bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-Free DNA GWAS Reveals Importance of p.Arg206Cys in DNASE1L3 for Non-Invasive Testing
Authors: Linthorst Jasper , Nivard Michel , Sistermans Erik A.
Published: August 2024

Properties of cell-free DNA (cfDNA) are intensely studied for their potential as non-invasive biomarkers. We explored the effect of common genetic variants on concentration and fragmentation properties of cfDNA using a GWAS based on low-coverage whole genome sequencing data of 140.000 Dutch Non-Invasive Prenatal Tests (NIPT). Our GWAS detects many genome-wide significant loci, functional enrichments for Phagocytes, Liver, Adipose tissue, Macrophages and genetic correlations with autoimmune and cardiovascular disease. A common (7%) missense variant inDNASE1L3(p.Arg206Cys), strongly affects all cfDNA properties. It increases the size of fragments, lowers cfDNA concentrations, affects the distribution of cleave-site motifs and increases the fraction of circulating fetal DNA during pregnancy. For the application of NIPT, and potentially other cfDNA-based tests, this variant has direct clinical consequences as it increases the odds of inconclusive results and impairs the sensitivity of NIPT by causing predictors to overestimate the fetal fraction.

HIGHLIGHTS

Common variants affect properties of plasma cell-free DNA

p.Arg206Cys inDNASE1L3strongly affects the size of cell-free DNA fragments

Fragmentomics-based fetal fraction predictors are affected by p.Arg206Cys

Genetics behind cfDNA overlaps with autoimmune and cardiovascular diseases
Discriminatory experiences and depression among Chinese lesbian, gay, and bisexual individuals in the United States: A moderated mediation modeling analysis
Authors: Xie Hui , Lin Binx Yezhe , Jiang Xinyi , Deng Wisteria
Published: August 2024

Chinese individuals in the U.S. have suffered substantial discrimination during the COVID19 pandemic, a stressor exacerbated by multiple minority identities (e.g., sexual and gender minority). This study aimed to explore the mechanisms of discriminatory experiences, specifically how it interacted with stressors like internalized homophobia and protective factors such as resilience, to affect depressive symptoms among Chinese individuals with multiple minority identities. Between 2022-2023, 272 Chinese LGB individuals residing in the U.S. (Mean[age]=28.36; SD=5.01) was surveyed anonymously using the Everyday discrimination Scale, the Internalized Homophobia Scale, the Conner-Davidson Resilience scale, and the Center for Epidemiologic Studies Depression Scale. Moderation and mediation analyses were conducted using STATA 17 and JASP 0.18.3. Replicating the positive association between discriminatory experience and depressive symptoms, we found that discrimination explained depressive symptoms directly and through increasing internalized homophobia. As a protective factor, resilience moderated the internalized homophobia-depressive symptoms link, but not the discrimination-depressive symptoms link. For Chinese LGB individuals with higher levels of resilience, the positive impact of internalized homophobia on depressive symptoms was weaker compared to those with lower resilience. Our findings further the understanding of the mediating and moderating mechanisms between discriminatory experiences and depressive symptoms among individuals with multiple minority identities. Continued research and intervention development on promoting resilience and other protective factors tailored to Chinese LGB individuals in the U.S. are crucial for improving mental health.
Genetic basis of resistance in hosts facing alternative infection strategies by a virulent bacterial pathogen
Authors: Mathieu-Bégné Eglantine , Gattis Sabrina , Ebert Dieter
Published: August 2024

Having alternative infection routes is thought to help parasites circumvent host resistance, provided that these routes are associated with different host resistance loci. This study examines whether alternate infection routes of the parasitePasteuria ramosaare linked to distinct resistance loci in its crustacean host,Daphnia magna. We focus on theP. ramosaisolate P15, which can attach and penetrate the host through either the hindgut or the foregut. Using a global panel of 174D. magnagenotypes supplemented with breeding experiments, we analyzed resistance patterns for each of these infection routes. Our findings confirm our hypothesis: inD. magna, hindgut attachment is determined by the D locus, while foregut attachment is controlled by a newly identified G locus. We established a gene model for the G locus that indicated Mendelian segregation and epistatic interaction with at least one other resistance locus forP. ramosa, the C locus. Using genomic Pool-sequencing data, we localized the G locus within a known Pasteuria Resistance Complex on chromosome 4 ofD. magna, whereas the D locus is on chromosome 7. Two candidate genes for the G locus, belonging to the Glycosyltransferase gene family, were identified. Our study sheds new light on host–parasite coevolution and enhances our understanding of how parasites evolve infection strategies.

