level statistics using linear mixed-effects models demonstrated distinct patterns of activity across different locations, timepoints, and frequency bands, suggesting the presence of multiple audiovisual mechanisms supporting speech perception processes in auditory cortex.
Effects of phylogeny on coexistence in model communities

A species’ traits influence the way in which it interacts with the environment. Thus, we expect traits to play a role in determining whether a given set of species coexists. Traits are, in turn, the outcome of an eco-evolutionary process summarized by a phylogenetic tree. Therefore, the phylogenetic tree associated with a set of species should encode information about the assembly properties of the community. Many studies have high-lighted the potentially complex ways in which phylogenetic information is translated into species’ ecological properties. However, much less emphasis has been placed on developing expectations for community properties under a particular hypothesis. In this work, we couple a simple model of trait evolution on a phylogenetic tree with local community dynamics governed by Lotka-Volterra equations. This allows us to derive properties of the community of coexisting species as a function of the number of traits, tree topology and the size of the species pool. Our results highlight how phylogenies and traits, in concert, affect the coexistence of a set of species. In this way, our work provides new baseline expectations for the ways in which phylogenetic information is reflected in the structure of and coexistence within local communities.
Roles of OB-Fold Proteins in Replication Stress

Accurate DNA replication is essential for maintaining genome stability. However, this stability becomes vulnerable when replication fork progression is stalled or slowed – a condition known as replication stress. Prolonged fork stalling can cause DNA damage, leading to genome instabilities. Thus, cells have developed several pathways and a complex set of proteins to overcome the challenge at stalled replication forks. Oligonucleotide/oligosaccharide binding (OB)-fold containing proteins are a group of proteins that play a crucial role in fork protection and fork restart. These proteins bind to single-stranded DNA with high affinity and prevent premature annealing and unwanted nuclease digestion. Among these OB-fold containing proteins, the best studied in eukaryotic cells are replication protein A (RPA) and breast cancer susceptibility protein 2 (BRCA2). Recently, another RPA-like protein complex CTC1-STN1-TEN1 (CST) complex has been found to counter replication perturbation. In this review, we discuss the latest findings on how these OB-fold containing proteins (RPA, BRCA2, CST) cooperate to safeguard DNA replication and maintain genome stability.