bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of pharmacological and interventional treatment for resistant hypertension-a network meta-analysis
Authors: Tian Zhejia , Barbosa Clara Vollmer , Lang Hannah , Bauersachs Johann , Melk Anette , Schmidt Bernhard MW 
Published: April 2023

AbstractBackgroundResistant hypertension is associated with a high risk of cardiovascular disease, chronic kidney disease and mortality. Yet, its management is challenging. This study aims to establish the comparative effectiveness of pharmacologic and interventional treatments by conducting a network meta-analysis.MethodsMEDLINE, Cochrane Register of Controlled Trials and Web of Science Core Collection were systematically searched in March 2022. Randomized controlled trials comparing treatment options for management of resistant hypertension were included. Outcomes were blood pressure changes, measured in the office and in 24h ambulatory blood pressure measurement. We applied a frequentist random effects model to perform a network meta-analysis combining placebo medication and sham procedure as the reference comparator.ResultsFrom 4771 records, 24 studies met the inclusion criteria with 3458 included patients in total. 12 active treatment alternatives were analyzed. Among all comparators, spironolactone had the highest-ranking probability and was considered the most effective treatment to reduce office systolic blood pressure (−13.30 mmHg [−17.89; −8.72];P< 0.0001) and 24h systolic blood pressure (−8.46 mmHg [−12.54; −4.38]; P < 0.0001) in patients with resistant hypertension.ConclusionAmong all pharmacologic and interventional treatments, spironolactone is the most effective in reducing office and 24h systolic blood pressure in patients with resistant hypertension. More comparative trials and especially trials with long-term follow up are needed.Graphical Abstract
Learning from the expert: studyingSalicorniato understand salinity tolerance
Authors: Salazar Octavio R. , Chen Ke , Melino Vanessa J. , Reddy Muppala P. , Hřibová Eva , Čížková Jana , Beránková Denisa , Aranda Manuel , Jaremko Lukasz , Jaremko Mariusz , Fedoroff Nina V. , Tester Mark , Schmöckel Sandra M. 
Published: April 2023

AbstractSalinity remains a major inhibitor of crop production in irrigated and marginal lands. The identification of genes involved in salinity tolerance has been predominantly limited to model plants and crop species. However, plants naturally adapted to highly saline environments can provide key insights into mechanisms of salinity tolerance. Plants of the genusSalicorniagrow in coastal salt marshes, and their growth is even stimulated by NaCl – much can be learnt from them. We generated genome sequences of twoSalicorniaspecies and studied the transcriptomic and proteomic responses ofSalicornia bigeloviito NaCl. Through the generation of subcellular membrane proteomes, we found that SbiSOS1, a homolog of the well-known SALT-OVERLY-SENSITIVE 1 (SOS1) protein, appears to localize to the tonoplast, where it could be involved in mediating Na+translocation into the vacuole to prevent toxicity in the cytosol. We identified 11 proteins of interest which, when expressed in yeast, altered salinity tolerance. One of these proteins, SbiSALTY, substantially improves yeast growth on saline media. Structural characterization using NMR showed it to be an intrinsically disordered protein and to localize to the endoplasmic reticulumin planta, where it could interact with ribosomes and RNA, potentially stabilizing or protecting them during salt stress. The study and understanding of the molecular mechanisms providing high salinity tolerance inS. bigeloviiis likely to provide significant insights for improving salinity tolerance of crop plants.
Astrocyte-Derived Exosomes Regulate Sperm miR-34c Levels to Mediate the Transgenerational Effects of Paternal Chronic Social Instability Stress
Authors: Champroux Alexandre , Sadat-Shirazi Mitra , Chen Xuan , Hacker Jonathan , Yang Yongjie , Feig Larry A. 
Published: April 2023