Author summary

Parasites continuously evolve strategies to overcome host resistance, including the use of alternative infection routes. However, this strategy is advantageous only if host resistance loci are specific to each entry point; otherwise, a single host gene could provide resistance to all infection routes. In this study, we tested this hypothesis using the freshwater crustaceanDaphnia magnaand a strain of the parasitePasteuria ramosathat can infect its host via the esophagus (foregut) or the hindgut. By conducting a phenotypic assay ofP. ramosaattachment on a global panel ofD. magnagenotypes, we demonstrate that foregut and hindgut infections are associated with independent genetic host resistance loci. Through a breeding experiment on a subset ofD. magnagenotypes, we were able to propose a gene model for the newly discovered G locus linked to foregut attachment, while the previously identified D locus is linked to hindgut attachment. We also discovered that the foregut infection route is influenced by an epistatic interaction between the G locus and anotherP. ramosaresistance locus, the C locus. Using genomic data, we confirmed that the G and D loci are not overlapping, with the G locus being part of the Pasteuria Resistance Complex on chromosome 4, whereas the D locus is on chromosome 7. Two potential genes involved in glycosylation processes were identified as candidates for the G locus. Overall, our study confirms a key postulate in the understanding of host–parasite co-evolution, highlighting the importance of infection strategies in host resistance.
Valine restriction extends survival in aDrosophilamodel of short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency
Authors: Mele Sarah , Martelli Felipe , Barlow Christopher K. , Jefferies Grace , Dworkin Sebastian , Christodoulou John , Schittenhelm Ralf B. , Piper Matthew D.W. , Johnson Travis K.
Published: August 2024

Short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare genetic disorder caused by biallelic pathogenic variants in theECHS1gene. ECHS1D is characterised by severe neurological and physical impairment that often leads to childhood mortality. Therapies such as protein and single nutrient-restricted diets show poor efficacy, whereas development of new treatments is hindered by the low prevalence of the disorder and a lack of model systems for treatment testing. Here we report on the establishment of aDrosophilamodel of ECHS1D. Flies carrying mutations inEchs1(CG6543) were characterised for their physical and metabolic phenotypes, and dietary intervention to improve fly model health was explored. TheEchs1null larvae recapitulated human ECHS1D phenotypes including elevated biomarkers (S-(2-carboxypropyl)cysteamine and 2,3-dihydroxy-2-methylbutyric acid), poor motor behaviour and early mortality, and could be rescued by expression of a humanECHS1transgene. We observed that both restriction of valine in isolation, or all branched-chain amino acids (BCAAs - leucine, isoleucine, and valine) together, extended larval survival, supporting the idea that reducing BCAA pathway catabolic flux is beneficial in this disorder. Further, metabolic profiling revealed substantial changes to carbohydrate metabolism, suggesting thatEchs1loss causes widespread metabolic dysregulation beyond valine metabolism. The similarities betweenDrosophilaand human ECHS1D suggest that the fly model is a valuable animal system in which to explore mechanisms of pathogenesis and novel treatment options for this disorder.
ETS TRANSCRIPTION FACTOR POINTED CONTROLS GERMLINE SURVIVAL IN DROSOPHILA
Authors: Rosales-Nieves Alicia E , Marin-Menguiano Miriam , Lopez-Onieva Lourdes , Garrido-Maraver Juan , Gonzalez-Reyes Acaimo
Published: August 2024

Proper gonad development is a pre-requisite for gametogenesis and reproduction. During female gonad formation in Drosophila, the EGF receptor (EGFR) signalling pathway ensures the correct number of primordial germ cells (PGCs) populate the larval gonad. We study the gene pointed (pnt), which acts downstream of the EGFR receptor and belongs to the ETS transcription factor family, with a previously unknown function in gonadogenesis. We report that pnt is expressed in female larval gonads and later in the adult ovarian germline niche and that it is required to sustain proper gametogenesis. Loss of pnt function in female larval gonads, similar to the EGFR, induced PGC overproliferation. Conversely, we isolated a novel loss-of-function allele, pntaga, which resulted in agametic gonads and ovaries. While pntaga embryos developed gonads containing a normal complement of PGCs, these are subsequently lost by apoptosis during late larval and pupal stages. Molecular characterization of pntaga revealed reduced expression levels of the different pnt isoforms, unveiling a complex autoregulatory network involving the three Pnt proteins. We propose that germ line survival in Drosophila gonads requires a precise tuning of EGFR signalling to ensure the appropriate transcriptional activation of its target pnt.
Electrical Synapse Rectification Enables Dual-Network Activity in the crab Cancer borealis
Authors: Fahoum Savanna-Rae H , Nadim Farzan , Blitz Dawn M
Published: August 2024

