bluuebunny/crossref_metadata_2025_split huggingface dataset:
A soybean pattern recognition receptor conferring broad-spectrum pathogen and pest resistance regulates expression of several NLR receptor proteins
Authors: Ngaki Micheline N. , Srivastava Subodh K. , Feifei Wang , Bhattacharyya Madan K. 
Published: April 2023

SummaryOverexpressors ofGlycine max disease resistant 1(GmDR1) exhibits broad-spectrum resistance againstFusarium virguliforme, soybean cyst nematode (SCN), spider mites, and soybean aphids in soybean. To understand the mechanisms of broad-spectrum immunity mediated byGmDR1, we investigated the transcriptomes of a strong and a weakGmDR1-overexpressors following treatment with chitin, a pathogen- and pest-associated molecular pattern (PAMP) found in these organisms. The strong and weakGmDR1-overexpressors exhibited altered expression of 6,098 and 992 genes, respectively, as compared to the nontransgenic control following chitin treatment. However, only 192 of these genes exhibited over two-fold changes in expression levels in both strong and weakGmDR1-overexpressors as compared to the control. MapMan analysis of the 192 genes revealed 64 biotic stress-related genes, of which 53 were induced and 11 repressed as compared to the control. The 53 chitin-induced genes include nine that encode receptor kinases, 13 encodenucleotide-binding leucine-richrepeat (NLR) receptor proteins, seven encoding WRKY transcription factors, four ethylene response factors, and three MYB-like transcription factors. Investigation of a subset of these genes revealed three receptor protein kinases, seven NLR proteins, and one WRKY transcription factor genes that are induced followingF. virguliformeand SCN infection. The integral plasma membrane GmDR1 protein most likely recognizes PAMPs including chitin and activates transcription of genes encoding receptor kinases and NLR proteins. GmDR1 could be a pattern recognition receptor that regulates the expression of several NLRs for expression of PAMP-triggered immunity and/or priming the effector triggered immunity.
Impaired centrosome biogenesis in kidney stromal progenitors reduces abundance of interstitial lineages and accelerates injury-induced fibrosis
Authors: Langner Ewa , Cheng Tao , Kefaloyianni Eirini , Gluck Charles , Wang Baolin , Mahjoub Moe R. 
Published: April 2023

SummaryDefective centrosome function can disrupt embryonic kidney development, by causing changes to the renal interstitium that leads to fibrocystic disease pathologies. Yet, it remains unknown how mutations in centrosome genes impact kidney interstitial cells. Here, we examined the consequences of defective centrosome biogenesis on stromal progenitor cell growth, differentiation and fate. Conditional deletion ofCep120, a ciliopathy gene essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of pericytes, interstitial fibroblasts and mesangial cells. This was due to delayed mitosis, increased apoptosis, and changes in Wnt and Hedgehog signaling essential for differentiation of stromal lineages.Cep120ablation resulted in hypoplastic kidneys with medullary atrophy and delayed nephron maturation. Finally, centrosome loss in the interstitium sensitized kidneys of adult mice, causing rapid fibrosis via enhanced TGF-β/Smad3-Gli2 signaling after renal injury. Our study defines the cellular and developmental defects caused by centrosome dysfunction in embryonic kidney stroma.Graphical AbstractHighlightsDefective centrosome biogenesis in kidney stroma causes:Reduced abundance of stromal progenitors, interstitial and mesangial cell populationsDefects in cell-autonomous and paracrine signalingAbnormal/delayed nephrogenesis and tubular dilationsAccelerates injury-induced fibrosis via defective TGF-β/Smad3-Gli2 signaling axis
Adventitial macrophage accumulation impairs perivascular nerve function in mesenteric arteries with inflammatory bowel disease
Authors: Grunz Elizabeth A. , Jones Benjamin W. , Lateef Olubodun , Sen Sidharth , Wilkenson Katie , Joshi Trupti , Boerman Erika M. 
Published: April 2023

