bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Beta Blockers on Exercise Capacity, Diastolic Function, and Quality of Life in Patients with Heart Failure with Preserved Ejection Fraction: A Secondary Analysis of INDIE-HFpEF and RELAX
Authors: Weigel Frank R. , Miller Alexandria , Patel Vaiibhav , Haas Garrie , Smith Sakima 
Published: September 2024

ABSTRACTBackgroundThe use of beta blockers in patients with heart failure with preserved ejection fraction (HFpEF) is common, with about 75% of patients in recent landmark clinical trials on beta blockers. Though the implementation of this medication class is routine, there is sparse data to support their use. Furthermore, beta blocker effects on exercise capacity, diastolic function, and quality of life in HFpEF patients is unclear.MethodsA retrospective cohort study was completed using patient-level data from two prior randomized trials. Cohorts were generated based on beta blocker use at the time of trial enrollment, demographic information was compared. Primary outcomes assessed were exercise capacity, diastolic function, and quality of life metrics. The results of baseline testing were utilized to avoid potential bias from each trial’s intervention.ResultsAfter multivariate linear regression, HFpEF patients on beta blockers had no difference in exercise capacity (peak VO2 (mL/kg/min): 12.5 vs 13.5, P=0.933), diastolic function (average E/e’: 16 vs 14, P=0.125; left atrial volume index (mL/m2): 47 vs 42, P=0.665; peak tricuspid regurgitation velocity (m/s): 2.85 vs 2.70, P=0.165), or quality of life survey scores (KCCQ: 54 vs 60, P=0.206; MLHFQ 44 vs 48, P=0.762) compared to those not taking beta blockers.ConclusionsIn this secondary analysis of patient-level data, there was no association with beta blocker use and worsened exercise capacity, diastolic function, or quality of life in HFpEF patients. Randomized controlled trials are necessary to definitively determine the clinical and functional impact of beta blockers in HFpEF.RESEARCH PERSPECTIVEIn this secondary analysis or INDIE-HFpEF and RELAX, there was no significant association with beta blocker use and worsened exercise capacity, diastolic dysfunction, or quality of life in HFpEF patients.With little available evidence to suggest clinical or functional benefits from implementation of beta blockers in HFpEF, randomized controlled trials are warranted to more definitively evaluate the potential effects of this medication class.Evaluating unique HFpEF phenotypes with different comorbidity profiles would provide specific insights that could be translated to the clinical management of HFpEF patients.
Solid-State Nanopore Real Time Assay for Monitoring Cas9 Endonuclease Reactivity
Authors: Chau Chalmers C. , Weckman Nicole E. , Thomson Emma E. , Actis Paolo 
Published: September 2024

AbstractThe field of nanopore sensing is now moving beyond nucleic acid sequencing. An exciting new avenue is the use of nanopore platforms for the monitoring of biochemical reactions. Biological nanopores have been used to investigate the dynamics of enzymatic reactions but solid-state nanopore approaches have lagged. This is partially due to the necessity of using higher salt conditions (e.g.4M LiCl) to improve the signal-to-noise ratio. These conditions are often incompatible with monitoring biological activities such as restriction enzyme and CRISPR-Cas9 endonuclease activities, as their abilities to digest DNA are largely abolished under high salt conditions. We pioneered a polymer electrolyte based solid-state nanopore approach that can maintain a high signal-to-noise ratio even at a physiologically relevant salt concentration. Based on this, we report monitoring the endonuclease activities at physiological salt conditions in real time with a polymer electrolyte nanopore. We successfully monitor the dsDNA cleavage activity of the restriction enzyme SwaI in in a range of digestion buffers and the off-target activity of CRISPR-Cas9 RNP endonuclease in the presence of single base pair mismatches. This approach enables solid-state nanopore technology for the dynamic monitoring of biochemical reactions at single molecule resolution.
Endosymbionts impact ladybird predation rates of aphids in a temperature-dependent manner
Authors: Thomsen Katrine Bitsch , Ross Perran A. , Gill Alex , Yang Qiong , Stelmach Monica , Callahan Ashley , Ørsted Michael , Hoffmann Ary A. , Kristensen Torsten N. 
Published: September 2024

