bluuebunny/crossref_metadata_2025_split huggingface dataset:
RapA opens the RNA polymerase clamp to disrupt post-termination complexes and prevent cytotoxic R-loop formation
Authors: Brewer Joshua J. , Inlow Koe , Mooney Rachel A. , Bosch Barbara , Olinares Paul Dominic B. , Marcelino Leandro Pimentel , Chait Brian T. , Landick Robert , Gelles Jeff , Campbell Elizabeth A. , Darst Seth A. 
Published: October 2024

ABSTRACTFollowing transcript release during intrinsic termination,Escherichia coliRNA polymerase (RNAP) often remains associated with DNA in a post-termination complex (PTC). RNAPs in PTCs are removed from the DNA by the Swi2/Snf2 ATPase RapA. Here, we determined PTC structures on negatively-supercoiled DNA as well as of RapA engaged to dislodge the PTC. We found that core RNAP in the PTC can unwind DNA and initiate RNA synthesis but is prone to producing R-loops. We show that RapA helps control cytotoxic R-loop formationin vivo, likely by disrupting PTCs. Nucleotide binding to RapA triggers a conformational change that opens the RNAP clamp, allowing DNA in the RNAP cleft to reanneal and dissociate. We suggest that analagous ATPases acting on PTCs to suppress transcriptional noise and R-loop formation may be widespread. These results hold significance for the bacterial transcription cycle and highlight a role for RapA in maintaining genome stability.
Suppression of cyclooxygenase-2 predisposes to heart failure with preserved ejection fraction
Authors: Ricciotti Emanuela , Haines Philip G. , Beerens Manu , Kartoun Uri , Castro Cecilia , Tang Soon Yew , Ghosh Soumita , Das Ujjalkumar S. , Lahens Nicholas F. , Wang Tao , Griffin Jules L. , Shaw Stanley Y. , MacRae Calum A. , FitzGerald Garret A. 
Published: October 2024

AbstractHeart failure (HF) is one of the most strongly associated adverse cardiovascular events linked to the use of cyclooxygenase (COX)-2 selective and non-selective nonsteroidal anti-inflammatory drug (NSAID). Nevertheless, it remains uncertain whether NSAID exposure is more likely to lead to heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF).In adult mice, postnatal genetic deletion or pharmacological inhibition of COX-2 did not affect cardiac function. In contrast, aged female inducible COX-2 (iCOX-2) knockout (KO) mice displayed diastolic dysfunction, cardiac hypertrophy, pulmonary congestion, and elevated levels of plasma N-terminal pro B-type natriuretic peptide (BNP) when compared to age- and sex- matched controls, while their ejection fraction (EF) remained preserved (≥ 50%). No such phenotype was observed in aged male iCox-2 KO mice. Aged female iCox-2 KO mice showed a shift from prostanoid to leukotriene biosynthesis, along with changes in the expression of mitochondrial genes and calcium-handling proteins in the myocardium. The ratio of phospholamban to SERCA2a was increased, indicating an inhibitory effect on SERCA2a activity, which may contribute to impaired myocardial relaxation. In larval zebrafish, COX-2 inhibition by celecoxib caused a modest yet significant reduction in heart rate and diastolic function, while EF was preserved. Additionally, celecoxib increased BNP expression and ventricular calcium transient amplitude. Diabetic patients in the Harvard-Partners electronic medical record exposed to NSAIDs selective for COX-2 inhibition were more strongly associated with an increased risk of HFpEF compared to HFrEF.Collectively, these findings indicate that COX-2 deletion or inhibition does not impair systolic cardiac function but instead leads to an HFpEF phenotype in mice, zebrafish, and humans. An imbalance in calcium handling may mediate the impairment of myocardial relaxation following COX-2 suppression.SummaryGenetic deletion or pharmacological inhibition of COX-2 results in heart failure with preserved ejection fraction across zebrafish, mice, and humans.
Kinetochore-centrosome feedback linking CENP-E and Aurora kinases controls chromosome congression
Authors: Vukušić Kruno , Tolić Iva M. 
Published: October 2024