1.AbstractIntroduction:Inflammatory bowel disease (IBD) involves aberrant immune responses and is associated with both cardiovascular disease risk and altered intestinal blood flow. However, little is known about how IBD affects regulation of perivascular nerves that mediate blood flow. Previous work found perivascular nerve function is impaired in mesenteric arteries with IBD. The purpose of this study was to determine the mechanism of impaired perivascular nerve function.Methods:RNA sequencing was performed on mesenteric arteries from IL10-/-mice treated withH.hepaticusto induce disease (IBD) or left non-gavaged (Control). For all other studies, Control and IBD mice received either saline or clodronate liposome injections to study the effect of macrophage depletion. Perivascular nerve function was assessed using pressure myography and electrical field stimulation. Leukocyte populations, and perivascular nerves, and adventitial neurotransmitter receptors were labeled using fluorescent immunolabeling.Results:IBD was associated with increased in macrophage-associated gene expression, and immunolabeling showed accumulation of adventitial macrophages. Clodronate liposome injection eliminated adventitial macrophages, which reversed significant attenuation of sensory vasodilation, sympathetic vasoconstriction and sensory inhibition of sympathetic constriction in IBD. Acetylcholine-mediated dilation was impaired in IBD and restored after macrophage depletion, but sensory dilation remained nitric oxide independent regardless of disease and/or macrophage presence.Conclusion:Altered neuro-immune signaling between macrophages and perivascular nerves in the arterial adventitia contributes to impaired vasodilation, particularly via dilatory sensory nerves. Targeting the adventitial macrophage population may help preserve intestinal blood flow in IBD patients.
SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19
Authors: Rong Zhouyi , Mai Hongcheng , Kapoor Saketh , Puelles Victor G. , Czogalla Jan , Schädler Julia , Vering Jessica , Delbridge Claire , Steinke Hanno , Frenzel Hannah , Schmidt Katja , Caliskan Özüm Sehnaz , Wettengel Jochen Martin , Cherif Fatma , Ali Mayar , Kolabas Zeynep Ilgin , Ulukaya Selin , Horvath Izabela , Zhao Shan , Krahmer Natalie , Tahirovic Sabina , Yildirim Ali Önder , Huber Tobias B. , Ondruschka Benjamin , Bechmann Ingo , Ebert Gregor , Protzer Ulrike , Bhatia Harsharan Singh , Hellal Farida , Ertürk Ali 
Published: April 2023

ABSTRACTCoronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the virus’s acute and potential chronic impact on the central nervous system. In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis. Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spike’s persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway. Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities.Graphical SummaryShort SummaryThe accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis presents potential molecular mechanisms and therapeutic targets for neurological complications in long-COVID-19 patients.
RSim: A Reference-Based Normalization Method via Rank Similarity
Authors: Yuan Bo , Wang Shulei 
Published: April 2023

AbstractMicrobiome sequencing data normalization is crucial for eliminating technical bias and ensuring accurate downstream analysis. However, this process can be challenging due to the high frequency of zero counts in microbiome data. We propose a novel reference-based normalization method called normalization via rank similarity (RSim) that corrects sample-specific biases, even in the presence of many zero counts. Unlike other normalization methods, RSim does not require additional assumptions or treatments for the high prevalence of zero counts. This makes it robust and minimizes potential bias resulting from procedures that address zero counts, such as pseudo-counts. Our numerical experiments demonstrate that RSim reduces false discoveries, improves detection power, and reveals true biological signals in downstream tasks such as PCoA plotting, association analysis, and differential abundance analysis.
Erythropoietic, hematinic and leucocytic activities of the aqueous extracts of the fruits and leaves ofSolanum torvum
Authors: Ibrahim Ilyas , Bardoe Denis , Hayford Daniel 
Published: April 2023