ABSTRACTAphids are worldwide pests causing major economic losses to growers. Current management strategies rely heavily on pesticides, but some effective pesticides are being withdrawn and the efficiency of remaining pesticides is also decreasing as aphids build up resistance. Biological control using predators can provide a sustainable alternative to pesticides under some circumstances, while the deliberate introduction of facultative bacterial endosymbionts that induce host fitness costs and reduce plant virus transmission provides another potential future strategy to combat aphid pests. However, new control options should not be antagonistic, with the concern that the effectiveness of biocontrol might be altered by endosymbiont presence in hosts. We, therefore, tested if predation by two aphidophagous ladybirds,Adalia bipunctataandHarmonia conformis, on the green peach aphid,Myzus persicae, and the oat aphid,Rhopalosiphum padi, was affected by transinfectedRickettsiella viridisand both native and transinfectedRegiella insecticolaendosymbionts at different temperatures. The predation rate of aphids infected by either endosymbiont was higher at 14 ° C than the rate for uninfected aphids of both species, but the opposite pattern was apparent at 20 °C and for one host-endosymbiont combination at 26 °C. Overall, the results showed that higher temperatures increased predation, while differences between intermediate and low temperatures were species-dependent. No transmission of endosymbionts from aphid to ladybird through predation was detected. These findings point to a lack of consistent effects of the investigated endosymbionts on predation rates in these major aphid pests. The temperature dependence of endosymbiont-predation interactions suggests that the impact of seasonal climate should be considered when assessing the potential of endosymbionts in a biological control setting.HIGHLIGHTS-Aphid endosymbiont effects on ladybird predation rates are temperature-dependent-Ladybird predation rate of aphids increases as temperature rises-Prey (aphid) endosymbionts are not transferred to predators (ladybirds)
TBX15 regulates a network of immune response genes in adipose tissue and alters fat mass and depot weight in heterozygous knockout mice
Authors: Zolkiewski L. , Simon M. , Harrison J. , Vizor L. , Ireson E. , Moir L. , Yon M. , Beresford L. , Rodrigues A. , Hill S. , Hawkins J. , Bentley L. , Cox R. D. , Dumbell R. 
Published: September 2024

AbstractAdipose tissue distribution in the body is an indicator of metabolic disease risk, independent of body mass index (BMI), and is indirectly measured by waist-hip-ratio (WHR). T-Box transcription factor-15 (TBX15) has been implicated in regulation of adipose distribution in multiple human and mouse studies, and theTBX15-WARS2genome-wide association study locus has been associated with BMI-adjusted-WHR signals in multiple investigations. As a potential mediator of this signal, we investigated the role ofTbx15using heterozygous and homozygous mouse knockout models to determine if loss of this gene alters adipose physiology, and to identify the transcriptional network regulated byTbx15in adipose tissue and preadipocyte cells. In a metabolic phenotyping experiment we provided either low fat diet (LFD) or high fat diet (HFD) to male and female heterozygousTbx15+/-and wildtypeTbx15+/+mice from weaning and maintained for 24 weeks. OnlyTbx15+/-mice maintained on LFD weighed less than wildtype LFD controls, and female LFDTbx15+/-mice had lower fat mass overall. We found that in LFDTbx15+/-mice, multiple visceral fat depots weighed less than wildtype controls, and this was maintained when corrected for body mass for both gonadal and mesenteric visceral adipose depots. When comparing adipocyte size in multiple adipose depots, some reduction in number of larger adipocytes was detected in the perirenal adipose tissue of female HFDTbx15+/-vsTbx15+/+mice, mesenteric adipose tissue from female LFDTbx15+/-vsTbx15+/+mice and male HFDTbx15+/-vsTbx15+/+mice. RNA-sequencing of subcutaneous (inguinal) adipose tissues from 12-week old male and female knockoutTbx15-/-,Tbx15+/-andTbx15+/+mice raised on a standard chow diet identified 897 upregulated genes and 2328 downregulated genes in femaleTbx15-/-mice compared toTbx15+/+mice. We then combined this dataset with TBX15 ChIP-sequencing data from mouse preadipocyte 3T3-L1 cells overexpressingTBX15to identify acredible setof genes directly regulated by TBX15. These 52 genes were enriched for B- and T-cell receptor signalling, JAK-STAT signalling and haematopoietic cell lineage pathways; suggesting a direct regulatory role for TBX15 in these pathways in adipose tissue. Together, these data highlight a role for TBX15 in regulation of differential adipose tissue expansion, particularly under low caloric conditions. Further, we identify a potentially important role for TBX15 in the well described adipocyte-immune cell crosstalk associated with obesity and type 2 diabetes mellitus.
An explainable map of human gastruloid morphospace reveals gastrulation failure modes and predicts teratogens
Authors: Rufo Joseph , Qiu Chongxu , Han Dasol , Baxter Naomi , Daley Gabrielle , Wilson Maxwell Z. 
Published: September 2024

