bluuebunny/crossref_metadata_2025_split huggingface dataset:
Water and chloride as allosteric inhibitors in WNK kinase osmosensing
Authors: Teixeira Liliana R. , Akella Radha , Humphreys John M. , He Haixia , Goldsmith Elizabeth J. 
Published: September 2023

ABSTRACTOsmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1and CWN2). Here we show that PEG400 applied to crystals of dimeric uWNK1 induces de-dimerization. Both the WNK1 the water networks and the chloride binding site and are disrupted by PEG400. CWN1 is surrounded by a cluster of pan-WNK-conserved charged residues. Here we mutagenized these charges in WNK3, a highly active WNK isoform kinase domain, and WNK1, the isoform best studied crystallographically. Mutation of E314 in the Activation Loop of WNK3 (WNK3/E314Q and WNK3/E314A, and the homologous WNK1/E388A) enhanced the rate of autophosphorylation, and reduced chloride sensitivity. Other WNK3 Cluster mutants reduced the rate of autophosphorylation activity coupled with greater chloride sensitivity than wild-type. The water and chloride regulation thus appear linked. The lower activity of some mutants may reflect effects on catalysis. Crystallography showed that activating mutants introduced conformational changes in similar parts of the structure to those induced by PEG400. WNK activating mutations and crystallography support a role for CWN1 in WNK inhibition consistent with water functioning as an allosteric ligand.
Saccharomycotina yeasts defy longstanding macroecological patterns
Authors: David Kyle T. , Harrison Marie-Claire , Opulente Dana A. , LaBella Abigail L. , Wolters John F. , Zhou Xiaofan , Shen Xing-Xing , Groenewald Marizeth , Pennell Matt , Hittinger Chris Todd , Rokas Antonis 
Published: September 2023

AbstractThe Saccharomycotina yeasts (“yeasts” hereafter) are a fungal clade of scientific, economic, and medical significance. Yeasts are highly ecologically diverse, found across a broad range of environments in every biome and continent on earth1; however, little is known about what rules govern the macroecology of yeast species and their range limits in the wild2. Here, we trained machine learning models on 12,221 occurrence records and 96 environmental variables to infer global distribution maps for 186 yeast species (∼15% of described species from 75% of orders) and to test environmental drivers of yeast biogeography and macroecology. We found that predicted yeast diversity hotspots occur in mixed montane forests in temperate climates. Diversity in vegetation type and topography were some of the greatest predictors of yeast species richness, suggesting that microhabitats and environmental clines are key to yeast diversification. We further found that range limits in yeasts are significantly influenced by carbon niche breadth and range overlap with other yeast species, with carbon specialists and species in high diversity environments exhibiting reduced geographic ranges. Finally, yeasts contravene many longstanding macroecological principles, including the latitudinal diversity gradient, temperature-dependent species richness, and latitude-dependent range size (Rapoport’s rule). These results unveil how the environment governs the global diversity and distribution of species in the yeast subphylum. These high-resolution models of yeast species distributions will facilitate the prediction of economically relevant and emerging pathogenic species under current and future climate scenarios.
Potassium-mediated bacterial chemotactic response
Authors: Zhang Chi , Zhang Rongjing , Yuan Junhua 
Published: September 2023

AbstractBacteria in biofilms secrete potassium ions to attract free swimming cells. However, the basis of chemotaxis to potassium remains poorly understood. Here, using a microfluidic device, we found thatEscherichia colican rapidly accumulate in regions of high potassium concentration on the order of millimoles. Using a bead assay, we measured the dynamic response of individual flagellar motors to stepwise changes in potassium concentration, finding that the response resulted from the chemotaxis signaling pathway instead of the motor response to changes in the proton motive force (PMF). To characterize the chemotactic response to potassium, we exposed the bacteria to a range of potassium concentrations and measured the dose-response curve and adaptation kinetics via a FRET assay, finding that the chemotaxis pathway exhibited a sensitive response and fast adaptation to potassium. We further found that the two major chemoreceptors Tar and Tsr respond differently to potassium. Tar receptors exhibit a biphasic response, whereas Tsr receptors respond to potassium as an attractant. These different responses were consistent with the responses of the two receptors to intracellular pH changes. Therefore, bacteria may sense the change in potassium concentration by sensing the change in intracellular pH. The sensitive response and fast adaptation allow bacteria to sense and localize small changes in potassium concentration. As the ratio of the two major chemoreceptors changes with bacterial growth stages, the differential responses of Tar and Tsr receptors to potassium suggest that cells at different growth stages respond differently to potassium and may have different requirements for potassium.
Cystic fibrosis transmembrane conductance regulator (CFTR) downregulates the excitability of deep pyramidal neurons in the rodent cortex
Authors: Cheng Zongyue , Sun Xuan , Xing Wang , Luo Fei , Chan Hsiao Chang , Gan Wenbiao , Li Baoming 
Published: September 2023