AbstractThe Turkey berry(Solanum torvum)plant is globally exploited for its medicinal and pharmacological benefits. This study was conducted to investigate the erythropoietic, hemanitic and leucocytic activities of the aqueous extracts of the fruits and leaves ofSolanum torvum. Three groups of rabbits with five replicates each (aged 6-8 weeks) where either given the aqueous extracts of fresh turkey berry fruits, fresh turkey berry leafs, or distilled water at a dose of 0.5ml and a concentration of 100g of leaf or fruit against 100ml of distilled water (1g per 1ml of distilled water) per day over a six-week period. The rabbits were fedad libitumwith concentrate and water throughout the experimental period. A full blood count (FBC) using a BC 2600 hematology analyzer was conducted on the collected blood samples of the experimental animals at the end of the sixth week of extract administration. The blood samples of the rabbits given the aqueous extracts of the fruit and leaf of turkey berry at the end of the six weeks of treatment administration showed a significant (p<0.05) increase in red blood cell count, hemoglobin level, white blood cell count and hematocrit. The results indicated thatSolanum torvumhad a positive erythropoietic, hemanitic and leucocytic properties. This implies thatSolanum torvumis effective in improving the quality of blood and hence can prevent some hematological disorders.
GENI: a web server to identify gene set enrichments in tumor samples
Authors: Hayashi Arata , Ruppo Shmuel , Heilbrun Elisheva E. , Mazzoni Chiara , Adar Sheera , Yassour Moran , Rmaileh Areej Abu , Shaul Yoav D. 
Published: April 2023

SummaryThe Cancer Genome Atlas (TCGA) and other projects provide informative tumor-associated genomic data for the broad research community. Hence, several useful web-based tools have been generated to ease non-expert users with the analysis and characterization of a specific gene behavior in selected tumors. However, none of the existing tools offer the user the means to evaluate the expression profile of a given gene in the context of the whole transcriptome. Currently, such analyses require prior bioinformatic knowledge and expertise. Therefore, we developed GENI (Gene ENrichment Identifier) as a fast, user-friendly tool to analyze the TCGA expression data for gene set enrichments. GENI analyzes large-scale tumor-associated gene expression datasets and evaluates biological relevance, thus offering researchers a simplified means to analyze cancer patient-derived data.Availability and implementationGENI is a freely available fast web-based tool developed using the R programming language. It is accessible via the URL:https://yoavshaul-lab.shinyapps.io/gsea-geni/. The complete script can be found athttps://github.com/ArataHayashi/GENI-Gene-ENrichment-Identifier.
Arsenite methyltransferase 3 regulates hepatic energy metabolism which dictates the hepatic response to arsenic exposure
Authors: Delaney Patrice , Khan Nouf , O’Connor Matthew J. , Ambrosio Elizabeth Mayela , Garcia-Sabaté Anna , M. Teo Jeremy C. , Pergantis Spiros A. , Ober Elke , Sadler Kirsten C. 
Published: April 2023

ABSTRACTInorganic arsenic (iAs(III)) is among the most pervasive environmental toxicants in the world. The iAs metabolizing enzyme, arsenite methyltransferase (AS3MT), is a key mediator of iAs(III) toxicity and has been almost exclusively investigated in the context of iAs(III) exposure. We use functional genomics approach with zebrafishas3mtmutants which lack arsenite methyltransferase activity to uncover novel, arsenic-independent functions for As3mt. Transcriptomic analysis of untreated whole larvae, and the larval and adult livers fromas3mtmutants revealed thousands of differentially expressed genes (DEGs) compared to wild-type controls. These were enriched for genes functioning in the ribosome or mitochondria. Nearly all genes in the citric acid cycle and mitochondrial transport were downregulated inas3mtmutant livers. This resulted in reduction in reactive oxygen species levels by half and fatty liver in 81% ofas3mtmutant larvae. An inverse expression pattern was detected for over 2,000 of the As3mt regulated DEGs in the liver of larvae with transgenic overexpression of As3mt in hepatocytes. Replacingas3mtexpression in hepatocytes ofas3mtmutants prevented fatty liver, demonstrating that As3mt has novel, cell-autonomous and arsenic-independent functions regulating mitochondrial metabolism. We suggest that these functions contribute to iAs toxicity, as the mitochondrial function genes that were downregulated in the liver of unexposedas3mtmutants were further downregulated upon iAs exposure andas3mtmutants were sensitized to iAs. This indicates that As3mt regulates hepatic energy metabolism and demonstrates that, in addition to its role in iAs detoxification, the physiological functions of As3mt contribute to arsenic toxicity.SIGNIFICANCEArsenic is an endemic environmental toxicant, and the current paradigm is that susceptibility to arsenic toxicity is dictated by levels of expression of the arsenite 3 methyltransferase gene (As3mt), which is dedicated enzyme involved in arsenic detoxification. Our data showing that As3mt serves arsenic-independent functions in energy metabolism challenge this paradigm. We show that zebrafishas3mtmutants have loss of mitochondrial function and develop fatty liver and suggest thatas3mtmutants are sensitized to arsenic toxicity due, in part, to impaired mitochondrial function. This finding opens an entirely new area of study to identify the cellular function of As3mt and further advances the understanding of how genetic variants in As3mt confer sensitivity arsenic toxicology.
Beyond a PPR-RNA recognition code: Many aspects matter for the multi-targeting properties of RNA editing factor PPR56
Authors: Yang Yingying , Ritzenhofen Kira , Otrzonsek Jessica , Schallenberg-Rüdinger Mareike , Knoop Volker 
Published: April 2023