Flexibility of rhythmic networks includes neuromodulator-elicited changes in neuronal participation between networks. We are examining the role of rectifying electrical synapses in this neuronal switching. Electrical synapses can have complex, non-intuitive effects on network output. However, it is often difficult to measure and manipulate rectification across conditions to determine their functional contributions. Here, we use the Jonah crab Cancer borealis to investigate rectification in well-described rhythmic networks. In an established modulatory state, stimulating the projection neuron MCN5 or bath applying its neuropeptide Gly1-SIFamide causes the two LPG neurons to switch from pyloric rhythm-only (food filtering, 1 Hz) activity to dual pyloric and gastric mill rhythm (chewing, 0.1 Hz) activity. Typically, LPG is co-active with the two PD and single AB pyloric pacemaker neurons due to rectifying electrical coupling. In Gly1-SIFamide, LPG continues to burst in pyloric time with AB/PD but periodically escapes and generates intrinsic longer-duration gastric mill-timed bursts, decreasing its overall synchrony with AB/PD, while AB/PD retain their synchronous pyloric timing. Using two-electrode voltage clamp recordings, we find that Gly1-SIFamide does not alter electrical coupling strength or the rectification between LPG and AB/PD. However, in a computational model, rectification is necessary for LPG to escape AB/PD electrical coupling and generate longer, gastric mill-timed bursts. This was confirmed in the biological system by adding a dynamic clamp non-rectifying electrical synapse between LPG and PD, which decreased the LPG escape from AB/PD and its gastric mill-timed activity. Thus, rectification between electrically coupled oscillators can underlie modulator-elicited changes in their synchrony.
Epidemiology of urinary tract infection among community-living seniors aged 50 plus: population estimates and risk factors
Authors: Foxman Betsy , Bangura Marie , Kamdar Neil , Morgan Daniel M
Published: August 2024

Background

Urinary tract infection (UTI) is common in all ages but risk factors among adults 50 and older are not well studied. One unexplored potential risk factor is constipation, a known UTI risk factor among children.

Objective

Describe the UTI incidence among U.S. women and men aged 50 and older and the association between constipation and other risk factors and UTI.

Methods

A web interview was administered October 12-16, 2023 to U.S. adults aged 50 and older participating in a probability-based panel representative of the U.S. household population age 50 or older. The primary study outcome was self-reported healthcare provider diagnosed and treated UTI in the previous 12 months. All results were weighted to represent the U.S. household population.

Results

The 12-month UTI incidence was 19.8% among women and 6.4% among men. Recurrence was common: 10% of women and 7% of men with a UTI had 3 more UTIs in the previous 12 months. 32% of the population reported being constipated sometimes, frequently or always. UTI incidence increased with more frequent constipation in a dose response manner among women and men. After adjusting for age, gender, having a body mass index >30 and an overnight hospital stay in the previous 12 months, those reporting sometimes being constipated were 3.69 times, and those often or always constipated were 5.48 times more likely than those never constipated to have a UTI in the previous 12 months.

Discussion

This is the first report of an association between UTI and constipation among older adults. Reducing constipation might reduce UTI incidence among older women and men.
BMI-related Genetic Factors and COPD Imaging Phenotypes
Authors: Zhang Jingzhou , Moll Matthew , Debban Catherine L. , Hobbs Brian D. , Rijhwani Heena , Washko George R. , Celli Bartolome R. , Silverman Edwin K. , Bakke Per , Oelsner Elizabeth C. , Barr R. Graham , Agustí Alvar , Faner Rosa , Bruselle Guy G. , Humphries Stephen M. , Lynch David A. , Dupuis Josée , Manichaikul Ani W. , O’Connor George T. , Cho Michael H.
Published: August 2024

Background

While low body mass index (BMI) is associated with emphysema and obesity is associated with airway disease in chronic obstructive pulmonary disease (COPD), the underlying mechanisms are unclear.