ABSTRACTChromosome congression is crucial for accurate cell division, with key roles played by kinetochore components such as CENP-E/kinesin-7 and Aurora B kinase. However, Aurora kinases can both inhibit and promote congression, suggesting the presence of a larger, yet poorly understood, signaling network. Our study demonstrates that centrosomes primarily inhibit congression initiation when CENP-E is inactive or absent by regulating the activity of kinetochore components. Depleting centrioles via Plk4 inhibition allows chromosomes near acentriolar poles to initiate congression independently of CENP-E. In contrast, at centriolar poles high Aurora A activity enhances Aurora B activity, increasing phosphorylation of microtubule-binding proteins at kinetochores and preventing stable microtubule attachments in the absence of CENP-E. Conversely, inhibiting Aurora A reduces Aurora B activity, enabling congression initiation even without CENP-E. These findings suggest a feedback network involving Aurora kinases and CENP-E that regulates timing of chromosome movement by modulating kinetochore-microtubule interactions, with centrosomes and the Aurora A activity gradient providing critical spatial cues for the network’s function.
A minimalist model lipid system mimicking the biophysical properties ofEscherichia coli’smembrane
Authors: Tormena Nicolo , Pilizota Teuta , Voitchovsky Kislon 
Published: October 2024

AbstractBiological membrane are highly complex systems that are of fundamental importance to the development and survival of organisms. Native membranes typically comprise different types of lipids, biomolecules and proteins assembled around a lipid bilayer structure. This complexity can render investigations challenging, with many studies relying on model membranes such as artificial vesicles and supported lipid bilayers (SLBs). The purpose of a model system is to capture the desired dominant features of the native context while remaining uniquely defined and simpler. Here, we search for a minimal lipid-only model system of theEscherichia coliinner membrane. We aim to retain the main lipidomic components in their native ratio while mimicking the membrane thermal and mechanical properties. We design a collection of candidate model systems reflecting the main aspects of the known native lipidomic composition and narrow down our selection based on the systems’ phase transition temperature. We further test our candidate model systems by independently measuring their elastic properties. We identify 3 ternary model systems able to form stable bilayers that closely mimicE. coli’s inner membrane lipid composition and mechanical properties. These model systems are made of commercially available synthetic 16:0-18:1 phosphatidylethanolamine (POPE), 16:0-18:1 phosphatidylglycerol (POPG), and 16:0-18:1 Cardiolipin (CL). We anticipate our results to be of interest for future studies making use ofE. colimodels, for example investigating membrane proteins’ function or macromolecule-membrane interactions.Significance StatementEscherichia Colimembranes serve as model systems for numerous fundamental and technological applications in the field of membrane biophysics. Being a Gram-negative bacterium,E. Coliis characterized by a thin cell wall that separates two phospholipid membranes: the inner and outer membranes. These membranes are complex, comprising many different lipids, proteins and other biomolecules. Here we develop a minimalist system to mimic the biophysical properties and lipidic composition of E. Coli’s inner membrane. Using only commercially available lipids, we develop a model membrane that can be used for studies where simplicity is needed to aid interpretation of the results, for example to investigate protein-induced mechano-transduction across E. Coli membranes.
Lgl resets Par complex membrane loading at mitotic exit to enable asymmetric neural stem cell division
Authors: LaFoya Bryce , Welch Sarah E. , Prehoda Kenneth E. 
Published: October 2024

SummaryThe Par complex regulates cell polarity in diverse animal cells1–4, but how its localization is restricted to a specific membrane domain remains unclear. We investigated how the tumor suppressor Lethal giant larvae (Lgl) polarizes the Par complex inDrosophilaneural stem cells (NSCs or neuroblasts). In contrast to epithelial cells, where Lgl and the Par complex occupy mutually exclusive membrane domains, Lgl is cytoplasmic when the Par complex is apically polarized in NSCs5. Importantly, we found that Lgl’s key function is not in directly regulating metaphase Par polarity, but rather in removing the Par complex from the membrane at the end of mitosis, creating a "polarity reset" for the next cell cycle. Without this Lgl-mediated reset, we found that residual Par complex remains on the basal membrane during subsequent divisions, disrupting fate determinant polarization and proper asymmetric cell division. These findings reveal a novel mechanism of polarity regulation by Lgl and highlight the importance of the pre-polarized state in Par-mediated polarity.
Efficient Derivation of Immortalized, Isogenic Cell Lines from Genetically Defined Murine Hepatoblastomas
Authors: Wang Huabo , Lu Jie , Chen Keyao , Ma Bingwei , Henchy Colin , Knapp Jessica , Ranganathan Sarangarajan , Prochownik Edward V. 
Published: October 2024

