Miracle-dz/UniFAR-FTUs huggingface dataset:
The SARS-CoV-2 Envelope and Membrane proteins modulate maturation and retention of the Spike protein, allowing optimal formation of VLPs in presence of Nucleoprotein

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a β-coronavirus, is the causative agent of the COVID-19 pandemic. Like for other coronaviruses, its particles are composed of four structural proteins, namely Spike S, Envelope E, Membrane M and Nucleoprotein N proteins. The involvement of each of these proteins and their interplays during the assembly process of this new virus are poorly-defined and are likely β-coronavirus-type different. Therefore, we sought to investigate how SARS-CoV-2 behaves for its assembly by expression assays of S, in combination with E, M and/or N. By combining biochemical and imaging assays, we showed that E and M regulate intracellular trafficking of S and hence its furin-mediated processing. Indeed, our imaging data revealed that S remains at ERGIC or Golgi compartments upon expression of E or M, like for SARS-CoV-2 infected cells. By studying a mutant of S, we showed that its cytoplasmic tail, and more specifically, its C-terminal retrieval motif, is required for the M-mediated retention in the ERGIC, whereas E induces S retention by modulating the cell secretory pathway. We also highlighted that E and M induce a specific maturation of S N-glycosylation, which is observed on particles and lysates from infected cells independently of its mechanisms of intracellular retention. Finally, we showed that both M, E and N are required for optimal production of virus-like-proteins. Altogether, our results indicated that E and M proteins influence the properties of S proteins to promote assembly of viral particles. Our results therefore highlight both similarities and dissimilarities in these events, as compared to other β-coronaviruses. Author Summary The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Its viral particles are composed of four structural proteins, namely Spike S, Envelope E, Membrane M and Nucleoprotein N proteins, though their involvement in the virion assembly remain unknown for this particular coronavirus. Here we showed that presence of E and M influence the localization and maturation of S protein, in term of cleavage and N-glycosylation maturation. Indeed, E protein is able to slow down the cell secretory pathway whereas M-induced retention of S requires the retrieval motif in S C-terminus. We also highlighted that E and M might regulate the N glycosylation maturation of S independently of its intracellular retention mechanism. Finally, we showed that the four structural proteins are required for optimal formation of virus-like particles, highlighting the involvement of N, E and M in assembly of infectious particles. Altogether, our results highlight both similarities and dissimilarities in these events, as compared to other β-coronaviruses.
Response to reviewers comments

This study investigates the origin of upper-level potential vorticity anomalies contributing to wintertime Euro – Atlantic blocking in reanalysis data by making use of backward air parcel computations. The authors find substantial contributions from ascending, diabatically heated air masses, thus contributing to the growing body of evidence for the importance of diabatic processes in blocking formation and maintenance. As such this is not completely novel, but this study additionally asks about the specific pathways and history of the involved air masses, as well as the source regions of moisture contributing to these air parcels, which to my knowledge has not been previously done in that detail. In particular, the authors find that (I) the oceanic frontal zones in the Atlantic and the Pacific are key for supplying moisture to these ascending air parcels, (II) an important portion of air parcels originates in the Pacific, where it ascends and then moves quasi-isentropically towards the block along with the jet, (III) a small but nevertheless interesting group of air parcels first ascends in the Pacific, then descends over North America, and picks up moisture in the western Atlantic from where it ascends again into the block.
Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

Aging and type 2 diabetes mellitus (T2DM) are associated with impaired skeletal muscle function and degeneration of the skeletal muscle microenvironment. However, the origin and mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscles of T2DM patients exhibit pathological degenerative remodeling of the extracellular matrix that was associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90) - the FAPCD90+. We identified Platelet-derived growth factor (PDGF) signaling as key regulator of human FAP biology, as it promotes proliferation and collagen production at the expense of adipogenesis, an effect accompanied with a metabolic shift towards glycolytic lactate fermentation. FAPsCD90+ showed a PDGF-mimetic phenotype, with high proliferative activity and clonogenicity, increased production of extracellular matrix production and enhanced glycolysis. Importantly, the pathogenic phenotype of T2DM FAPCD90+ was reduced by treatment with the anti-diabetic drug Metformin. These data identify PDGF-driven conversion of a sub-population of FAPs as a key event in the pathogenic accumulation of extracellular matrix in T2DM muscles.
Inhibiting coronavirus replication in cultured cells by chemical ER stress

Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types, (partially) restores the virus-induced translational shut-down, and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide data sets revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including HERPUD1, an essential factor of ER quality control, and ER-associated protein degradation complexes. The data show that thapsigargin hits a central mechanism required for CoV replication, suggesting that thapsigargin (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs. One Sentence Summary / Running title Suppression of coronavirus replication through thapsigargin-regulated ER stress, ERQC / ERAD and metabolic pathways
SARS-CoV-2 neutralizing human antibodies protect against lower respiratory tract disease in a hamster model