AbstractHuman gastrulation is a critical stage of development where many pregnancies fail due to poorly understood mechanisms. Using the 2D gastruloid, a stem cell model of human gastrulation, we combined high-throughput drug perturbations and mathematical modelling to create an explainable map of gastruloid morphospace. This map outlines patterning outcomes in response to diverse perturbations and identifies variations in canonical patterning and failure modes. We modeled morphogen dynamics to embed simulated gastruloids into experimentally-determined morphospace to explain how developmental parameters drive patterning. Our model predicted and validated the two greatest sources of patterning variance: cell density-based modulations in Wnt signaling and SOX2 stability. Assigning these parameters as axes of morphospace imparted interpretability. To demonstrate its utility, we predicted novel teratogens that we validated in zebrafish. Overall, we show how stem cell models of development can be used to build a comprehensive and interpretable understanding of the set of developmental outcomes.
Nuclear body reorganization by the viral RNAkaposinpromotes Kaposi’s sarcoma-associated herpesvirus gene expression
Authors: Kleer Mariel , Johnston Michael J. , Corcoran Jennifer A. 
Published: September 2024

SummaryKaposinis the most abundantly expressed viral RNA in tumours caused by the oncogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV); however, its role in viral replication is not well understood. Here we show that during KSHV infection,kaposinactsin cisas an architectural RNA to rebuild cellular nuclear speckles (NSs) to sites proximal to the viral genome to optimize viral gene expression. We showkaposinRNA is both necessary and sufficient for NS remodelling, and ablatingkaposincolocalization with NSs using kaposin-deficient recombinant viruses impairs viral gene expression. This is the first example of an RNA (cellular or viral) capable of scaffolding NS and the first study to definekaposinas an important regulator of KSHV gene expression and, by extension, KSHV-associated disease.Graphical AbstractHighlightsThekaposintranscript is the first RNA (cellular or viral) identified as sufficient to scaffold NSs.Kaposinscaffolding of NSs requires repetitive nucleotide sequences and cellular SRRM2.Lack ofkaposin-NS colocalization during KSHV infection impairs viral gene expression.Kaposinfunctionsin cisto locally influence gene expression.
The molecular basis for prognosis of isoniazid resistance inMycobacterium tuberculosis
Authors: Valafar Siavash J. , Valafar Aram A. , Elmaraachli Wael 
Published: September 2024