ABSTRACTThe effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content that induce stress-specific phenotypes in their offspring. But how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known. We showed previously that exposure of male mice to chronic social instability (CSI) stress results in elevated anxiety and reduced sociability specifically in their female offspring across multiple generations because it reduces miR-34c levels in sperm of stressed males and their unstressed male offspring. Here we describe evidence thatastrocyte-derivedexosomes (A-Exos) carrying miR-34c mediate how CSI stress has this transgenerational effect on sperm. We found that CSI stress decreases miR-34c carried by A-Exos in the prefrontal cortex and amygdala, as well as in the blood of males. Importantly, miR-34c A-Exos levels are also reduced in these tissues in their F1 male offspring, who despite not being exposed to stress exhibit reduced sperm miR-34c levels and transmit the same stress-associated traits to their male and female offspring. Furthermore, restoring A-Exos miR-34c content in the blood of CSI-stressed males by intravenous injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal an unexpected role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.
CNC Knitting Micro-Resolution Mosquito Bite Blocking Textiles
Authors: Holt Bryan , Oswalt Kyle , England Alexa , Murphy Richard , Owens Isabella , Finney Micaela , Wong Natalie , Adhikari Sushil , McCann James , Beckmann John 
Published: April 2023

AbstractMosquitoes and other biting arthropods transmit diseases worldwide, causing over 700,000 deaths each year, and costing about 3 billion annually forAedesspecies alone. These insects also pose a significant threat to agricultural animals. While clothing could provide a simple solution to vector-borne diseases, modern textiles do not effectively block mosquito bites. To address this issue, we have designed three micro-resolution knitted structures, with five adjustable parameters, that can block bites. These designs were integrated into a computer numerical control knitting robot for mass production of bite-blocking garments with minimal human labor. We then quantified the comfort of blocking garments. Our knits enable individuals to protect themselves from insects amidst their day-to-day activities without impacting the environment.One Sentence SummaryWe create micro-resolution mosquito bite blocking knits produced by robotic manufacturing to protect humans against vector-borne disease.
Phylogeny, morphology, virulence, ecology, and host range ofOrdospora pajunii(Ordosporidae), a microsporidian symbiont ofDaphniaspp
Authors: Dziuba Marcin K. , McIntire Kristina M. , Seto Kensuke , Davenport Elizabeth S. , Rogalski Mary A. , Gowler Camden D. , Baird Emma , Vaandrager Megan , Huerta Cristian , Jaye Riley , Corcoran Fiona E. , Withrow Alicia , Ahrendt Steven , Salamov Asaf , Nolan Matt , Tejomurthula Sravanthi , Barry Kerrie , Grigoriev Igor V. , James Timothy Y. , Duffy Meghan A. 
Published: April 2023

AbstractImpacts of microsporidia on host individuals are frequently subtle and can be context dependent. A key example of the latter comes from a recently discovered microsporidian symbiont ofDaphnia,the net impact of which was found to shift from negative to positive based on environmental context. Given this, we hypothesized low baseline virulence of the microsporidian; here, we investigated the impact of infection on hosts in controlled conditions and the absence of other stressors. We also investigated its phylogenetic position, ecology and host range. The genetic data indicates that the symbiont isOrdospora pajunii, a newly described microsporidian parasite ofDaphnia. We show thatO. pajuniiinfection damages the gut, causing infected epithelial cells to lose microvilli and then rupture. The prevalence of this microsporidian could be high (up to 100% in the lab and 77% of adults in the field). Its overall virulence was low in most cases, but some genotypes suffered reduced survival and/or reproduction. Susceptibility and virulence were strongly host-genotype dependent. We found that North AmericanO. pajuniiwere able to infect multipleDaphniaspecies, including the European speciesD. longispina, as well asCeriodaphnia spp. Given the low, often undetectable virulence of this microsporidian, and potentially far reaching consequences of infections for the host when interacting with other pathogens or food, thisDaphnia-O. pajuniisymbiosis emerges as a valuable system for studying the mechanisms of context-dependent shifts between mutualism and parasitism, as well as for understanding how symbionts might alter host interactions with resources.ImportanceThe net outcome of symbiosis depends on the costs and benefits to each partner. Those can be context dependent, driving the potential for an interaction to change between parasitism and mutualism. Understanding the baseline fitness impact in an interaction can help us understand those shifts; for an organism that is generally parasitic, it should be easier for it to become a mutualist if its baseline virulence is relatively low. Recently, a microsporidian was found to become beneficial to itsDaphniahosts in certain ecological contexts, but little was known about the symbiont (including its species identity). Here, we identify it as the microsporidiumOrdospora pajunii. Despite the parasitic nature of microsporidia, we foundO. pajuniito be, at most, mildly virulent; this helps explain why it can shift towards mutualism in certain ecological contexts and helps establishO. pajuniiis a valuable model for investigating shifts along the mutualism-parasitism continuum.
Evaluating Large Language Models on Medical Evidence Summarization
Authors: Tang Liyan , Sun Zhaoyi , Idnay Betina , Nestor Jordan G , Soroush Ali , Elias Pierre A. , Xu Ziyang , Ding Ying , Durrett Greg , Rousseau Justin , Weng Chunhua , Peng Yifan 
Published: April 2023

