bluuebunny/crossref_metadata_2025_split huggingface dataset:
Routine antimicrobial therapy for severe fever with thrombocytopenia syndrome does not improve prognosis: overlap weighting analysis using a nationwide inpatient database
Authors: Kutsuna Satoshi , Ohbe Hiroyuki , Matsui Hiroki , Yasunaga Hideo 
Published: June 2024

AbstractBackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an infectious disease that presents a formidable challenge due to the absence of established therapeutic strategies that are explicitly tailored to its management. This study aimed to assess the impact of routine antimicrobial therapy on patients diagnosed with SFTS in Japan. We conducted a comprehensive retrospective cohort analysis using extensive data from a national inpatient database.Methodology/Principal FindingsThis study scrutinized data from adult patients with SFTS and categorized them based on whether they received antimicrobial treatment within the initial 2 days of hospital admission. A meticulous evaluation was carried out on a range of outcomes, such as in-hospital mortality rates, overall costs associated with hospitalization, and length of hospital stay. Overlap weighting was applied along with multivariate regression models to enhance the reliability of the findings through confounder adjustment. The outcomes showed no significant improvement in the prognosis of patients with SFTS who received routine antimicrobial therapy. The use of antimicrobials did not yield statistically significant improvements in in-hospital mortality rates or other secondary outcomes, suggesting that such therapeutic interventions may not be necessary during the early stages of hospital admission.Conclusion/SignificanceThis study underscores that the indiscriminate administration of antimicrobials does not substantively enhance the prognosis of patients with severe SFTS, hence dissuading the universal implementation of antimicrobials as a conventional component of therapeutic strategies in managing severe cases of SFTS.Author summarySevere fever with thrombocytopenia syndrome is a tick-borne infection that is endemic in East Asia, including Japan, China, and South Korea. At present, there are no effective antiviral drugs against SFTS. It has been reported that patients who received antimicrobial agents for SFTS early on had a better prognosis. To validate this study, we compared SFTS patients who received antimicrobials within 2 days of admission with those who did not, using Japanese DPC data. Overlap weighting was applied along with multivariate regression models to enhance the reliability of the findings through confounder adjustment. The results showed no difference in in-hospital mortality, hospitalization costs, or hospital days between the two groups. In conclusion, the analysis of patients with SFTS using a nationwide inpatient database revealed that routine antimicrobials did not improve patient prognosis. Further, our findings do not support the universal use of antimicrobials in patients with severe SFTS.
Spatially structured competition and cooperation alters algal carbon flow to bacteria
Authors: Kim Hyungseok , Brisson Vanessa L. , Casey John R. , Swink Courtney , Rolison Kristina A. , Golini Amber N. , Northen Trent R. , Weber Peter K. , Veličković Dušan , Buie Cullen R. , Mayali Xavier , Stuart Rhona K. 
Published: June 2024

Abstract

Microbial communities regulate the transformations of carbon in aquatic systems through metabolic interactions and food-web dynamics that can alter the balance of photosynthesis and respiration. Direct competition for resources is thought to drive microbial community assembly in algal systems, but other interaction modes that may shape communities are more challenging to isolate. Through untargeted metabolomics and metabolic modeling, we predicted the degree of resource competition between bacterial pairs when growing on model diatom
Phaeodactylum tricornutum-
derived substrates. In a subsequent sequential media experiment, we found that pairwise interactions were consistently more cooperative than predicted based on resource competition alone, indicating an unexpected role for cooperation in algal carbon processing. To link this directly to algal carbon fate, we chose a representative cooperative and competitive ‘influencer’ isolate and a model ‘recipient’ and applied single-cell isotope tracing in a custom porous microplate cultivation system. In the presence of live algae, the recipient drew down more algal carbon in the presence of the cooperative influencer compared to the competitive influencer, supporting the sequential experiment results. We also found that total carbon assimilation into bacterial biomass, integrated over influencer and recipient, was significantly higher for the cooperative interaction. Our findings support the notion that non-competitive interactions are critical for predicting algal carbon fate.