AbstractThe mitochondrial C-to-U RNA editing factor PPR56 of the mossPhyscomitrium patensis an RNA-binding pentatricopeptide repeat protein equipped with a terminal DYW-type cytidine deaminase domain. Transferred intoEscherichia coli,PPR56 works faithfully on its two native RNA editing targets, nad3eU230SL and nad4eU272SL, and also converts cytidines into uridines at over 100 off-targets in the bacterial transcriptome. Accordingly, PPR56 is attractive for detailed mechanistic studies in the heterologous bacterial setup, allowing for scoring differential RNA editing activities of many target and protein variants in reasonable time. Here, we report (i) on the effects of numerous individual and combined PPR56 protein and target modifications, (ii) on the spectrum of off-target C-to-U editing in the bacterial background transcriptome for PPR56 and two variants engineered for target re-direction and (iii) on combinations of targets in tandem or separately at the 5’- and 3’-ends of large mRNAs. The latter experimentation finds enhancement of RNA editing at weak targets in many cases, including cox3eU290SF as a new candidate mitogenome target. We conclude that C-to-U RNA editing can be much enhanced by transcript features also outside the region ultimately targeted by PPRs of a plant editing factor, possibly facilitated by its enrichment or scanning along transcripts.
Whole-genome sequencing confirms multiple species of Galapagos giant tortoises
Authors: Gaughran Stephen J. , Gray Rachel , Jones Menna , Fusco Nicole , Ochoa Alexander , Miller Joshua M. , Poulakakis Nikos , de Queiroz Kevin , Caccone Adalgisa , Jensen Evelyn L. 
Published: April 2023

AbstractGalapagos giant tortoises are endemic to the Galapagos Archipelago, where they are found in isolated populations. While these populations are widely considered distinguishable in morphology, behavior, and genetics, the recent divergence of these taxa has made their status as species controversial. Here, we apply multispecies coalescent methods for species delimitation to whole genome resequencing data from 38 tortoises across all 13 extant taxa to assess support for delimiting these taxa as species. In contrast to previous studies based solely on divergence time, we find strong evidence to reject the hypothesis that all Galapagos giant tortoises belong to a single species. Instead, a conservative interpretation of model-based and divergence-based results indicates that these taxa form a species complex consisting of a minimum of 9 species, with some analyses supporting as many as 13 species. There is mixed support for the species status of taxa living on the same island, with some methods delimiting them as separate species and others suggesting multiple populations of a single species per island. These results make clear that Galapagos giant tortoise taxa represent different stages in the process of speciation, with some taxa further along in that evolutionary process than others. A better understanding of the more complex parts of that process is urgently needed, given the threatened status of Galapagos giant tortoises.Lay SummarySpecies delimitation is a challenging problem in evolutionary biology, but one that is central to the field. Distinguishing species can affect conservation management practices, from conservation status assessments to strategies for breeding programs. More fundamentally, understanding species boundaries affects our ability to assess biodiversity and to study evolutionary processes. The Galapagos Archipelago presents several radiations of closely related taxa that inspired Charles Darwin to develop his theory of evolution by natural selection and later led to foundational case studies in speciation. The Galapagos giant tortoises were one such inspiration. Nearly two centuries later, there is still an ongoing debate about the taxonomic status of these tortoises, with opinions on their status ranging from barely differentiated populations to separate species. Here, we present the first genomic species delimitation of Galapagos giant tortoises and provide convincing evidence that this group is a complex consisting of between 9 and 13 species. These results provide valuable guidance to conservation stakeholders in the Galapagos, while also adding an important case study to the delimitation of island species.
AI-Guided Discovery of Novel SARS-CoV-2 PLpro Inhibitors: Accelerating Antiviral Drug Development in the Fight Against COVID-19
Authors: Spagnoli Will , Danter Wayne R 
Published: April 2023