AbstractBackground & AimsMolecularly, hepatoblastoma (HB), the most common childhood liver cancer, is the simplest of all human neoplasms, with the vast majority deregulating the Wnt/β-catenin, Hippo and/or NFE2/NRF2 signaling pathways. Murine HBs can be generated by over-expressing any pairwise or triple combination of mutant forms of these pathways’ terminal effectors, namely β-catenin (B), YAP (Y) and NFE2L2/NRF (N). Each molecular subtypes displays distinct features resembling those of human HBs. However, research has been hampered by a paucity of established cell lines of any species.MethodsWe show here that immortalized cell lines can be routinely established from murine HBs that over-express B+Y and B+Y+N. This is facilitated by the concurrentin vivo,Crispr-mediated inactivation of theCdkn2atumor suppressor locus.ResultsEight BY and 3 BYN cell lines have been generated and characterized and are available to the HB research community. Ten of these lines can be regrown as subcutaneous and metastatic lung tumors in the immuno-competent mice from which they originated while retaining their original histologic features. During maintenance as spheroidsin vitro, or duringin vivopropagation, tumor cells express endothelial cell markers, particularly in regions that are hypoxic and/or in proximity to incipient blood vessels.ConclusionsThe ability to generate isogenic HB cell lines with defined oncogenic drivers should facilitate studies that are best performedin vitro. The approach may also be useful for deriving HB cell lines associated with less common molecular drivers and from human tumors.SynopsisThe derivation of multiple immortalized murine hepatoblastoma cell lines driven by defined oncogenes is described. These lines are isogenic, retain their tumorigenicity in immuno-competent mice, readily form spheroids and express endothelial markers in response to hypoxia. They will allow studies that have heretofore been difficult or impossible to performin vivo.
Thrifty superorganism phenotypes emerge as a plastic response to extreme environments in the Hercules ant
Authors: Plante Érik , Abouheif Ehab , Lessard Jean-Philippe 
Published: October 2024

AbstractHigh-altitude human populations are a classic example of adaptation to extremely stressful environments through thrifty phenotypes, where individuals adapt plastically by reducing specific organ size, like limbs, while maintaining overall size. However, it remains unknown, whether other organisms exhibit thrifty phenotypes, and which external factors may shape them. Here, we address these questions in ant colonies, considered superorganisms. Thethrifty phenotype hypothesisapplied to eusocial organisms predicts that colonies experiencing food shortage should reduce investment in costly individuals. In polymorphic colonies, the largest workers known as “majors” are costly to produce and should therefore be less abundant in colonies experiencing food shortage. Alternatively, thestarvation resistance hypothesisposits that colonies in stressful environments should maintain larger colonies, which provide a nutritional buffer in times of food shortage. We show that the proportion of majors in colonies of the Hercules ant,Camponotus herculeanus, decreases plastically with increasing latitude across the temperate and boreal forest biomes of eastern Canada, independently of their average body size, or colony size, resulting in a thrifty superorganism phenotype. Furthermore, we find that the low number of days, annually, when workers can nurse the brood, best predicts these phenotypes. Our study reinforces claims that eusocial organisms may adapt plastically to fluctuating environments, and that extreme environments favour thrifty phenotypes in both humans and ants.
Disrupted functional brain network associated with presence of hallucinations in Parkinson’s Disease
Authors: Montagnese Marcella , Mehta Mitul A , ffytche Dominic , Firbank Michael , Lawson Rachael A , Taylor John-Paul , Bullmore Edward T , Morgan Sarah E 
Published: October 2024