Significance Statement
Microbial interactions have widely been studied in the context of host resources but testing and measuring direct interactions in a lab has been particularly challenging. By combining untargeted metabolomics, sequential/(co-)culture, and metabolic modeling, we demonstrate that the presence of an unexpected interaction mode in a live system and show how it impacts the flow of host-derived resources. This top-down approach can help identify novel bacterial interactions that play a crucial role in microbial community-host ecosystems, which may have an impact in holobiont phenotypes including alga, fungal, or plant systems.
Transcriptomic comparison of in vitro models of the human placenta
Authors: Lapehn Samantha , Nair Sidharth , Firsick Evan J. , MacDonald James , Thoreson Ciara , Litch James A , Bush Nicole R. , Kadam Leena , Girard Sylvie , Myatt Leslie , Prasad Bhagwat , Sathyanarayana Sheela , Paquette Alison G. 
Published: June 2024

AbstractStudying the human placenta through in vitro cell culture methods is necessary due to limited access and amenability of human placental tissue to certain experimental methods as well as distinct anatomical and physiological differences between animal and human placentas. Selecting an in vitro culture model of the human placenta is challenging due to representation of different trophoblast cell types with distinct biological roles and limited comparative studies that define key characteristics of these models. Therefore, the aim of this research was to create a comprehensive transcriptomic comparison of common in vitro models of the human placenta compared to bulk placental tissue from the CANDLE and GAPPS cohorts (N=1083). We performed differential gene expression analysis on publicly available RNA sequencing data from 6 common in vitro models of the human placenta (HTR-8/SVneo, BeWo, JEG-3, JAR, Primary Trophoblasts, and Villous Explants) and compared to CANDLE and GAPPS bulk placental tissue or cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast cell types derived from bulk placental tissue. All in vitro placental models had a substantial number of differentially expressed genes (DEGs, FDR<0.01) compared to the CANDLE and GAPPS placentas (Average DEGs=10,873), and the individual trophoblast cell types (Average DEGs=5,346), indicating that there are vast differences in gene expression compared to bulk and cell-type specific human placental tissue. Hierarchical clustering identified 53 gene clusters with distinct expression profiles across placental models, with 22 clusters enriched for specific KEGG pathways, 7 clusters enriched for high-expression placental genes, and 7 clusters enriched for absorption, distribution, metabolism, and excretion genes. In vitro placental models were classified by fetal sex based on expression of Y-chromosome genes that identified HTR-8/SVneo cells as being of female origin, while JEG-3, JAR, and BeWo cells are of male origin. Overall, none of the models were a close approximation of the transcriptome of bulk human placental tissue, highlighting the challenges with model selection. To enable researchers to select appropriate models, we have compiled data on differential gene expression, clustering, and fetal sex into an accessible web application:“Comparative Transcriptomic Placental Model Atlas (CTPMA)”which can be utilized by researchers to make informed decisions about their selection of in vitro placental models.
Coastal bacteria and protists assimilate viral carbon and nitrogen
Authors: Martínez Joaquín Martínez , Talmy David , Kimbrel Jeffrey A. , Weber Peter K. , Mayali Xavier 
Published: June 2024