Effective clinical intervention strategies for COVID-19 are urgently needed. Although several clinical trials have evaluated the use of convalescent plasma containing virus-neutralizing antibodies, the effectiveness has not been proven. We show that hamsters treated with a high dose of human convalescent plasma or a monoclonal antibody were protected against weight loss showing reduced pneumonia and pulmonary virus replication compared to control animals. However, a ten-fold lower dose of convalescent plasma showed no protective effect. Thus, variable and relatively low levels of virus neutralizing antibodies in convalescent plasma may limit their use for effective antiviral therapy, favouring concentrated, purified (monoclonal) antibodies.
Assessing distribution changes of selected native and alien invasive plant species under changing climatic conditions in Nyeri County, Kenya

Changes in climatic conditions increases the risks of native and alien taxa expanding in geographical range and causing habitat transformations. The role of climate change in enhancing bio-invasions in local natural environments need to be assessed to guide on effective species management policy formulations. In this present study, we used species presence records, predictor variables and an ensemble of General Circulation Models data to predict suitable ecological niches for five of the selected invasive plant species within Nyeri County, Kenya. We predicted species distributions under RCP2.6, RCP4.5, and RCP8.5 emission scenarios for the years 2050 and 2070. We analysed species distribution changes to identify invasive species requiring immediate management action. Our analysis indicated that three of the five study species were suitable in ~50% of the study area while the other two were suitable in ~30% under the current climate. Lantana camara L. and Solanum campylacanthum Hochst. ex A. Rich species would experience the largest range shift distance of ~6 – 10km and the largest habitat gain of ~12 – 33% in the future. Caesalpinia decapetala (Roth) Alston, Opuntia stricta (Haw.) Haw. and Senna didymobotrya (Fresen.) H.S. Irwin & Barneby species on the other hand would have a decline in habitat range under future climate change scenarios. Although, S. didymobotrya is considered a native species, it would lose half of its current suitable habitat in the future. Range shift analysis showed all study species would generally shift to the north west direction or towards the Aberdare ranges. From this study we conclude that invasive species management programs for smaller geographical areas ought to consider projecting species distributions under climate change scenarios to identify areas with high possible biodiversity changes. This would be important to conservationists when prioritizing management actions of invasive species in the region where data on invasive species is still limited.
SARS-CoV-2 infection of human iPSC-derived cardiac cells predicts novel cytopathic features in hearts of COVID-19 patients

Although COVID-19 causes cardiac dysfunction in up to 25% of patients, its pathogenesis remains unclear. Exposure of human iPSC-derived heart cells to SARS-CoV-2 revealed productive infection and robust transcriptomic and morphological signatures of damage, particularly in cardiomyocytes. Transcriptomic disruption of structural proteins corroborated adverse morphologic features, which included a distinct pattern of myofibrillar fragmentation and numerous iPSC-cardiomyocytes lacking nuclear DNA. Human autopsy specimens from COVID-19 patients displayed similar sarcomeric disruption, as well as cardiomyocytes without DNA staining. These striking cytopathic features provide new insights into SARS-CoV-2 induced cardiac damage, offer a platform for discovery of potential therapeutics, and raise serious concerns about the long-term consequences of COVID-19.
Effects of Diatomaceous earth in amelioration of Aflatoxin induced patho-morphological changes in broilers

The ability of Diatomaceous earth (DAE) in reducing the detrimental effects of aflatoxin (AF) in broiler diet was evaluated. DAE was supplemented @ 400 and 800 mg Kg −1 of feed along with 0.5 and 1 ppm of AF Kg −1 of feed. A total of 360 healthy day old broiler chicks were divided into 9 groups comprising of control and treatment groups. Feeding of AF caused increased relative weight of liver, kidneys, heart and pancreas compared to the control group. However, the relative weight of thymus, spleen and bursa of Fabricius decreased in the aflatoxin fed birds. The prominent gross lesions were enlargement, yellowish discoloration, friable texture, varying degree of congestion in liver and kidneys. The lymphoid organs revealed reduction in size of the thymus, spleen and bursa of Fabricius. Histopathologically, liver revealed congestion, cellular swelling and fatty changes, degeneration and necrosis of hepatocytes, periportal and perivascular infiltration of mononuclear cells and connective tissue proliferation. Kidneys revealed mild to moderate degree of congestion and haemorrhages, tubular epithelial degeneration and infiltration of mononuclear cells along with heterophils. Lymphocytolysis and depletion of lymphoid cells were seen in thymus, spleen, bursa of Fabricius and caecal tonsils. Intestines showed degeneration and necrosis of villus epithelium.
Soil nutrient availability alters tree carbon allocation dynamics during drought