AbstractThe cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding chloride channel that is regulated by intracellular cAMP/PKA phosphorylation. CFTR is widely expressed in peripheral tissues and organs of mammals and plays a vital role in maintaining chloride balance and cellular homeostasis. While preliminary studies have identified CFTR expression in the central nervous system (CNS), it is not clear whether this channel also modulates the neural network of the cerebral cortex by regulating the intracellular chloride level of neurons. In this study, we employed immunohistochemical staining, patch-clamp recording, and two-photon imaging techniques to comprehensively analyze the functions of the CFTR channel in the rodent cortex. Our results indicate that CFTR is primarily distributed in the deep pyramidal somata and superficial axons of the cerebral cortex. Regulation of CFTR has the potential to alter the resting membrane potential and evoke action potentials of layer V pyramidal neurons, which produces significant changes in inhibitory synaptic transmission. Furthermore, we found that inhibiting CFTR channels increased the calcium activity of axon boutons and somata of the primary motor cortex in vivo, promoting motor learning. Overall, these findings implicate a crucial role of CFTR in modulating Cl-homeostasis and neuronal excitability in the cerebral cortex, furthering our understanding of the functions of the chloride channel in the central nervous system.
Genetically predicted 25-Hydroxyvitamin D levels on Hypothyroidism: A two-sample Mendelian Randomization
Authors: Akbarzadeh Mahdi , Fateh Sahand Tehrani , Moeinafshar Aysan , Habibi Danial , Ghanooni Amir Hossein , Saeidian Amir Hesam , Riahi Parisa , Zarkesh Maryam , Lanjanian Hossein , Jahangiri Mina , Moazzam-Jazi Maryam , Teymoori Farshad , Azizi Fereidoun , Hedayati Mehdi , Daneshpour Maryam Sadat 
Published: September 2023

AbstractBackgroundAlterations in levels of 25-Hydroxyvitamin D have been associated with the risk of thyroid disease. This study uses Mendelian randomization (MR) to infer the possible causal association of 25-Hydroxyvitamin D with hypothyroidism.MethodsWe performed two-sample MR using the summary statistics data from genome-wide association studies (GWAS) from populations with European ancestry to infer the causality of genetically controlled levels of 25-Hydroxyvitamin D on the risk of hypothyroidism, Hashimoto’s thyroiditis, as well as biochemical parameters of thyroid diseases. The inverse-variance method (IVW) was used as the primary method to calculate the combined effect of all SNPs. Other methods were adopted to evaluate the stability and reliability of the results. Comprehensive sensitivity analyses were conducted to ensure that none of the MR analysis’s primary assumptions were violated.ResultsThe results of the IVW analysis revealed a significant causal association between higher levels of 25-Hydroxyvitamin D and lower risk of hypothyroidism (beta = −0.197, 95% CI (− 0.301, −0.093); SE = 0.053, Pbeta= 2.256×10-4) as well as increased levels of free T4 (beta = 0.204, 95% CI (0.305, 0.094); SE = 0.056, Pbeta= 3.0506×10−4). On the other hand, no significant causality was determined for higher levels of 25-Hydroxyvitamin D in association with Hashimoto’s thyroiditis (beta=-0.047, 95% CI (−0.245, 0.151), p=0.641) and TSH levels (beta = −0.024, 95% CI (−0.099, - 0.051); Pbeta= 0.524).ConclusionThe results of this two-sample MR study provide evidence supporting the potential of 25-Hydroxyvitamin D supplementation in reducing the risk of hypothyroidism.
The COVID-19 pandemic has increased health inequalities by altering patterns of engagement with a mass participation event after resumption post-lockdown
Authors: Gilburn Andre S. 
Published: September 2023