AbstractRecent advances in large language models (LLMs) have demonstrated remarkable successes in zero- and few-shot performance on various downstream tasks, paving the way for applications in high-stakes domains. In this study, we systematically examine the capabilities and limitations of LLMs, specifically GPT-3.5 and ChatGPT, in performing zero-shot medical evidence summarization across six clinical domains. We conduct both automatic and human evaluations, covering several dimensions of summary quality. Our study has demonstrated that automatic metrics often do not strongly correlate with the quality of summaries. Furthermore, informed by our human evaluations, we define a terminology of error types for medical evidence summarization. Our findings reveal that LLMs could be susceptible to generating factually inconsistent summaries and making overly convincing or uncertain statements, leading to potential harm due to misinformation. Moreover, we find that models struggle to identify the salient information and are more error-prone when summarizing over longer textual contexts.
CDK7 is a Novel Therapeutic Vulnerability in Fibrolamellar Carcinoma
Authors: Nukaya Manabu , Cafferty Crystal , Zahed Katerina , Yun Isabelle , Al-Adra David P. , Kazim Noor A. , Farghli Alaa R. , Chan Marina , Kratz Jeremy D. , Berres Mark E. , Yen Andrew , Gujral Taranjit S. , Sethupathy Praveen , Bradfield Christopher A. , Ronnekleiv-Kelly Sean M. 
Published: April 2023

SummaryFibrolamellar carcinoma (FLC) is a rare and lethal cancer that afflicts young individuals. The tumor arises in the background of a healthy liver, and patients typically present with advanced cancer at the time of diagnosis. Unfortunately, for these patients with advanced or recurrent cancer, no proven systemic therapies exist resulting in only 30-45% of patients surviving to 5 years. Investigations into the molecular underpinning of FLC have revealed a unique gene fusion between heat shock protein 40 (DNAJB1) and the catalytic subunit alpha of protein kinase A (PRKACA), leading to the formation of an oncoprotein (DNAJ-PKAc) that retains kinase activity and is a proven tumor-causing event in FLC. To uncover potential therapeutic targets, we engineered an FLC cell line by introducing theDNAJB1-PRKACAoncogene rearrangement into human hepatocellular cells using CRISPR/Cas9. We identified aberrant cell cycle progression, and follow-up molecular analysis revealed evidence of enhanced cyclin dependent kinase 7 (CDK7) activation in theDNAJB1-PRKACAexpressing FLC cells. These findings were confirmed in human samples of FLC. In turn, targeting CDK7 with selective inhibitors demonstrated efficacy in several patient-derived models of FLC, with minimal toxicity to normal liver. Collectively, this work uncovers a novel candidate therapeutic vulnerability in FLC.
Facilitators and Barriers for Telemedicine Systems in India from Multiple Stakeholder Perspectives and Settings
Authors: Venkataraman Aparna , Fatma Najiya , Edirippulige Sisira , Ramamohan Varun 
Published: April 2023