AbstractFree viruses are the most abundant type of biological particles in the biosphere, but the lack of quantitative knowledge about their consumption by heterotrophic protists and bacterial degradation has hindered the inclusion of virovory in biogeochemical models. Here, using isotope-labeled viruses added to three independent microcosm experiments with natural microbial communities followed by isotope measurements with single-cell resolution and flow cytometry, we quantified the flux of viral C and N into virovorous protists and bacteria and compared the loss of viruses due to abiotic vs biotic factors. We found that some protists can obtain most of their C and N requirements from viral particles and that viral C and N get incorporated into bacterial biomass. We found that bacteria and protists were responsible for increasing the daily removal rate of viruses by 33% to 85%, respectively, compared to abiotic processes alone. Our laboratory incubation experiments showed that abiotic processes removed roughly 50% of the viruses within a week, and adding biotic processes led to a removal of 83% to 91%. Our data provide direct evidence for the transfer of viral C and N back into the microbial loop through protist grazing and bacterial breakdown, representing a globally significant flux that needs to be investigated further to better understand and predictably model the C and N cycles of the hydrosphere.
Deciphering the RNA Modification Landscape in Arabidopsis Chloroplast tRNAs and rRNAs Reveals a Blend of Ancestral and Acquired Characteristics
Authors: Gołębiewska Kinga , Gregorová Pavlína , Sarin L. Peter , Gawroński Piotr 
Published: June 2024

ABSTRACTChloroplasts in plant leaves are essential for protein synthesis, relying on transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) encoded by the chloroplast genome. Although post-transcriptional modifications of these non-coding RNAs are common in many systems, chloroplast tRNA and rRNA modifications are not well characterised.In this study, we investigated the post-transcriptional modifications in chloroplast tRNAs and rRNAs ofArabidopsis thalianausing tRNA sequencing, liquid chromatography-mass spectrometry, targeted rRNA sequencing, and analysis of public data.Our results revealed similarities between chloroplast non-coding RNAs and bacterial systems (e.g.,Escherichia coli), such as modification patterns at the anticodon-adjacent position and the variable loop of tRNAs, along with conserved modifications in the small subunit rRNA. Additionally, we identified features shared with eukaryotic systems that likely contribute to the correct three-dimensional structure of chloroplast tRNAs. Unique modifications were also discovered, including a potential novel modification at wobble position in tRNA-IleCAU, which may be crucial for distinguishing isoleucine codons from methionine codons, and chloroplast-specific rRNA modifications that likely compensate for altered ribosome structure.These findings suggest that the chloroplast translation machinery, through co-evolution with its eukaryotic host, has adopted features beyond those typically found in bacteria, reflecting a blend of ancestral and acquired characteristics.
A new oculomotor model demystifies “Remarkable Saccades”
Authors: Heinen  , Chandna  , Singh  , Watamaniuk  
Published: June 2024

AbstractHering’s Law of binocular eye movement control guides most oculomotor research and supports diagnosis and treatment of clinical eye misalignment (strabismus). The law states that all eye movements are controlled by a unitary conjugate signal and a unitary vergence signal that sum. Recent evidence of temporally asynchronous inter-eye rotations during vergence (Chandna et al., 2021) challenges the viability of a unitary vergence signal. An alternative theory that might explain these anomalous results posits that the eyes are controlled independently. Yet independent control fails to explain a phenomenon known as “Remarkable Saccades” where an inappropriate saccade occurs from an eye aligned on a target during asymmetric vergence (Enright, 1992). We introduce a new model formulated to describe the Chandna et al. (2021) midline vergence result that generates remarkable saccades as an emergent property. The Hybrid Binocular Control model incorporates independent controllers for each eye with a cortical origin that interact with a unitary conjugate controller residing in brainstem. The model also accounts for behavioral variations in remarkable saccades when observers attend to an eye. Furthermore, it suggests more generally how the eyes are controlled during vergence and other voluntary eye movements, thus challenging documented oculomotor neural circuitry and suggesting that refinements are needed for clinical oculomotor interventions.
Oral vancomycin treatment alters levels of indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes during EAE
Authors: Bianchimano Paola , Leone Paola , Smith Emma M. , Gutierrez-Vazquez Cristina , Wind-andersen Erli , Bongers Gerold , Cristancho Sebastian , Weiner Howard L. , Clemente Jose C. , Tankou Stephanie K. 
Published: June 2024