Methods

We aggregated genetic variants from population-based genome-wide association studies to generate a polygenic score of BMI (PGSBMI). We calculated this score for participants from COPD-enriched and community-based cohorts and examined associations with automated quantification and visual interpretation of computed tomographic emphysema and airway wall thickness (AWT). We summarized the results using meta-analysis.

Results

In the random-effects meta-analyses combining results of all cohorts (n=16,349), a standard deviation increase of the PGSBMIwas associated with less emphysema as quantified by log-transformed percent of low attenuation areas ≤ 950 Hounsfield units (β= -0.062,p<0.0001) and 15thpercentile value of lung density histogram (β=2.27,p<0.0001), and increased AWT as quantified by the square root of wall area of a 10-mm lumen perimeter airway (β=0.016,p=0.0006) and mean segmental bronchial wall area percent (β=0.26,p=0.0013). For imaging characteristics assessed by visual interpretation, a higher PGSBMIwas associated with reduced emphysema in both COPD-enriched cohorts (OR for a higher severity grade=0.89,p=0.0080) and in the community-based Framingham Heart Study (OR for the presence of emphysema=0.82,p=0.0034), and a higher risk of airway wall thickening in the COPDGene study (OR=1.17,p=0.0023).

Conclusions

In individuals with and without COPD, a higher body mass index polygenic risk is associated with both quantitative and visual decreased emphysema and increased AWT, suggesting genetic determinants of BMI affect both emphysema and airway wall thickening.
Protein Arginine Methylation of the Translation Initiation Factor eIF1A Increases Usage of a Near-cognate Start Codon
Authors: Wegman Rebecca , Langberg Michael , Davis Richoo B. , Liu Xiaozhuo , Luo Minkui , Yu Michael C. , Walker Sarah E.
Published: August 2024

Protein arginine methylation has emerged as a key post-translational modification responsible for many facets of eukaryotic gene expression. To better understand the extent of this modification in cellular pathways, we carried out bioorthogonal methylation profiling inSaccharomyces cerevisiaeto comprehensively identify thein vivosubstrates of the major yeast protein arginine methyltransferase Hmt1. Gene ontology analysis of candidate substrates revealed an enrichment of proteins involved in the process of translation. We verified one such factor, eIF1A, byin vitromethylation. Three sites on eIF1A were found to be responsible for its methylation: R13, R14, and R62, with varied capacity by which each site contributed to the overall methylation capacityin vitro. To determine the role of methylation in eIF1A function, we used a battery of arginine-to-alanine substitution mutants to evaluate translation fidelity in these mutants. Our data show that substitution mutants at R13 and R14 in the N-terminal tail improved the fidelity of start codon recognition in an initiation fidelity assay. Overall, our data suggest that Hmt1-mediated methylation of eIF1A fine-tunes the fidelity of start codon recognition for proper translation initiation.
Nernst Equilibrium, Rectification, and Saturation: Insights into Ion Channel Behavior
Authors: Carlsen Ryan , Weckel-Dahman Hannah , Swanson Jessica MJ
Published: August 2024

The dissipation of electrochemical gradients through ion channels plays a central role in biology. Herein we use voltage responsive kinetic models of ion channels to explore how electrical and chemical potentials differentially influence ion transport properties. These models demonstrate how electrically driven flux is greater than the Nernstian equivalent chemically driven flux, yet still perfectly cancels when the two gradients oppose each other. We find that the location and relative stability of ion binding sites dictates rectification properties by shifting the location of the most voltage sensitive transitions. However, these rectification properties invert when bulk concentrations increase relative to the binding site stabilities, moving the rate limiting steps from uptake into a relatively empty channel to release from an ion-blocked full channel. Additionally, the origin of channel saturation is shown to depend on the free energy of uptake relative to bulk concentrations. Collectively these insights provide framework for interpreting and predicting how channel properties manifest in electrochemical transport behavior.
SARS-CoV-2 Damages Cardiomyocytes Mitochondria and Implicates Long COVID-associated Cardiovascular Manifestations
Authors: Che Wenliang , Guo Shuai , Wang Yanqun , Wan Xiaohua , Tan Bingyu , Li Hailing , Alifu Jiasuer , Zhu Mengyun , Chen Cesong , Li Peiyao , Zhang Zhaoyong , Wang Yiliang , Huang Xiaohan , Wang Xinsheng , Zhu Jian , Pan Xijiang , Zhang Fa , Wang Peiyi , Zhao Jincun , Xu Yawei , Liu Zheng
Published: August 2024