AbstractTelemedicine is viewed as a crucial tool for addressing the challenges of limited medical resources at healthcare facilities. However, its adoption in healthcare is not entirely realised due to perceived barriers. This systematic review outlines the critical facilitators and barriers that influence the implementation of telemedicine in the Indian healthcare system, observed at the infrastructural, socio-cultural, regulatory and financial levels, from the perspectives of healthcare providers, patients, patient caregivers, society, health organisations and the government. This review complies with the current PRISMA-P protocol. 1200 peer-reviewed studies published from December 2016 to December 2021 in the PubMed, Cochrane, Scopus, Web of Science, CINAHL, MEDLINE and PsycInfo databases were considered for the title and abstract screening, after which 157 articles were chosen for the full-text review. In the end, 26 studies were selected for data synthesis. Data privacy and security concerns, doctor and patient resistance to information and communications technology (ICT), poor infrastructure, and lack of ICT training were considered significant barriers to implementing telemedicine. However, reduced healthcare delivery costs, improved patient access to healthcare in remote areas, and reduced patient waiting times all helped promote telemedicine implementation. The review outcomes also revealed that the barriers and facilitators at the regulatory and financial level largely influenced the adoption of telemedicine systems in India, with 59% (n=20) articles citing a reduction in healthcare delivery costs as the critical facilitator and 59% citing fear of violation of patient privacy and security as the significant barrier.
Screening non-conventional yeasts for organic acid tolerance and engineeringPichia occidentalisfor production ofcis,cis-muconic acid
Authors: Pyne Michael E. , Bagley James A. , Narcross Lauren , Kevvai Kaspar , Exley Kealan , Davies Meghan , Wang Qingzhao , Whiteway Malcolm , Martin Vincent J.J. 
Published: April 2023

ABSTRACTSaccharomyces cerevisiae is a workhorse of industrial biotechnology owing to the organism’s prominence in alcohol fermentation and the suite of sophisticated genetic tools available to manipulate its metabolism. However, S. cerevisiae is not suited to overproduce many bulk bioproducts, as toxicity constrains production at high titers. Here we employ a high-throughput assay to screen 108 publicly accessible yeast strains for tolerance to 20 g L−1adipic acid (AA), a nylon precursor. We identify 15 tolerant yeasts and select Pichia occidentalis for production of cis,cis-muconic acid (CCM), a precursor to AA. By developing a genome editing toolkit for P. occidentalis, we demonstrate fed-batch production of CCM with a maximum titer (38.8 g L−1), yield (0.134 g g−1glucose) and productivity (0.511 g L−1h−1) that surpasses all metrics achieved using S. cerevisiae. This work brings us closer to the industrial bioproduction of AA and underscores the importance of host selection in bioprocessing.
Cortical cellular encoding of thermotactile integration
Authors: Schnepel Philipp , Paricio-Montesinos Ricardo , Ezquerra-Romano Ivan , Haggard Patrick , Poulet James FA 
Published: April 2023

SummaryRecent evidence suggests that primary sensory cortical regions play a role in the integration of information from multiple sensory modalities. How primary cortical neurons integrate multisensory information is unclear, partly because multisensory interactions in the cortex are typically weak or modulatory. To address this question, we take advantage of the robust representation of thermal (cooling) and tactile stimuli in mouse forepaw primary somatosensory cortex (fS1). Using a thermotactile detection task, we show that the perception of threshold level cool or tactile information is enhanced when they are presented simultaneously compared to presentation alone. To investigate the cortical correlates of thermotactile integration, we performed in vivo extracellular recordings from fS1 during unimodal and bimodal stimulation of the forepaw. Unimodal stimulation evoked thermal- or tactile- specific excitatory and inhibitory responses of fS1 neurons. The most prominent features of bimodal, thermotactile stimulation are the recruitment of unimodally silent fS1 neurons, non-linear integration features and a change in the response dynamics to favor longer response durations. Together, we identify quantitative and qualitative changes in cortical encoding that may underlie the improvement in perception of multisensory, thermotactile surfaces during haptic exploration.
Early embryogenesis in CHDFIDD mouse model reveals facial clefts and altered craniofacial neurogenesis
Authors: Hampl M , Jandova N , Luskova D , Novakova M , Prochazka J , Kohoutek J , Buchtova M 
Published: April 2023

