Miracle-dz/UniFAR-FTUs huggingface dataset:
Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a lethal X-linked muscular disease caused by defective expression of the cytoskeletal protein dystrophin (Dp427). Selected autonomic and central neurons, including retinal neurons, express Dp427 and/or dystrophin shorter isoforms. Because of this, DMD patients may also experience different forms of cognitive impairment, neurological and autonomic disorders, and specific visual defects. DMD-related damages to the nervous system are established during development, suggesting a role for all dystrophin isoforms in neural circuit development and differentiation; however, to date, their function in retinogenesis has never been investigated. In this large-scale study, we analyzed whether the lack of Dp427 affects late retinogenesis in the mdx mouse, the most well studied animal model of DMD. Retinal gene expression and layer maturation, as well as neural cell proliferation, apoptosis, and differentiation, were evaluated in E18 and/or P0, P5, P10, and adult mice. In mdx mice, expression of Capn3, Id3 (E18-P5), and Dtnb (P5) genes, encoding proteins involved in different aspects of retina development and synaptogenesis (e.g., Calpain 3, DNA-binding protein inhibitor-3, and β-dystrobrevin, respectively), was transiently reduced compared to age-matched wild type mice. Concomitantly, a difference in the time required for the retinal ganglion cell layer to reach appropriate thickness was observed (P0–P5). Immunolabeling for specific cell markers also evidenced a significant dysregulation in the number of GABAergic amacrine cells (P5–P10), a transient decrease in the area immunopositive for the Vesicular Glutamate Transporter 1 (VGluT1) during ribbon synapse maturation (P10) and a reduction in the number of calretinin+ retinal ganglion cells (RGCs) (adults). Finally, the number of proliferating retinal progenitor cells (P5–P10) and apoptotic cells (P10) was reduced. These results support the hypothesis of a role for Dp427 during late retinogenesis different from those proposed in consolidated neural circuits. In particular, Dp427 may be involved in shaping specific steps of retina differentiation. Notably, although most of the above described quantitative alterations recover over time, the number of calretinin+ RGCs is reduced only in the mature retina. This suggests that alterations subtler than the timing of retinal maturation may occur, a hypothesis that demands further in-depth functional studies.
Distribution of Bacterial Blight Resistance Genes in the Main Cultivars and Application of Xa23 in Rice Breeding

Bacterial blight (BB) is an important constraint on achieving a high and stable rice grain yield. An increasing number of BB resistance (R) genes have been identified and cloned to increase the available options for rice disease resistance breeding. However, it is necessary to understand the distribution of R genes in rice varieties for rational distribution and breeding. Here, we genotyped five R genes, i.e. Xa4, Xa7, Xa21, Xa23, and Xa27, in seventy main cultivars from Guangdong Province, South China using the corresponding specific markers. Our results showed that 61 varieties carried Xa4, only three varieties carried Xa27, and Xa7, Xa21, or Xa23 was not detected in all tested varieties. Notably, only 33 varieties exhibited resistance to pathotype IV Xoo strains. These results indicate that Xa4 is no longer suitable for widespread use in rice breeding, although Xa4 is widely present in tested varieties. Remarkably, the strongly virulent BB strains of pathotype IX evolved quickly in southern China, and Xa23 was found to effectively confer resistance against the pathotype IX strains. Subsequently, we successfully bred two novel inbred rice varieties as also being restorer lines and two photoperiod- and thermo-sensitive genic male sterility (P/TGMS) lines using the broad-spectrum resistance gene Xa23 through marker-assisted selection (MAS) combined with phenotypic selection. All of the developed lines and derived hybrids exhibited enhanced resistance to BB with excellent yield performance. Our research may potentially facilitate both of the inbred and hybrid rice disease resistance breeding.
Multi-Year Density Variation of Queen Conch (Aliger gigas) on Serrana Bank, Seaflower Biosphere Reserve, Colombia: Implications for Fisheries Management

Citation: Ardila NE, Hernández H, Muñoz-Ortiz A, Ramos ÓJ, Castro E, Bolaños N, Rojas A and Sánchez JA (2020) Multi-Year Density Variation of Queen Conch (Aliger gigas) on Serrana Bank, Seaflower Biosphere Reserve, Colombia: Implications for Fisheries Management. Front. Mar. Sci. 7:646. doi: 10.3389/fmars.2020. 00646 Multi-Year Density Variation of Queen Conch (Aliger gigas) on Serrana Bank, Seaflower Biosphere Reserve, Colombia: Implications for Fisheries Management
Use of organic exudates from two polar diatoms by bacterial isolates from the Arctic Ocean