AbstractThe global pandemic caused by SARS-CoV-2 has highlighted the urgent need for effective antiviral drugs. The papain-like protease (PLpro) is a key viral enzyme involved in the replication and immune evasion of SARS-CoV-2, making it a promising target for antiviral drug development. In this study, we employed an artificial intelligence (AI)-driven drug discovery platform, LIME, to generate novel inhibitors of the SARS-CoV-2 PLpro. LIME is based on generative language models that can generate diverse, valid, and synthetically accessible compounds. The LIME software was used to identify potential inhibitors with strong binding affinity and specificity to the target protein. The top 13 hit compounds were tested in vitro, and the top 5 inhibitors with strong binding affinity and specificity were selected for further analysis. A top candidate molecule, CSEMRS-1376, exhibited similar binding energies and structural similarities to the known SARS-CoV-2 PLpro inhibitor, XR8-89. Computational analysis of the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of the hit compounds and XR8-89 showed that both CSEMRS-1376 and XR8-89 demonstrated favorable ADMET profiles. Overall, the LIME software successfully identified several novel molecules, including CSEMRS-1376, with strong potential as a therapeutic agent against SARS-CoV-2. The study highlights the potential of AI-driven drug discovery platforms, such as LIME, to accelerate the drug development process and pave the way for more efficient and effective therapeutics.
Expansion of triplet nucleotide repeats in primates and other vertebrates: an evolutionary perspective
Authors: Murthy Saketh , Mishra Rakesh K 
Published: April 2023

ABSTRACTTriplet nucleotide repeat (TNR) expansion has been linked to more than 40 inheritable neurological, neuromuscular and neurodegenerative disorders. Increase in copy number beyond a threshold causes further rapid expansion of the repeats, leading to instability and disease via gain/loss of function, toxic RNA products or chromosome instability. An analysis of these repeat regions across vertebrates shows that these repeats have consistently either arisen late or have increased in copy number in vertebrates, most significantly in primates and particularly in humans. Many of the known diseases have neurological basis, suggests positive selection of these repeats for neuronal function. Late occurrence of the diseases implicates a lack of negative selection. This evolutionary trade-off, a higher neuronal capability at the cost of disease susceptibility, is further supported by the observation that most of the genes associated with TNR expansion diseases have neuronal function.
TcHRG plays a central role in orchestrating heme uptake inTrypanosoma cruziepimastigotes
Authors: Tevere Evelyn , Di Capua Cecilia Beatriz , Chasen Nathan Michael , Etheridge Ronald Drew , Cricco Julia Alejandra 
Published: April 2023

ABSTRACTTrypanosoma cruzi, a heme auxotrophic parasite, can control intracellular heme content by modulatingTcHRG expression when a free heme source is added to axenic culture. Herein, we explore the role ofTcHRG protein in regulating the uptake of heme derived from hemoglobin in epimastigotes. It was found that the parasite’s endogenousTcHRG (protein and mRNA) responds similarly to bound (hemoglobin) and free (hemin) heme. Additionally, the overexpression ofTcHRG leads to an increase in intracellular heme content. The localization ofTcHRG is also not affected in parasites supplemented with hemoglobin as the sole heme source. Endocytic null epimastigotes do not show a significant difference in growth profile, intracellular heme content andTcHRG protein accumulation compared to WT when feeding with hemoglobin or hemin as a source of heme. These results suggest that the uptake of hemoglobin-derived heme likely occurs through extracellular proteolysis of hemoglobinviathe flagellar pocket, and this process is governed byTcHRG. In sum,T. cruziepimastigotes controls heme homeostasis by modulatingTcHRG expression independently of the source of available heme.