Our study investigates the persistent cardiovascular symptoms observed in individuals long after contracting SARS-CoV-2, a condition commonly referred to as “Long COVID”, which has significantly affected millions globally. We meticulously describe the cardiovascular outcomes in five patients, encompassing a range of severe conditions such as sudden cardiac death during exercise, coronary atherosclerotic heart disease, acute inferior myocardial infarction, and acute myocarditis. All five patients were diagnosed with myocarditis, confirmed through endomyocardial biopsy and histochemical staining, which identified inflammatory cell infiltration in their heart tissue. Crucially, electron microscopy revealed widespread mitochondrial vacuolations and the presence of myofilament degradation within the cardiomyocytes of these patients. These findings were mirrored in SARS-CoV-2-infected mice, suggesting a potential underlying cellular mechanism for the cardiac effects associated with Long COVID. Our report sheds light on the cardiovascular implications of Long COVID and underscores the importance of further research to understand its cellular underpinnings.
The First General Consent Implementation in Swiss Traditional Chinese Medicine Practices. A Prospective One-Year Study
Authors: Wang Xiaying , Lv Xiaoying , Chen Bingjun , Pradhan Saroj , Bauder Ralf , Li Yiming , Furian Michael
Published: August 2024

Background

Traditional Chinese Medicine (TCM) encompasses a wide range of treatments focused on diagnosing and managing illnesses, with increasing adoption in Western countries. TCM is often applied in isolated practices, therefore, rigorous research and real-world data collection remain challenging. The implementation of the General Consent (GC) facilitates this research, therefore, the aim was to investigate the acceptance rate of the GC during the first year of its implementation in TCM practices.

Methods

This prospective cohort study was conducted from 1stJanuary to 31stDecember 2023 in five TCM practices located in Bad Zurzach, Baden, Lenzburg, Wil, and Zug in Switzerland. GC, together with other registration forms, were sent to patients prior to their appointments, collected during their first visit, and recorded by clinic secretaries. Logistic regression analysis was performed to investigate demographic factors influencing GC acceptance, considering variables such as age, sex, and practice location.

Results

The study recorded 1,095 patients who sought TCM treatments in 2023, of which 73.6% returned a valid GC document. Overall, the GC acceptance rate was 611/1,095 (55.8%); of those returning the GC, the acceptance rate was 611/806 (75.8%). The median[IQR] age of patients was 52[37,64] years and female patients were twice as likely to seek TCM treatments compared to male patients. Logistic regression analysis, odds ratio (95%CI), revealed no difference in GC acceptance rate with older age: 1.015 (0.996 to 1.034), p=0.115; female sex: 1.847 (0.588 to 5.804), p=0.294 and age*female sex: 0.983 (0.962 to 1.004), p=0.119. Significant differences in GC acceptance rates were observed across the five TCM practices.

Conclusion

The GC implementation in TCM practices was feasible, and the GC was well accepted by patients, independent of sex and age. The observed practice-related differences in GC acceptance require further investigation. More TCM practices should implement the GC to enable practice-based TCM research.
Decreased cardio-respiratory information transfer is associated with deterioration and a poor prognosis in critically ill patients with sepsis
Authors: Morandotti Cecilia , Wikner Matthew , Li Qijun , Ito Emily , Tan Calix , Chen Pin-Yu , Cawthorn Anika , Lilaonitkul Watjana , Mani Ali R
Published: August 2024