ABSTRACTAstrocytes play important roles in the central nervous system (CNS) during health and disease. Prior studies have shown that gut commensals derived indole derivatives as well as secondary bile acids modulate astrocyte function during the late stage of EAE (recovery phase). Here we show that administering vancomycin to mice starting during the early stage of EAE improved disease recovery, an effect that is mediated by the gut microbiota. We observed that 6 taxa within theClostridia vadin BB60group were enriched in vancomycin treated mice compared to untreated EAE mice. Vancomycin-treated EAE mice also had elevated serum levels of the anti-inflammatory tryptophan derived metabolite, indole-3-lactic acid and decreased levels of deoxycholic acid, a pro-inflammatory secondary bile acid. RNA sequencing revealed altered expression of several genes belonging to the mammalian target of rapamycin (mTOR) pathway in astrocytes obtained during the late stage of EAE from vancomycin treated EAE mice. Furthermore, we observed a link between serum levels of indole derivatives and bile acids and expression of several genes belonging to the mTOR pathway. Interestingly, the mTOR signaling cascades have been implicated in several key biological processes including innate (e.g., astrocyte) immune responses as well as neuronal toxicity/degeneration. In addition, rapamycin, a specific inhibitor of mTOR, has been shown to inhibit the induction and progression of established EAE. Collectively, our findings suggest that the neuroprotective effect of vancomycin is at least partially mediated by indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes.HIGHLIGHTSVancomycin attenuated established EAE through regulation of the microbiotaVancomycin induced increased serum levels of indole-3-lactic acid, decreased serum levels of indoxyl-3-sulfate, p-cresol and decreased stool levels of deoxycholic acidVancomycin modulated the expression of mTOR pathway genes in astrocytesLactobacillus reuteriregulated the expression of mTOR pathway genes in astrocytesSerum levels of indole-3-lactic acid, indoxyl-3-sulfate, p-cresol and deoxycholic acid correlated with expression of mTOR pathway genes in astrocytes
A haplotype-resolved view of human gene regulation
Authors: Vollger Mitchell R. , Swanson Elliott G. , Neph Shane J. , Ranchalis Jane , Munson Katherine M. , Ho Ching-Huang , Sedeño-Cortés Adriana E. , Fondrie William E. , Bohaczuk Stephanie C. , Mao Yizi , Parmalee Nancy L. , Mallory Benjamin J. , Harvey William T. , Kwon Younjun , Garcia Gage H. , Hoekzema Kendra , Meyer Jeffrey G. , Cicek Mine , Eichler Evan E. , Noble William S. , Witten Daniela M. , Bennett James T. , Ray John P. , Stergachis Andrew B. 
Published: June 2024

AbstractMost human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We demonstrate that Fiber-seq Inferred Regulatory Elements (FIREs) enable the accurate quantification of chromatin accessibility across the 6 Gbp diploid human genome with single-molecule and single-nucleotide precision. We find that cells can harbor >1,000 regulatory elements with haplotype-selective chromatin accessibility (HSCA) and show that these elements preferentially localize to genomic loci containing the most human genetic diversity, with the human leukocyte antigen (HLA) locus showing the largest amount of HSCA genome-wide in immune cells. Furthermore, we uncover HSCA elements with sequence non-deterministic chromatin accessibility, representing likely somatic epimutations, and show that productive transcription from the inactive X chromosome is buttressed by clustered promoter-proximal elements that escape X chromosome inactivation.
Calorie Restriction Induces Degeneration of Neurons with Mitochondrial DNA Depletion by Altering ER-Mitochondria Calcium Transfer
Authors: Zhou Lingyan , Bao Feixiang , Zheng Jiajun , Ding Yingzhe , Xiao Jiahui , Zhang Jian , Qin Yongpeng , Yang Liang , Wu Yi , Meng Qi , Lu Manjiao , Long Qi , Hu Lingli , Wang Haitao , Huang shijuan , Chen Gong , Liu Xingguo 
Published: June 2024