Global warming affects primary producers in the Arctic, with potential consequences for the bacterial community composition through the consumption of microalgae-derived dissolved organic matter (DOM). To determine the degree of specificity in the use of an exudate by bacterial taxa, we used simple microalgae–bacteria model systems. We isolated 92 bacterial strains from the sea ice bottom and the water column in spring–summer in the Baffin Bay (Arctic Ocean). The isolates were grouped into 42 species belonging to Proteobacteria, Bacteroidetes, Actinobacteria and Firmicutes. Forty strains were tested for their capacity to grow on the exudate from two Arctic diatoms. Most of the strains tested (78%) were able to grow on the exudate from the pelagic diatom Chaetoceros neogracilis, and 33% were able to use the exudate from the sea ice diatom Fragilariopsis cylindrus. 17.5% of the strains were not able to grow with any exudate, while 27.5% of the strains were able to use both types of exudates. All strains belonging to Flavobacteriia (n = 10) were able to use the DOM provided by C. neogracilis, and this exudate sustained a growth capacity of up to 100 times higher than diluted Marine Broth medium, of two Pseudomonas sp. strains and one Sulfitobacter strain. The variable bioavailability of exudates to bacterial strains highlights the potential role of microalgae in shaping the bacterial community composition. This article is part of the theme issue ‘The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning'.
Alcohol Use Disorder, Neurodegeneration, Alzheimer’s and Parkinson’s Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

Alcohol use disorder (AUD) has been associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Prolonged excessive alcohol intake contributes to increased production of reactive oxygen species that triggers neuroimmune response and cellular apoptosis and necrosis via lipid peroxidation, mitochondrial, protein or DNA damage. Long term binge alcohol consumption also upregulates glutamate receptors, glucocorticoids and reduces reuptake of glutamate in the central nervous system, resulting in glutamate excitotoxicity, and eventually mitochondrial injury and cell death. In this review, we delineate the following principles in alcohol-induced neurodegeneration: (1) alcohol-induced oxidative stress, (2) neuroimmune response toward increased oxidants and lipopolysaccharide, (3) glutamate excitotoxicity and cell injury, and (4) interplay between oxidative stress, neuroimmune response and excitotoxicity leading to neurodegeneration and (5) potential chronic alcohol intake-induced development of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease.
Variation in Seeds Physical Traits of Bambara Groundnut ( Vigna subterranea ) Collected in Cameroon

Vigna subterranea is a leguminous species which produces edible seeds (Bambara groundnut). Its seeds are included in the daily diet to compensate the lack of proteins in the food which occurs frequently in populations under the tropics. However information regarding the extent and pattern of variation in Bambara groundnut accessions in Cameroon is limited. The objective of this study was to estimate variation in seed physical traits of twelve Bambara accessions collected in different regions in Cameroon. Seeds of Twelve Bambara accessions were harvested in Janaury Original Research Article
Host cell responses to dengue virus infection

Flaviviruses are the most prevalent arthropod-borne viruses worldwide, and nearly half of the 70 Flavivirus members identified are human pathogens. Despite the huge clinical impact of flaviviruses, there is no specific human antiviral therapy available to treat infection with any of the flaviviruses. Therefore, there is a continued search for novel therapies, and this review describes the current knowledge on the usage of RNA interference (RNAi) in combating flavivirus infections. RNAi is a process of sequence-specific gene silencing triggered by double-stranded RNA. Antiviral RNAi strategies against arthropod-borne flaviviruses have been reported and although several hurdles must be overcome to employ this technology in clinical applications, they potentially represent a new therapeutic tool.
Generating property-matched decoy molecules using deep learning