Drought alters allocation patterns of carbon (C) and nutrients in trees and eventually impairs tree functioning. Elevated soil nutrient availability might alter the response of trees to drought. We hypothesize that increased soil nutrient availability stimulates root metabolism and carbon allocation to belowground tissues under drought stress. To test this hypothesis, we subjected three-year-old Pinus sylvestris saplings in open-top cambers during two subsequent years to drought using three different water treatments (100%, 20% and 0% plant available water in the soil) and two soil nutrient regimes (ambient and nitrogen-phosphorus-potassium (N-P-K) fertilization corresponding to 5 g N/m2/yr) and released drought thereafter. We conducted a 15N and 13C labelling experiment during the peak of the first-year drought by injecting 15N labelled fertilizer in the soil and exposing the tree canopies to 13C labelled CO2. The abundance of the N and C isotopes in the roots, stem and needles was assessed during the following year. C uptake was slightly lower in drought stressed trees, and extreme drought inhibited largely the N uptake and transport. Carbon allocation to belowground tissues was decreased under drought, but not in combination with fertilization. Our results indicate a potential positive feedback loop, where fertilization improved the metabolism and functioning of the roots, stimulating the source activity and hence C allocation to belowground tissues. This way, soil nutrients compensated for drought-induced loss of root functioning, mitigating drought stress of trees.
A pathway for error-free non-homologous end joining of resected meiotic double-strand breaks

Programmed DNA double-strand breaks (DSBs) made during meiosis are repaired by recombination with the homologous chromosome to generate, at selected sites, reciprocal crossovers that are critical for the proper separation of homologs in the first meiotic divisions. Backup repair processes can compensate when the normal meiotic recombination processes are non-functional. We describe a novel backup repair mechanism that occurs when the homologous chromosome is not available in Drosophila melanogaster meiosis. In the presence of a previously described mutation (Mcm5A7) that disrupts chromosome pairing, DSB repair is initiated by homologous recombination but is completed by non-homologous end joining (NHEJ). Remarkably, this process yields precise repair products. Our results provide support for a recombination intermediate recently discovered in mouse meiosis, in which an oligonucleotide bound to the Spo11 protein that catalyzes DSB formation remains bound after resection. We propose that this oligonucleotide functions as a primer for fill-in synthesis to allow scarless repair by NHEJ.
Cell-type-specific epigenomic variations associated with BRCA1 mutation in pre-cancer human breast tissues

BRCA1 germline mutation carriers are predisposed to breast cancers. Epigenomic regulations have been known to strongly interact with genetic variations and potentially mediate biochemical cascades involved in tumorigenesis. Due to the cell-type specificity of epigenomic features, profiling of individual cell types is critical for understanding the molecular events in various cellular compartments within complex breast tissue. Here we report cell-type-specific profiling of genome-wide histone modifications including H3K27ac and H3K4me3 in basal, luminal progenitor, mature luminal, and stromal cells extracted from pre-cancer BRCA1 mutation carriers and non-carriers, conducted using a low-input technology that we developed. We discover that basal and stromal cells present the most extensive epigenomic differences between mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+) while luminal progenitor and mature luminal cells are relatively unchanged with the mutation. Furthermore, the epigenomic changes in basal cells due to BRCA1 mutation appear to facilitate their transformation into luminal progenitor cells. Our findings shed light on the pre-cancer epigenomic dynamics due to BRCA1 mutation and how they may contribute to eventual development of predominantly basal-like breast cancer.
Identification of an N-acetylneuraminic acid-presenting bacteria isolated from a healthy human microbiome

N-acetylneuraminic acid is the most abundant sialic acid in humans and is generally expressed as the terminal sugar on intestinal mucus glycans. Several pathogenic bacterial species harvest sialic acid from the mucus, diet, as well as other intestinal sources and display this sugar on their own surface to evade sialic acid-binding immunoglobulin-type lectin (Siglec)-mediated host immune surveillance. While previous studies have identified bacterial enzymes associated with sialic acid catabolism, no reported methods permit the selective labeling, tracking, and quantitation of sialic acid-presenting microbes within complex multi-microbial systems. Here, we apply an interdisciplinary approach combining metabolic labeling, click chemistry, metagenomic, and whole-genome sequencing to selectively track and identify sialic acid-presenting microbes from a cultured healthy human fecal microbiome. We isolated and identified a new strain of Escherichia coli that incorporates sialic acid onto its own surface. Analysis of the sequence data reveals that this E. coli strain encodes for the NanT, NeuA, and NeuS genes necessary for harvesting environmental sialic acid and generating the capsular polysialic acid. We envision that this method is applicable to the detection and quantitation of sialic acid-presenting bacteria from human, animal, and environmental microbiomes, as well as investigating the importance of other carbohydrates to commensal and pathogenic bacteria.
RDC complex executes a dynamic piRNA program during Drosophila spermatogenesis to safeguard male fertility