AbstractBackgroundHallucinations negatively impact quality of life in Parkinson’s disease, yet their neural mechanisms remain poorly understood, particularly in early disease stages. This study aimed to identify functional connectivity differences associated with visual hallucinations in early Parkinson’s Disease and to validate these findings across independent datasets.MethodsResting state fMRI data from two prior independent studies was used (total N=185; N=84 hallucinators and N=101 non-hallucinators). Group differences in functional connectivity were assessed within predefined cytoarchitectonic cortical classes and functional networks, followed by whole-brain analysis using Network-Based Statistics (NBS). Associations with clinical measures, including hallucination severity, motor symptoms, cognition, and attention, were also evaluated.ResultsNBS identified a subnetwork of reduced functional connectivity in hallucinators, connecting regions involved in the default mode, somatomotor and attentional networks. This subnetwork was replicated in a matched sample from our independent cohort (N=50; p<0.01). Functional connectivity within the identified network was significantly associated with hallucination severity (R² = 0.35, p = 0.01), and with baseline and future motor symptoms, cognition, and attention in hallucinators.ConclusionsThe identified functional subnetwork shows promise as a potential biomarker and therapeutic target for Parkinson’s disease psychosis, warranting further investigation and validation in future studies.
Pretrained Patient Trajectories for Adverse Drug Event Prediction Using Common Data Model-based Electronic Health Records
Authors: Kim Junmo , Kim Joo Seong , Lee Ji-Hyang , Kim Min-Gyu , Kim Taehyun , Cho Chaeeun , Park Rae Woong , Kim Kwangsoo 
Published: October 2024

AbstractBackgroundPretraining electronic health record (EHR) data using language models by treating patient trajectories as natural language sentences has enhanced performance across various medical tasks. However, EHR pretraining models have never been utilized in adverse drug event (ADE) prediction. We constructed and externally validated the EHR pretraining model for several ADE prediction tasks and qualitatively analyzed the important features of each ADE cohort.MethodsA retrospective study was conducted on observational medical outcomes partnership (OMOP)-common data model (CDM) based EHR data from two separate tertiary hospitals. The data included patient information in various domains such as diagnosis, prescription, measurement, and procedure. For pretraining, codes were randomly masked, and the model was trained to infer the masked tokens utilizing preceding and following history. In this process, we adopted domain embedding (DE) to provide information about the domain of the masked token, preventing the model from finding codes from irrelevant domains. For qualitative analysis, we identified important features using the attention matrix from each finetuned model.Results510,879 and 419,505 adult inpatients from two separate tertiary hospitals were included in internal and external datasets. EHR pretraining model with DE outperformed all the other baselines in all cohorts. For feature importance analysis, we demonstrated that the results were consistent with priorly reported background clinical knowledge. In addition to cohort-level interpretation, patient-level interpretation was also available.ConclusionsEHR pretraining model with DE is a proper model for various ADE prediction tasks. The results of the qualitative analysis were consistent with background clinical knowledge.
Altered association of plasmatic oxytocin with affective stress response in alcohol use disorder
Authors: Mayer Annalina V. , Schwarze Yana , Stierand Janine , Voges Johanna , Schröder Alexander , Gablentz Janina von der , Junghanns Klaus , Voß Oliver , Krach Sören , Paulus Frieder M. , Rademacher Lena 
Published: October 2024

AbstractOxytocin has been proposed to play a role in the development and maintenance of alcohol use disorder (AUD) through its interactions with stress pathways. Empirical evidence that indicates altered associations between endogenous oxytocin and stress reactivity in AUD is currently lacking. In this study, we investigated baseline plasmatic oxytocin concentrations of early-abstinent patients with AUD (N= 40) and matched healthy control participants (N= 37), who completed the Trier Social Stress Test (TSST) as well as a control task on two separate visits. We measured salivary cortisol and pulse rate as indicators of a physiological stress response, and anxiety ratings as an indicator of an affective stress response at multiple time points. Baseline oxytocin levels did not significantly differ between the groups. However, our results suggest an altered association of oxytocin and affective stress responses in participants with AUD: while participants with AUD showed a positive relationship between plasmatic oxytocin levels and stress-induced anxiety increase, the opposite relationship was found in control participants. We did not find evidence for an association of oxytocin with physiological stress responses. Assuming that affective stress responses mediate addiction-related behaviors like craving and relapse, our findings suggest that administering exogenous oxytocin might not be beneficial in treating AUD, at least during the early stages of abstinence.
Beta-blockers Increase Cardiovascular Mortality in Hemodialysis Patients with Orthostatic Hypotension
Authors: Schiavone M. , Castellaro C , Pereira Redondo JC. , Diaz C. , Laham G. 
Published: October 2024