An essential step in the development of virtual screening methods is the use of established sets of actives and decoys for benchmarking and training. However, the decoy molecules in commonly used sets are biased meaning that methods often exploit these biases to separate actives and decoys, rather than learning how to perform molecular recognition. This fundamental issue prevents generalisation and hinders virtual screening method development. We have developed a deep learning method (DeepCoy) that generates decoys to a user’s preferred specification in order to remove such biases or construct sets with a defined bias. We validated DeepCoy using two established benchmarks, DUD-E and DEKOIS 2.0. For all DUD-E targets and 80 of the 81 DEKOIS 2.0 targets, our generated decoy molecules more closely matched the active molecules’ physicochemical properties while introducing no discernible additional risk of false negatives. The DeepCoy decoys improved the Deviation from Optimal Embedding (DOE) score by an average of 81% and 66%, respectively, decreasing from 0.163 to 0.032 for DUD-E and from 0.109 to 0.038 for DEKOIS 2.0. Further, the generated decoys are harder to distinguish than the original decoy molecules via docking with Autodock Vina, with virtual screening performance falling from an AUC ROC of 0.71 to 0.63. The code is available at https://github.com/oxpig/DeepCoy. Generated molecules can be downloaded from http://opig.stats. ox.ac. uk/resources.
Color Polymorphism is a Driver of Diversification in the Lizard Family Lacertidae

Color polymorphism – two or more heritable color phenotypes maintained within a single breeding population – is an extreme type of intra-specific diversity widespread across the tree of life but rarely studied in a comparative framework. Color polymorphism is thought to be an engine for speciation, where morph loss or divergence between distinct color morphs within a species results in the rapid evolution of new lineages, and thus, color polymorphic lineages are expected to display elevated diversification rates. Lizards of the family Lacertidae have evolved multiple lineages with color polymorphism, but lack of a complete and robust phylogeny for the group has made comparative analysis difficult. Here, we produce a comprehensive species-level phylogeny of the lizard family Lacertidae to reconstruct the evolutionary history of color polymorphism and test if color polymorphism has been a driver of diversification. Accounting for phylogenetic uncertainty, we estimate an ancient macroevolutionary origin of color polymorphism within the Lacertini tribe (subfamily Lacertinae). Color polymorphism most likely evolved several times in the Lacertidae and has been lost at a much faster rate than gained. Evolutionary transitions to color polymorphism are associated with shifts in increased net diversification rate in this family of lizards. Taken together, our empirical results support long-standing theoretical expectations that color polymorphism is a driver of diversification.
Quantifying Physiological Synchrony through Windowed Cross-Correlation Analysis: Statistical and Theoretical Considerations

Interpersonal synchrony is a widely studied phenomenon. A great challenge is to statistically capture the dynamics of social interactions with fluctuating levels of synchrony and varying delays between responses of individuals. Windowed Cross-Correlation analysis accounts for both characteristics by segmenting the time series into smaller windows and shifting the segments of two interacting individuals away from each other up to a maximum lag. Despite evidence showing that these parameters affect the estimated synchrony level, there is a lack of guidelines on which parameter configurations to use. The current study aimed to close this knowledge gap by comparing the effect of different parameter configurations on two outcome criteria: (1) the ability to distinguish synchrony from pseudosynchrony by means of surrogate data analyses, and (2) the sensitivity to detect change in synchrony as measured by the difference between two within-subject conditions. Focusing on physiological synchrony, we performed these analyses on heartrate, skin conductance level, pupil size, and facial expressions data. Results revealed that a range of parameters was able to discriminate synchrony from pseudosynchrony. Window size was more influential than the maximum lag with smaller window sizes showing better discrimination. No clear patterns emerged for the second criterion. Integrating the statistical findings and theoretical considerations regarding the physiological characteristics and biological boundaries of the signals, we provide recommendations for optimizing the parameter settings to the signal of interest.
Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity.

The FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cells.
Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition

Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identification of this process in multiple sclerosis patients using post-contrast FLAIR imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 Tesla) MRI to perform post-contrast FLAIR imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced using immunization with proteolipid protein peptide (PLP139-151) and complete Freund’s adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time-points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which identified dense cellular infiltrates corresponding to areas of contrast-enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas – presence of peripheral node addressin (PNAd) positive structures, CXCL13 producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib (a Bruton’s tyrosine kinase inhibitor) for a period of 4 weeks. These mice underwent serial imaging and we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We utilized ultra-high field MRI imaging to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis and then utilized this model to identify Bruton’s tyrosine kinase inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.
Process-based model of fish incubation survival for designing reservoir operations: a case study for Sacramento River winter-run Chinook salmon