Assessing illness severity in the ICU is crucial for early prediction of deterioration and prognosis. Traditional prognostic scores often treat organ systems separately, overlooking the body’s interconnected nature. Network physiology offers a new approach to understanding these complex interactions. This study used the concept of transfer entropy (TE) to measure information flow between heart rate (HR), respiratory rate (RR), and capillary oxygen saturation (SpO2) in critically ill sepsis patients, hypothesizing that TE between these signals would correlate with disease outcome. The retrospective cohort study utilized the MIMIC III Clinical Database, including patients who met Sepsis-3 criteria on admission and had 30 minutes of continuous HR, RR, and SpO2data. TE between the signals was calculated to create physiological network maps. Cox regression assessed the relationship between cardiorespiratory network indices and both deterioration (SOFA score increase of ≥2 points at 48 hours) and 30-day mortality. Among 164 patients, higher information flow from SpO2to HR [TE(SpO2→HR)] and reciprocal flow between HR and RR [TE(RR→HR) and TE(HR→RR)] were linked to reduced mortality, independent of age, mechanical ventilation, SOFA score, and comorbidity. Reductions in TE(HR → RR), TE(RR→HR), TE(SpO2→RR), and TE(SpO2→HR) were associated with increased risk of 48-hour deterioration. After adjustment for potential confounders, only TE(HR→RR) and TE(RR→HR) remained statistically significant. The study confirmed that physiological network mapping using routine signals in sepsis patients could indicate illness severity and that higher TE values were generally associated with improved outcomes.

New & Noteworthy

This study adopts an integrative approach through physiological network analysis to investigate sepsis, with the goal of identifying differences in information transfer between physiological signals in sepsis survivors versus non-survivors. We found that greater information flow between heart rate, respiratory rate, and capillary oxygen saturation was associated with reduced mortality, independent of age, disease severity, and comorbidities. Additionally, reduced information transfer was linked to an increased risk of 48-hour deterioration in patients with sepsis.
Genetics of transient amnesia highlights a vascular role in memory
Authors: Rivas Manuel A. ,   FinnGen, Daly Mark J.
Published: August 2024

Where memory is stored and how it is processed is poorly understood. Traditionally, genetics of low prevalence traits have been used to get a better understanding of naturally occuring conditions across species. Here, we conduct a genome-wide association of transient global amnesia (TGA), a specific type of heritable amnesia characterized by a sudden, temporary episode of memory loss, across 4,303 patients and over 1 million controls from three population biobanks in Finland, United States, and the United Kingdom, to better understand the genetic basis of memory. We find nine loci associated with TGA (p < 5×10-8) including a missense variant inCRIP1with high posterior probability (> .9) of being the causally relevant variant using fine-mapping, replicated across 3 cohorts. Furthermore, we find enrichment for a specific cell type, pericyte cells, which are a key part of the neurovascular unit, which includes astrocytes and neurons, and control interactions between neurons and the cerebral vasculature, implicating a direct vascular role in memory formation and retrieval. We anticipate these genetic studies at a larger scale to bring new biological understanding and therapeutic insights into the brain and memory.
Penicillin Allergy as an Instrumental Variable for Estimating Antibiotic Effects on Resistance
Authors: Saciuk Yaki , Nevo Daniel , Chowers Michal , Obolski Uri
Published: August 2024

Antibiotic resistance is influenced by prior antibiotic use, but precise causal estimates are limited. This study uses penicillin allergy as an instrumental variable (IV) to estimate the causal effect of antibiotics on resistance. A retrospective cohort of 36,351 individuals withE. colipositive urine cultures and prior outpatient antibiotic use, with outcomes assessed up to one year post-exposure, was analyzed using data from Maccabi Healthcare Services (MHS), the second-largest non-profit health fund in Israel. IV methods estimated risk differences (RD) and numbers needed to harm (NNH) for penicillin versus other antibiotics. The RD for resistance was 11.4% (95% CI: 7.6%, 15.4%) for amoxicillin/clavulanic acid, 14.1% (95% CI: 9.0%, 19.4%) for ampicillin, and 0.8% (95% CI: 0.2%, 1.4%) for piperacillin/tazobactam, with NNHs of 8.8, 7.1, and 122.0, respectively. Risks declined over time since exposure. Gentamicin, used as a negative control, showed no effect (95% CI: -2.4%, 1.8%). When directly comparing penicillin and quinolone effects on their respective AMR, penicillin use within 180 days increased resistance to amoxicillin/clavulanic acid by an RD of 17.8% (95% CI: 2.1%, 35.2%; NNH: 5.6), while quinolones raised ciprofloxacin resistance by 43.7% (95% CI: 29.9%, 59.4%; NNH: 2.3). These findings provide quantitative evidence of the impact of prior penicillin use on resistance, with implications for clinical practice and prescription policies.
Machine-Learning Enhanced Diffusion Tensor Imaging with Four Encoding Directions
Authors: Ametepe Joshua Mawuli , Gholam James , Beltrachini Leandro , Cercignani Mara , Jones Derek Kenton
Published: August 2024

Purpose

This study aims to reduce Diffusion Tensor MRI (DT-MRI) scan time by minimizing diffusion-weighted measurements. Using machine learning, DT-MRI parameters are accurately estimated with just four tetrahedrally-arranged diffusion-encoded measurements, instead of the usual six or more. This significantly shortens scan duration and is particularly useful in ultra-low field (ULF) MRI studies and for non-compliant populations (e.g., children, the elderly, or those with movement disorders) where long scan times are impractical.