AbstractTuberculosis (TB), a disease that kills 1.5 million people every year, is a major global public health concern. The emergence of drug resistance inM. tuberculosis, the obligate pathogen of TB is a major challenge. The emergence of resistance seems to follow an order that might be exploited for novel therapeutic strategies. In most cases resistance to isoniazid (INH) emerges first, followed by rifampicin, then either pyrazinamide or ethambutol, and finally followed by resistance to second-line drugs. For this reason, it is thought that prevention of emergence of INH resistance may help the prevention of resistance to other drugs. In this manuscript we present the prognostic potential of specific mutations in predicting the emergence of the three most common canonical INH resistance (katG315, inhA-15, and inhA-8) with the hope that majority of resistance cases can be predicted and avoided. Here we present evidence that resistance to INH occurs in steps that in most cases follow specific evolutionary trajectory. Identifying these steps can therefore be used to predict and avoid the most common INH resistance mechanism. In our approach, we used genomic and phenotypic data from over 16,000 samples collected by two large databases, the TB Portals and the CRyPTIC consortium. We used classical sensitivity and specificity values as well as a deep learning neural models to identify promising predictive mutations using TB Portals data. We then tested the prognostic potential of the identified mutations using the CRyPTIC consortium data. Here we report two mutations (Rv1258c581 indel &mshAA187V) as those carrying the highest potential for predicting the emergence of the three canonical mutations (accuracy of 73% and specificity of 96%). Our results point to a stepwise evolutionary trajectory toward the emergence of the three canonical mutations. Furthermore, the high negative predictive values provide an opportunity for clinicians to continue using INH in new regiments designed for nonresponsive patients whose samples do not contain the two precursor mutations. Finally, we present testable hypotheses describing the role of the precursor mutations in emergence of the three canonical mutations and the predicted trajectories. Mutagenesis experiments can confirm these hypotheses. Additional time course samples and analysis will undoubtedly uncover additional prognostic markers for other trajectories toward high-level INH resistance.
The Lived Experience of Infertility in Asian Americans: A Qualitative Study
Authors: Vu Michelle , Nguyen Anh-Tho Antoinette , Hyun Jinsol , Dye Timothy , Alur-Gupta Snigdha 
Published: September 2024

AbstractObjectiveTo identify psychosocial and cultural factors among Asian American patients diagnosed with infertility that may contribute to their disparate fertility outcomes.DesignA cross-sectional qualitative interview study was conducted with women ≥18-years-old who identified as Asian American and had a diagnosis of infertility. Semi-structured interviews were performed until thematic saturation was reached. The interviews were transcribed and coded. A codebook was developed to capture the grounded perspectives of participants. The web application Dedoose was utilized to conduct content analysis, identifying common themes and patterns.ResultsAsian Americans voice the importance of having children, emphasizing the cultural expectation to procreate. They reported that infertility caused immense mental and emotional distress, resulting in feelings of disappointment and grief. Participants noted that it is not common in their culture to talk about infertility-related issues. Religion and naturopathic remedies played a large role in helping participants adjust to their infertility journeys. Participants stated that the infertility evaluation was complicated and one particular area of frustration was the lack of individually centered treatment. Interestingly, participants expressed desire to help other Asian women who are also struggling with infertility.ConclusionInfertility is a difficult and complex experience for Asian American women. Parenthood is a strong expectation for people of Asian descent and results in emotional burden when complicated by infertility. Fertility concerns are considered taboo to openly discuss, which can cause additional feelings of isolation. Healthcare providers should work to address the culturally induced shame associated with infertility and provide more individualized care.
Intracellular diffusion in the cytoplasm increases with cell size in fission yeast
Authors: Tan Catherine , Lanz Michael C. , Swaffer Matthew , Skotheim Jan , Chang Fred 
Published: September 2024

ABSTRACTDiffusion in the cytoplasm can greatly impact cellular processes, yet regulation of macromolecular diffusion remains poorly understood. There is increasing evidence that cell size affects the density and macromolecular composition of the cytoplasm. Here, we studied whether cell size affects diffusion at the scale of macromolecules tens of microns in diameter. We analyzed the diffusive motions of intracellular genetically-encoded multimeric 40 nm nanoparticles (cytGEMs) in the cytoplasm of the fission yeastSchizosaccharomyces pombe. Using cell size mutants, we showed that cytGEMs diffusion coefficients decreased in smaller cells and increased in larger cells. This increase in diffusion in large cells may be due to a decrease in the DNA-to-Cytoplasm ratio, as diffusion was not affected in large multinucleate cytokinesis mutants. In investigating the underlying causes of altered cytGEMs diffusion, we found that the proteomes of large and small cells exhibited size-specific changes, including the sub-scaling of ribosomal proteins in large cells. Comparison with a similar dataset from human cells revealed that features of size-dependent proteome remodeling were conserved. These studies demonstrate that cell size is an important parameter in determining the biophysical properties and the composition of the cytoplasm.
Assessing Oxygen Perturbation and Over-Aeration Impacts on Soluble Microbial Products (SMP) Production and Release in Activated Sludge Systems
Authors: Zhou Xueyang , Manna Bharat , Lyu Boyu , Singhal Naresh 
Published: September 2024