Allocating reservoir flows to meet societal and ecosystem needs under increasing demands for water and increasing climatic variability presents challenges to resource managers. Often, regulated rivers have been operated to meet flow and temperature compliance points that mimic historical patterns. Because it is difficult to assess if this approach is efficient or equitable, new more process-based approaches to regulation are being advanced. This paper describes such an approach with a model of egg incubation survival of Sacramento River winter-run Chinook salmon (SRWRC, Oncorhynchus tshawytscha). Thermal mortality only occurs in a critical window around egg hatching when the embryo is most sensitive to temperature stress. The duration of the critical window has significant implications for Shasta Reservoir operations that are designed to control temperature during SRWRC incubation. Previous operations sought to maintain a low temperature over the entire incubation period. However, model analysis suggests that targeting cold water directly to the critical egg hatching stage provides higher survival while requiring less cold water resources. The calibrated model is publicly accessible through a web interface connected to real-time river and fish databases and a river temperature forecast model. The system is an example of the next step of river management that integrates databases with hydrological and process-based biological models for real-time analysis and for forecasting effects of river operations on the environment.
The circadian oscillator analysed at the single-transcript level

The circadian clock is an endogenous and self-sustained oscillator that anticipates daily environmental cycles and coordinates physiology accordingly. While rhythmic gene expression of circadian genes is well-described in populations of cells, the single-cell mRNA dynamics of multiple core-clock genes remain largely unknown. Here we use single molecule fluorescence in-situ hybridization (smFISH) at multiple time points to measure pairs of core-clock transcripts, Rev-erbα (Nr1d1), Cry1 and Bmal1, in mouse fibroblasts at single-molecule resolution. The mean mRNA level oscillates over 24 hours for all three genes, but mRNA numbers show considerable spread between cells. While transcript number scales with cell size for all genes, gene-to-gene correlations of mRNA number depends on the gene pair. To account for these features of the data, we develop a probabilistic model for multivariate smFISH mRNA counts that quantifies changes in transcriptional bursting across genes and over circadian time. We identify a mixture model of negative binomials as the preferred model of the mRNA count distributions, which accounts for cell-to-cell heterogeneity, notably in cell size. The paired count data and modelling allows the decomposition of mRNA variability into distinct noise sources, showing that circadian clock time contributes only a small fraction of the total variability in mRNA number between cells. Thus, our results highlight the intrinsic biological challenges in estimating circadian phase from single-cell mRNA counts and suggest that circadian phase in single cells is encoded post-transcriptionally.
SARS-CoV-2 variants with mutations at the S1/S2 cleavage site are generated in vitro during propagation in TMPRSS2-deficient cells

The spike (S) protein of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which facilitates viral entry. A polybasic motif detected at the cleavage site of the S protein has been shown to broaden the cell tropism and transmissibility of the virus. Here we examine the properties of SARS-CoV-2 variants with mutations at the S protein cleavage site that undergo inefficient proteolytic cleavage. Virus variants with S gene mutations generated smaller plaques and exhibited a more limited range of cell tropism compared to the wild-type strain. These alterations were shown to result from their inability to utilize the entry pathway involving direct fusion mediated by the host type II transmembrane serine protease, TMPRSS2. Notably, viruses with S gene mutations emerged rapidly and became the dominant SARS-CoV-2 variants in TMPRSS2-deficient cells including Vero cells. Our study demonstrated that the S protein polybasic cleavage motif is a critical factor underlying SARS-CoV-2 entry and cell tropism. As such, researchers should be alert to the possibility of de novo S gene mutations emerging in tissue-culture propagated virus strains.
Efficient generation of endogenous protein reporters for mouse preimplantation embryos

Fluorescent proteins and epitope tags can reveal protein localization in cells and animals. However, the large size of many tags hinders efficient genome targeting. Accordingly, many studies have relied on characterizing overexpressed proteins, which might not recapitulate endogenous protein activities. We present two approaches for higher throughput production of endogenous protein reporters. Our first approach makes use of a split fluorescent protein mNeonGreen2 (mNG2). Knock-in of a small portion of the mNG2 gene, in frame with gene coding regions of interest was highly efficient in embryos, eliminating the need to establish mouse lines. When complemented by the larger portion of the mNG2 gene, fluorescence was reconstituted and endogenous protein localization faithfully reported in living embryos. However, we report a threshold of detection using this approach. By contrast, the V5 epitope enabled high efficiency and higher sensitivity protein reporting. We describe complementary advantages and prospective applications of these two approaches. Highlights Split fluorescent protein for in vivo protein localization in living embryos V5 tagging for in vivo localization of low abundance proteins Bypassing the need for founder mouse lines for preimplantation studies Guidelines and strategies for implementation and prospective applications