AbstractThe global epidemic in physical inactivity has been exacerbated by lockdowns with concerning health inequalities accentuated as a result. Studies are needed of post-lockdown levels of activity to determine if there are lasting impacts beyond lockdown. This study uses parkrun in Scotland as a model system to address this urgent question. Generalised linear mixed models were used to identify patterns in the attendance, gender, age and performance of 500,000+ parkrun participations in Scotland for the year before the pandemic and the first year after lockdown. Total weekly attendance in Scotland had been increasing year-on-year but fell by 13% from 7,649 (95% CI 7,275 to 8.024) in the final-year pre-lockdown to 6,612 (95% CI 6,260 to 6,963) in the first-year post-lockdown. Attendance drops were disproportionately larger at events with larger attendances prior to lockdown. There was a disproportionate loss of female participants in more deprived areas. The gender gap in participation had been narrowing before lockdown but widened from 54.02% (95% CI 53.85 to 54.19%) in the final-year pre-lockdown to 56.29% male (95% CI 56.09 to 56.49%) in the first-year post-lockdown. The age of participants increased from 44.94 (95% CI 44.90 to 44.98) before lockdown to 46.58 (95% CI 46.53 to 46.64) after lockdown. The age gap between the genders widened after lockdown particularly at larger events and in more deprived areas. Performance was declining before lockdown but increased from 55.02% (95% CI 54.96 to 55.06%) to 55.93% (95% CI 55.88 to 55.97%) after lockdown. The pandemic has reduced attendance at parkrun in Scotland and the loss of participants has been non-random increasing health inequalities affecting women, the least fit and those in deprived areas. Some former participants are also now avoiding larger mass participation events. Investment and management strategies will be needed to address these worsening inequalities.
Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort
Authors: Amorim Gustavo , Jaworski James , Cordeiro-Santos Marcelo , Kritski Afrânio L. , Figueiredo Marina C. , Turner Megan , Andrade Bruno B. , Velez Edwards Digna R. , Santos Adalberto R. , Rolla Valeria C. , Sterling Timothy R. , Haas David W. ,   the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil network
Published: September 2023

AbstractBackgroundGenetic polymorphisms have been associated with risk of anti-tuberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil.MethodsParticipants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015-2019, and who were evaluable for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24 month follow-up. Analyses included 43 polymorphisms in 20 genes related to anti-tuberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset.ResultsAmong 903 participants in multivariable genetic association analyses,NAT2slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely amongNAT2rapid acetylators, but not statistically significant at the 5% level. AGSTM1polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity.SLCO1B1polymorphisms were associated with increased risk of treatment- related hepatoxicity and treatment failure/recurrence. Polymorphisms inNR1/2were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism inVTI1A, and the genesMETTL17andPRSS57, but none achieved genome-wide significance.ConclusionsIn a clinical cohort representing three regions of Brazil,NAT2acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations.
Risk Stratification for Ventricular Tachyarrhythmia in Patients with Non-Ischemic Cardiomyopathy
Authors: Goldenberg Ido , Younis Arwa , Huang David T. , Rosero Spencer , Kutyifa Valentina , McNitt Scott , Polonsky Bronislava , Steinberg Jonathan S. , Zareba Wojciech , Goldenberg Ilan , Aktas Mehmet K. 
Published: September 2023

ABSTRACTBackgroundThe implantable cardioverter defibrillator reduces mortality among patients with heart failure (HF) due to ischemic heart disease. Clinical trial data have called into question the benefit of an ICD in patients with HF due to non-ischemic cardiomyopathy (NICM).ObjectiveWe developed a risk stratification score for ventricular tachyarrhythmia (VTA) among patients with NICM receiving a primary prevention ICD.MethodsThe study population comprised of 1,515 patients with NICM who were enrolled in the landmark MADIT trials. Fine and Gray analysis was used to develop a model to predict the occurrence of VTAs and ICD therapies while accounting for the competing risk of non-arrhythmic mortality. External validation was carried out in the RAID Trial population.ResultsFour risk factors associated with increased risk for VTA were identified: male sex, left ventricular ejection fraction ≤25%, no indication for cardiac resynchronization therapy with a defibrillator (CRT-D), and Black race. A score was generated based on this model and patients were stratified into low (N=390), intermediate (N=728), and high-risk (N=387) groups. The five-year cumulative incidences of VTA were 15%, 24%, 42% respectively. Application of score groups for the secondary endpoints of Fast VT or VF and Appropriate ICD Shock revealed similar findings. Recurrent event analysis yielded consistent results. The AUC in the validation cohort for the endpoint of Appropriate ICD Shock was 69.3.ConclusionsOur study shows that patients with NICM can be risk stratified using demographic and clinical variables and may be used when evaluating such patients for a primary prevention ICD.CONDENSED ABSTRACTData regarding the effectiveness of the ICD is lacking in patients with HF and NICM. The purpose of this study was to develop a risk score for ventricular tachyarrhythmia (VTA) among patients with NICM. We included patients from the MADIT trials to generate a risk score. Four risk factors associated with increased risk for VTA were identified and incorporated into the score. Patients were stratified into low, intermediate, and high-risk groups. The five-year cumulative incidences of VTA were 15%, 24%, 42% respectively. Our risk prediction model can support patient-physician shared decision making regarding primary ICD implantation in patients with NICM.
Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis
Authors: Aygün Nil , Krupa Oleh , Mory Jessica , Le Brandon , Valone Jordan , Liang Dan , Love Michael I. , Stein Jason L. 
Published: September 2023