ABSTRACTUnderstanding the interplay between oxygen conditions and microbial activities in an activated sludge system is crucial for the optimization of wastewater treatment processes. This study explores the influence of various aeration patterns and dissolved oxygen (DO) levels on the microbial metabolic activities, with a particular focus on the synthesis and release of soluble microbial products (SMP), and the regulation of key metabolic genes and enzymes. The activated sludge system underwent different aeration patterns, including constant aeration, continuous perturbation, and intermittent perturbation under two distinct DO levels of 2mg/L and 8mg/L. We employed a combination of multi-omics techniques (metagenomics, metaproteomics, and metabolomics) along with chemical analytical methods for comprehensive sample analysis. Our results reveal an increased intracellular accumulation of amino acids and enhanced release of protein under the conditions of oxygen perturbation. Furthermore, elevated DO levels fostered the accumulation of poly-3-hydroxybutyrate intracellularly and the release of protein and fatty acids as SMP. This outcome is associated with the abundance of key metabolic genes and enzymes, thereby highlighting the metabolic flexibility of microbes under different oxygen conditions. These findings offer valuable insights into microbial metabolic dynamics under varying oxygen conditions, thereby providing guidance for more efficient and sustainable strategies in wastewater treatment and resource recovery.SYNOPSISThis study explores the complex interplay between varying oxygen conditions and microbial activity in activated sludge systems, focusing on the impact on the synthesis and release of soluble microbial products (SMP). Findings highlight the significant influence of oxygen perturbation and dissolved oxygen levels on protein synthesis and fatty acid metabolic processes.
Natural variations of adult neurogenesis and anxiety predict hierarchical status of inbred mice
Authors: Grieco Fabio , Balla Atik , Larrieu Thomas , Toni Nicolas 
Published: September 2024

AbstractHierarchy provides a survival advantage to social animals in challenging circumstances. In mice, social dominance is associated with trait anxiety and reduced stress resilience which are regulated by adult hippocampal neurogenesis. Here, we tested whether adult hippocampal neurogenesis may regulate social dominance behavior. We observed that future dominant individuals exhibited higher trait anxiety and lower levels of hippocampal neurogenesis prior to social hierarchy formation, suggesting that baseline neurogenesis might predict individual social status among a group. This phenotype persisted after social hierarchy was stable. Experimentally reducing neurogenesis prior to the stabilization of social hierarchy in group-housed males increased the probability of mice to become dominant and increased anxiety. Finally, when innate dominance was assessed in socially isolated and anxiety-matched animals, mice with impaired neurogenesis displayed a dominant status toward strangers. Together, these results indicate that adult neurogenesis predicts and regulates hierarchical and situational dominance behavior along with anxiety-related behavior. These results provide a framework to study the mechanisms underlying social hierarchy and the dysregulation of dominance behavior in psychiatric diseases related to anxiety.
Rapid and reversible regulation of cell cycle progression in budding yeast using optogenetics
Authors: Koutsoumpa Andriana , Milias-Argeitis Andreas 
Published: September 2024

AbstractThe regulatory complexity of the eukaryotic cell cycle poses technical challenges in experiment design and data interpretation, leaving gaps in our understanding of how cells coordinate cell cycle-related processes. Traditional methods, such as knockouts and deletions are often ineffective to compensatory interactions in the cell cycle control network, while chemical agents that cause cell cycle arrest can have undesired pleiotropic effects. Synthetic inducible systems targeting specific cell cycle regulators offer potential solutions but are limited by the need for external inducers, which make fast reversibility technically challenging. To address these issues, we developed an optogenetic tool (OPTO-Cln2) that enables light-controlled and reversible regulation of G1 progression in budding yeast. Through extensive validation and benchmarking via time-lapse microscopy, we verify that OPTO-Cln2-carrying strains can rapidly toggle between normal and altered G1 progression. By integrating OPTO-Cln2 with a readout of nutrient-sensing pathways (TORC1 and PKA), we show that the oscillatory activity of these pathways is tightly coordinated with G1 progression. Finally, we demonstrate that the rapid reversibility of OPTO-Cln2 facilitates multiple cycles of synchronous arrest and release of liquid cell cultures. Our work provides a powerful new approach for studying cell cycle dynamics and the coordination of growth- with division-related processes.