AbstractMitochondrial DNA (mtDNA) mutations and/or depletion are implicated in epilepsy and many neurodegenerative diseases. However, systematic investigation into how mtDNA alterations relate to epilepsy and neural degeneration is needed. Here, we established a mouse model where in mtDNA depletion induced by Herpes Simplex Virus Type 1 (HSV-1) protein-UL12.5 in the brain led to an epileptic phenotype characterized by abnormal electroencephalography (EEG) patterns and increased neural excitability in hippocampus. We also found that UL12.5 mediated mtDNA depletion in neuronsin vitro(rho-) causes epilepsy–like abnormal EEG. Caloric restriction (CR) is a strategy proven to reduce epileptic activity, however CR mimetic 2-deoxy-D-glucose (2-DG), induced degeneration in mtDNA depleted neurons. Mechanistically, mtDNA depletion increased mitochondria-endoplasmic reticulum (ER) contacts, facilitating CR-induced mitochondrial calcium overload. Rho-neurons did not show changes in mitochondrial motility or membrane potential. Our study revealed an unexpected axis of mtDNA depletion, ER-mitochondrial contacts, and calcium overload in the rho-neuron model. This is the first description of animal and neuronal models of mitochondrial epilepsy. Our findings with these models suggest that CR may not be a viable clinical intervention in patients with mtDNA depletion.
Cellular dsRNA interactome reveals the regulatory map of exogenous RNA sensing
Authors: Lim JinA , Lee Namseok , Ju Seonmin , Kim Jeesoo , Mun Subin , Jeon Moonhyeon , Lee Yong-ki , Lee Seok-Hoon , Ku Jayoung , Kim Sujin , Bae Sangsu , Kim Jong-Seo , Kim Yoosik 
Published: June 2024

SUMMARYRNA-binding proteins (RBPs) provide a critical post-transcriptional regulatory layer in determining RNA fate. Currently, UV crosslinking followed by oligo-dT pull-down is the golden standard in identifying the RBP repertoire, but such method is ineffective in capturing RBPs that recognize double-stranded RNAs (dsRNAs). Here, we utilize anti-dsRNA antibody immunoprecipitation followed by quantitative mass spectrometry to comprehensively identify RBPs bound to cellular dsRNAs without any external stimulus. Notably, our dsRNA interactome contains proteins involved in sensing N6-methyladenosine RNAs and stress granule components. We further perform targeted CRISPR-Cas9 knockout functional screening and discover proteins that can regulate the interferon (IFN) response during exogenous RNA sensing. Interestingly, depleting dsRBPs mostly attenuate the IFN response, and they act as antiviral factors during human β-coronavirus HCoV-OC43 infection. Our dsRNA interactome capture provides an unbiased and comprehensive characterization of putative dsRBPs and will facilitate our understanding of dsRNA sensing in both physiological and pathological contexts.
NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis
Authors: Naddaf Elie , Nguyen Thi Kim Oanh , Watzlawik Jens O. , Gao Huanyao , Hou Xu , Fiesel Fabienne C. , Mandrekar Jay , Kokesh Eileen , Harmsen William S. , Lanza Ian R. , Springer Wolfdieter , Trushina Eugenia 
Published: June 2024

AbstractBackgroundInclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients, highlighting sex differences.MethodsWe included 38 IBM patients and 22 age- and sex-matched controls without myopathy. Bulk RNA sequencing, Meso Scale Discovery ELISA, western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.ResultsWe demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated. On muscle histopathology, there is increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction—NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy, most significantly in males, with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction.NLRP3 RNAlevels correlated with p-S65-Ubiquitin levels in both sexes but with loss of in muscle strength only in males. Finally, we identified sex-specific molecular pathways in IBM, with females having activation of pathways that could offset some of the pathomechanisms of IBM.ConclusionsNLRP3 inflammasome is activated in IBM, along with altered mitophagy particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.