AbstractBackgroundOrthostatic hypotension (OH) is prevalent among dialysis patients and is a known cardiovascular (CV) risk factor. Beta-blockers (BBs) are commonly prescribed to mitigate CV mortality in this population, despite potential risks associated with OH. This study examines the impact of BBs on CV mortality among dialysis patients with OH.MethodsWe conducted a prospective analysis of 134 dialysis patients from the PRECADIA program at the Centro de Educación Médica e Investigaciones Clínicas (CEMIC), focusing on hemodynamic assessments including blood pressure changes from supine to standing positions, and evaluating CV mortality over a 3-year follow-up. OH was defined by a decrease of ≥10 mmHg in diastolic blood pressure or ≥20 mmHg in systolic blood pressure upon standing. Cox regression analyses were utilized to identify independent predictors of CV mortality.ResultsOf the patients, 23.1% were identified with OH. No significant differences in demographic or baseline clinical characteristics were observed between patients with and without OH, except for a higher diabetes prevalence in the OH group. OH patients treated with BBs demonstrated significantly higher CV mortality (29.6%) compared to those not receiving BBs. Independent predictors of CV mortality included age, time on dialysis, and BB use, with BBs significantly associated with increased CV mortality risk.ConclusionsDialysis patients with OH exhibit a high CV mortality rate, significantly influenced by BB usage. While BBs are recommended for managing CV risks in dialysis patients, their association with increased CV mortality in patients with OH necessitates careful consideration and management strategies.
Typhi Mykrobe: fast and accurate lineage identification and antimicrobial resistance genotyping directly from sequence reads for the typhoid fever agentSalmonellaTyphi
Authors: Ingle Danielle J. , Hawkey Jane , Hunt Martin , Iqbal Zamin , Keane Jacqueline A. , Afolayan Ayorinde O. , Ahmed Niyaz , Andleeb Saadia , Ashton Philip M. , Bogoch Isaac I. , Carey Megan E. , Chattaway Marie Anne , Crump John A. , Guevara Paula Diaz , Howden Benjamin P. , Izumiya Hidemasa , Jacob Jobin John , Judd Louise M. , Kapil Arti , Keddy Karen H. , Kim Justin Y. , Levine Myron M. , Morita Masatomo , Nair Satheesh , Octavia Sophie , Okeke Iruka N. , Osadebamwen Precious E. , Rahman Sadia Isfat Ara , Rokney Assaf , Rasko David A. , Shamanna Varun , Sikorski Michael J. , Smith Anthony M. , Sunmonu Gabriel T. , Tagg Kaitlin A. , Wick Ryan R. , Dyson Zoe A. , Holt Kathryn E. ,   Global Typhoid Genomics Consortium
Published: October 2024

AbstractBackgroundTyphoid fever results from systemic infection withSalmonella entericaserovar Typhi (Typhi) and causes 10 million illnesses annually. Disease control relies on prevention (water, sanitation, and hygiene interventions or vaccination) and effective antimicrobial treatment. Antimicrobial resistant (AMR) Typhi lineages have emerged and become established in many parts of the world. Knowledge of local pathogen populations informed by genomic surveillance, including of lineages (defined by the GenoTyphi scheme) and AMR determinants, is increasingly used to inform local treatment guidelines and to inform vaccination strategy. Current tools for genotyping Typhi require multiple read alignment or assembly steps and have not been validated for analysis of data generated with Oxford Nanopore Technologies (ONT) long-read sequencing devices. Here, we introduce Typhi Mykrobe, a command line software tool for rapid genotyping of Typhi lineages, AMR determinants, and plasmid replicons direct from sequencing reads.