ABSTRACTCongenital heart defects, facial dysmorphism and intellectual development disorder (CHDFIDD) is associated with mutations inCDK13gene which encodes a transcription regulating Cyclin-dependent kinase 13 (CDK13). Here we analyzed early embryonic stages of CHDFIDD mouse models with hypomorphic mutation inCdk13gene with very similar phenotypic manifestations plus cleft lip/palate and knockout ofCdk13which exhibits robust phenotype with midfacial cleft.Cdk13is strongly expressed in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme.In vitro,CDK13 protein is located not only in nuclear region but also in the cellular protrusions in cultured mesenchymal cells and cells isolated from dorsal root ganglia. InCdk13-deficient embryos, we found hypoplastic branches of the trigeminal nerve including maxillary branch and additionally we detected significant gene expression changes of molecules involved in neurogenesis (Mef2c,Pou4f1,Sod1,Cdk5rap2,Nrcam) within the developing palatal shelves. Key palate-associated molecules (Msx1andMeis2) were downregulated during early craniofacial development in mutant embryos. These results demonstrate the role of CDK13 in regulation of facial morphogenesis and also growth of craniofacial peripheral nerves.
Alpha Synuclein Modulates Mitochondrial Ca2+Uptake from ER During Cell Stimulation and Under Stress Conditions
Authors: Ramezani Meraj , Wagenknecht-Wiesner Alice , Wang Tong , Holowka David A. , Eliezer David , Baird Barbara A. 
Published: April 2023

ABSTRACTAlpha synuclein (a-syn) is an intrinsically disordered protein prevalent in neurons, and aggregated forms are associated with synucleinopathies including Parkinson’ disease (PD). Despite the biomedical importance and extensive studies, the physiological role of a-syn and its participation in etiology of PD remain uncertain. We showed previously in model RBL cells that a-syn colocalizes with mitochondrial membranes, depending on formation of N-terminal helices and increasing with mitochondrial stress.1We have now characterized this colocalization and functional correlates in RBL, HEK293, and N2a cells. We find that expression of a-syn enhances stimulated mitochondrial uptake of Ca2+from the ER, depending on formation of its N-terminal helices but not on its disordered C-terminal tail. Our results are consistent with a-syn acting as a tether between mitochondria and ER, and we show increased contacts between these two organelles using structured illumination microscopy. We tested mitochondrial stress caused by toxins related to PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) and carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and found that a-syn prevents recovery of stimulated mitochondrial Ca2+uptake. The C-terminal tail, and not N-terminal helices, is involved in this inhibitory activity, which is abrogated when phosphorylation site serine-129 is mutated (S129A). Correspondingly, we find that MPTP/MPP+ and CCCP stress is accompanied by both phosphorylation (pS129) and aggregation of a-syn. Overall, our results indicate that a-syn can participate as a tethering protein to modulate Ca2+flux between ER and mitochondria, with potential physiological significance. A-syn can also prevent cellular recovery from toxin-induced mitochondrial dysfunction, which may represent a pathological role of a-syn in the etiology of PD.
Stacked regressions and structured variance partitioning for interpretable brain maps
Authors: Lin Ruogu , Naselaris Thomas , Kay Kendrick , Wehbe Leila 
Published: April 2023

AbstractRelating brain activity associated with a complex stimulus to different properties of that stimulus is a powerful approach for constructing functional brain maps. However, when stimuli are naturalistic, their properties are often correlated (e.g., visual and semantic features of natural images, or different layers of a convolutional neural network that are used as features of images). Correlated properties can act as confounders for each other and complicate the interpretability of brain maps, and can impact the robustness of statistical estimators. Here, we present an approach for brain mapping based on two proposed methods:stackingdifferent encoding models andstructured variance partitioning. Our stacking algorithm combines encoding models that each use as input a feature space that describes a different stimulus attribute. The algorithm learns to predict the activity of a voxel as a linear combination of the outputs of different encoding models. We show that the resulting combined model can predict held-out brain activity better or at least as well as the individual encoding models. Further, the weights of the linear combination are readily interpretable; they show the importance of each feature space for predicting a voxel. We then build on our stacking models to introduce structured variance partitioning, a new type of variance partitioning that takes into account the known relationships between features. Our approach constrains the size of the hypothesis space and allows us to ask targeted questions about the similarity between feature spaces and brain regions even in the presence of correlations between the feature spaces. We validate our approach in simulation, showcase its brain mapping potential on fMRI data, and release a Python package. Our methods can be useful for researchers interested in aligning brain activity with different layers of a neural network, or with other types of correlated feature spaces.