Methods

To improve upon a previous tetrahedral encoding approach, this study used a deep learning (DL) model to predict parallel and radial diffusivities and the principal eigenvector of the diffusion tensor with four tetrahedrally-arranged diffusion-weighted measurements. Synthetic data were generated for model training, covering a range of diffusion tensors with uniformly distributed eigenvectors and eigenvalues. Separate DL models were trained to predict diffusivities and principal eigenvectors, then evaluated on a digital phantom and in vivo data collected at 64 mT.

Results

The DL models outperformed the previous tetrahedral encoding method in estimating diffusivities, fractional anisotropy, and principal eigenvectors, with significant improvements in ULF experiments, confirming the DL approach’s feasibility in low SNR scenarios. However, the models had limitations when the tensor’s principal eigenvector aligned with the scanner’s axes

Conclusion

The study demonstrates the potential of using DL to perform DT-MRI with only four directions in ULF environments, effectively reducing scan durations and addressing numerical instability seen in previous methods. These findings open new possibilities for ULF DT-MRI applications in research and clinical settings, particularly in pediatric neuroimaging
Benchmarking commercial healthcare claims data
Authors: Dahlen Alex , Deng Yaowei , Charu Vivek
Published: August 2024

Importance

Commercial healthcare claims datasets represent a sample of the US population that is biased along socioeconomic/demographic lines; depending on the target population of interest, results derived from these datasets may not generalize. Rigorous comparisons of claims-derived results to ground-truth data that quantify this bias are lacking.

Objectives

(1) To quantify the extent and variation of the bias associated with commercial healthcare claims data with respect to different target populations; (2) To evaluate how socioeconomic/demographic factors may explain the magnitude of the bias.

Design

This is a retrospective observational study. Healthcare claims data come from the Merative™ MarketScan® Commercial Database; reference data for comparison come from the State Inpatient Databases (SID) and the US Census. We considered three target populations, aged 18-64 years: (1) all Americans; (2) Americans with health insurance; (3) Americans with commercial health insurance.

Participants

We analyzed inpatient discharge records of patients aged 18-64 years, occurring between 01/01/2019 to 12/31/2019 in five states: California, Iowa, Maryland, Massachusetts, and New Jersey.

Outcomes

We estimated rates of the 250 most common inpatient procedures, using claims data and using reference data for each target population, and we compared the two estimates.

Results

The average rate of inpatient discharges per 100 person-years was 5.39 in the claims data (95% CI: [5.37, 5.40]) and 7.003 (95% CI: [7.002, 7.004]) in the reference data for all Americans, corresponding to a 23.1% underestimate from claims. We found large variation in the extent of relative bias across inpatient procedures, including 22.8% of procedures that were underestimated by more than a factor of 2. There was a significant relationship between socioeconomic/demographic factors and the magnitude of bias: procedures that disproportionately occur in disadvantaged neighborhoods were more underestimated in claims data (R2= 51.6%, p < 0.001). When the target population was restricted to commercially insured Americans, the bias decreased substantially (3.2% of procedures were biased by more than factor of 2), but some variation across procedures remained.

Conclusions and relevance

Naïve use of healthcare claims data to derive estimates for the underlying US population can be severely biased. The extent of bias is at least partially explained by neighborhood-level socioeconomic factors.
Protocol for Systematic Review and Meta-Analysis of Prehospital Large Vessel Occlusion Screening Scales
Authors: Suzuki Hidetaka , Okada Yohei , Hiroshi Yamagami , Hayakawa Mikito , Takeshi Yoshimoto , Kobata Hitoshi
Published: August 2024

Background

Large Vessel Occlusion (LVO) is a serious condition that causes approximately 24-46% of acute ischemic strokes (AIS). LVO strokes tend to have higher mortality rates and result in more severe longterm disabilities compared to non LVO ischemic strokes. Early intervention with endovascular therapy (EVT) is recommended; however, EVT is limited to tertiary care hospitals with specialized facilities. Therefore, identifying patients with a high probability of LVO in prehospital settings and ensuring their rapid transfer to appropriate hospitals is crucial. While LVO diagnosis typically requires advanced imaging like MRI or CT scans, various scoring systems based on neurological symptoms have been developed for prehospital use. Although previous systematic reviews have addressed some of these scales, recent studies have introduced new scales and additional data on their accuracy. This systematic review and meta-analysis aim to summarize the current evidence on the diagnostic accuracy of these prehospital LVO screening scales.