SummaryThe function of some genetic variants associated with brain-relevant traits has been explained through colocalization with expression quantitative trait loci (eQTL) conducted in bulk post-mortem adult brain tissue. However, many brain-trait associated loci have unknown cellular or molecular function. These genetic variants may exert context-specific function on different molecular phenotypes including post-transcriptional changes. Here, we identified genetic regulation of RNA-editing and alternative polyadenylation (APA), within a cell-type-specific population of human neural progenitors and neurons. More RNA-editing and isoforms utilizing longer polyadenylation sequences were observed in neurons, likely due to higher expression of genes encoding the proteins mediating these post-transcriptional events. We also detected hundreds of cell-type-specific editing quantitative trait loci (edQTLs) and alternative polyadenylation QTLs (apaQTLs). We found colocalizations of a neuron edQTL inCCDC88Awith educational attainment and a progenitor apaQTL inEP300with schizophrenia, suggesting genetically mediated post-transcriptional regulation during brain development lead to differences in brain function.
Sm-like protein Rof inhibits transcription termination factor ρ by binding site obstruction and conformational insulation
Authors: Said Nelly , Finazzo Mark , Hilal Tarek , Wang Bing , Selinger Tim Luca , Gjorgjevikj Daniela , Artsimovitch Irina , Wahl Markus C. 
Published: September 2023

AbstractTranscription termination factor ρ is a hexameric, RNA-dependent NTPase that can adopt active closed-ring and inactive open-ring conformations. The Sm-like protein Rof, a homolog of the RNA chaperone Hfq, inhibits ρ-dependent terminationin vivobut recapitulation of this activityin vitrohas proven difficult and the precise mode of Rof action is presently unknown. Our electron microscopic structures of ρ-Rof and ρ-RNA complexes show that Rof undergoes pronounced conformational changes to bind ρ at the protomer interfaces, undercutting ρ conformational dynamics associated with ring closure and occluding extended primary RNA-binding sites that are also part of interfaces between ρ and RNA polymerase. Consistently, Rof impedes ρ ring closure, ρ-RNA interactions, and ρ association with transcription elongation complexes. Structure-guided mutagenesis coupled with functional assays confirmed that the observed ρ-Rof interface is required for Rof-mediated inhibition of cell growth and ρ-terminationin vitro. Bioinformatic analyses revealed that Rof is restricted to Pseudomonadota and that the ρ-Rof interface is conserved. Genomic contexts ofrofdiffer betweenEnterobacteriaceaeandVibrionaceae,suggesting distinct modes of Rof regulation. We hypothesize that Rof and other cellular anti-terminators silence ρ under diverse, but yet to be identified, stress conditions when unrestrained transcription termination by ρ would be lethal.
Myelin dystrophy in the aging prefrontal cortex leads to impaired signal transmission and working memory decline: a multiscale computational study
Authors: Ibañez Sara , Sengupta Nilapratim , Luebke Jennifer I. , Wimmer Klaus , Weaver Christina M. 
Published: September 2023

ABSTRACTNormal aging leads to myelin alternations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are often correlated with cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First we built a multicompartment pyramidal neuron model fit to monkey dlPFC data, with axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions, to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination in a population of neurons. Lasso regression identified distinctive parameter sets likely to modulate an axon’s susceptibility to CV changes following demyelination versus remyelination. Next we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from electron microscopy up to behavior on aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.
Neural activity is modulated by spontaneous and volitionally controlled breathing
Authors: Karjalainen Suvi , Kujala Jan , Parviainen Tiina 
Published: September 2023

AbstractRecent studies have provided evidence regarding respiration-brain coupling, but how continuously varying dynamics of breathing modulate neural activity is not known. We examined whether the neural state differs between spontaneous and volitionally controlled breathing and across the phases of breathing, inspiration and expiration. Magnetoencephalography with a respiratory belt was used to record cortical oscillatory activity during spontaneous, deep, and square breathing (n=33). Alpha power was suppressed during inspiration and increased during expiration (p<0.01) indicating dynamically fluctuating neural states across the respiratory cycle. Compared to spontaneous and square breathing, alpha power increased during deep breathing (p<0.01). We also observed a steeper aperiodic slope and a broadband shift in the power spectrum during square breathing in comparison with spontaneous breathing suggesting that spectral characteristics of neural activity are modulated by the rate, depth, and pattern of breathing. Altogether, we demonstrate that neural activity is modulated by breathing techniques and phases of breathing.