piRNAs are small non-coding RNAs that guide the silencing of transposons and other targets in animal gonads. In Drosophila female germline, many piRNA source loci dubbed ‘piRNA clusters’ lack hallmarks of active genes and exploit an alternative path for transcription, which relies on the Rhino-Deadlock-Cutoff (RDC) complex. It remains to date unknown how piRNA cluster transcription is regulated in the male germline. We found that components of RDC complex are expressed in male germ cells during early spermatogenesis, from germline stem cells (GSCs) to early spermatocytes. RDC is essential for expression of dual-strand piRNA clusters and transposon silencing in testis; however, it is dispensable for expression of Y-linked Suppressor of Stellate piRNAs and therefore Stellate silencing. Despite intact Stellate repression, rhi mutant males exhibited compromised fertility accompanied by germline DNA damage and GSC loss. Thus, piRNA-guided repression is essential for normal spermatogenesis beyond Stellate silencing. While RDC associates with multiple piRNA clusters in GSCs and early spermatogonia, its localization changes in later stages as RDC concentrates on a single X-linked locus, AT-chX. Dynamic RDC localization is paralleled by changes in piRNA cluster expression, indicating that RDC executes a fluid piRNA program during different stages of spermatogenesis.
The feeding apparatus of dyrosaurids (Crocodyliformes)

Abstract Reconstructed soft-tissues of the craniocervical region of dyrosaurids are analysed under functional aspects to determine their prey-catching capabilities. Jaw adductors and jaw abductors are enlarged and possess longer muscle fibres that are increased by a long retroarticular process. This muscle enlargement resulted in a more forceful and quicker contraction, effective for movement of the long rostrum. The occipital joint and the cervical ribs, the long retroarticular process and the high cervical neural spines of dyrosaurids suggest a higher dorsoventral flexibility of the craniocervical region, whereas lateromedial flexibility was reduced. The epaxial muscles of the neck and scapular muscles were enlarged, and the supraspinal ligament most likely fanned out into a nuchal ligament. Suspension of the neck and skull of dyrosaurids was achieved by the scapular muscles, dorsal neck ligaments and epaxial muscles, whereas ventral bracing was reduced. From the reconstructed specializations of the feeding apparatus, an enhanced capability for movements in the vertical plane is postulated for dyrosaurids, together with reduced lateral movements of the craniocervical region. Besides laterally directed strokes for fish-catching, behaviours such as poking in the substrate, bottom feeding, multidirectional prey-catching strokes and improvement of diving skills were options for dyrosaurids and suggest a possible expansion of their diet. The longirostrine skull limited prey size, but the dentition allowed shelly prey items. The specialization of the food-capturing system in dyrosaurids and the resulting expansion of their food spectrum is one possible explanation for their evolutionary success, including their undisturbed transition of the Cretaceous–Palaeogene boundary.
Predicting drug sensitivity of cancer cells based on DNA methylation levels

Cancer cell lines, which are cell cultures developed from tumor samples, represent one of the least expensive and most studied preclinical models for drug development. Accurately predicting drug response for a given cell line based on molecular features may help to optimize drug-development pipelines and explain mechanisms behind treatment responses. In this study, we focus on DNA methylation profiles as one type of molecular feature that is known to drive tumorigenesis and modulate treatment responses. Using genome-wide, DNA methylation profiles from 987 cell lines from the Genomics of Drug Sensitivity in Cancer database, we applied machine-learning algorithms to evaluate the potential to predict cytotoxic responses for eight anti-cancer drugs. We compared the performance of five classification algorithms and four regression algorithms that use diverse methodologies, including tree-, probability-, kernel-, ensemble-, and distance-based approaches. For both types of algorithm, we artificially subsampled the data to varying degrees, aiming to understand whether training models based on relatively extreme outcomes would yield improved performance. We also performed an information-gain analysis to examine which genes were most predictive of drug responses. Finally, we used tumor data from The Cancer Genome Atlas to evaluate the feasibility of predicting clinical responses in humans based on models derived from cell lines. When using classification or regression algorithms to predict discrete or continuous responses, respectively, we consistently observed excellent predictive performance when the training and test sets both consisted of cell-line data. However, classification models derived from cell-line data failed to generalize effectively for tumors.