Methods

This systematic review and meta-analysis will be conducted in accordance with the PRISMA-DTA Statement and the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. We will include observational studies and randomized controlled trials that assess the utility of LVO scales in suspected stroke patients in prehospital settings. Eligible studies must provide sufficient data to calculate sensitivity and specificity, and those lacking such data or being case reports will be excluded. The literature search will cover CENTRAL, MEDLINE, and Ichushi databases, including studies in English and Japanese. Bias will be assessed using QUADAS-2, and meta-analysis will be conducted using a random effects model, with subgroup and sensitivity analyses to explore heterogeneity.
De Novo Genome Assembly and Annotation for the Webbing Clothes Moth (Tineola bisselliella): A Globally Distributed, Economically Important Pest
Authors: Alqassar Jasmine D , Aichelman Hannah E , Novick Isabel A , Mullen Sean P
Published: August 2024

Tineola bisselliella, the webbing clothes moth, is an economically important, globally distributed synanthropic pest species and member of the basal moth lineage Tineidae.Tineola bisselliellais facultatively keratinophagous. Therefore, their larvae can cause extensive damage, particularly to clothing, textiles, and museum specimens. Despite the economic and phylogenetic importance ofTineola bisselliella, there is a lack of quality genomic resources for this species, or for others within the Tineidae family. TheTineola bisselliellagenome presented here consists of 30 pseudochromosomes (29 autosomes and 1 Z chromosome) produced using synteny alignment to a closely related species,Tinea pellionella. The resulting final pseudochromosome-level assembly is 243.630 Mb and has an N50 length of 8.708 Mb. The assembly is highly contiguous and has similar or improved quality compared to other available Tineidae genomes, with 93.1% of lepidopteran orthologs complete and present. Annotation of the pseudochromosome-level genome assembly with the transcriptome we produced ultimately yielded 11,267 annotated genes. Synteny alignments between theTineola bisselliellagenome assembly and other Tineidae genomes found evidence for numerous small rearrangements with high synteny conservation. In contrast, synteny alignments performed betweenTineola bisselliellaand the more distantly relatedBombyx moriandMelitea cinxiarevealed more frequent small and large rearrangements as predicted by their evolutionary divergence. The reference quality annotated genome forTineola bisselliellapresented here will advance our understanding of the evolution of the lepidopteran karyotype by providing a chromosome-level genome for this basal moth lineage and provide future insights into the mechanisms underlying keratin digestion inTineola bisselliella.

Significance Statement

Tineola bisselliella, the webbing clothes moth, is a globally distributed synanthropic pest species that feeds on both keratin-based materials and detritus. This dietary habit can cause substantial damage to clothing, textiles, rugs, taxidermy, and museum specimens. In fact, keratinophagous organisms cause an estimated $1 billion worth of damage annually in the United States. However, the lack of a high-quality annotated reference genome for this basal moth species has thus far limited our understanding of the mechanisms underlying keratin digestion relevant to pest control efforts and has hampered efforts to investigate the broader phylogenetic relationships the Tineidae family necessary to reveal patterns of lepidopteran chromosome evolution. Here, we present the first reference quality genome forTineola bisselliellaand the first annotated genome for any member of the Tineidae family, providing a critical resource for the lepidopteran genomics and pest management communities.
Developmental variability in cotton fiber cell wall properties linked to important agronomic traits
Authors: Wilson Michael C. , Howell Alexander H. , Sood Anika , Lee Youngwoo , Yang Pengcheng , Yu Elena , Rani Heena , Mallery Eileen L. , Swaminathan Sivakumar , Grover Corrinne E. , Wendel Jonathan F. , Zabotina Olga A. , Xie Jun , Davis Chelsea S. , Szymanski Daniel B.
Published: August 2024

The economic value of cotton is based on its long, thin, strong, and twisted trichoblasts that emerge from the ovule epidermis. The mature dried fiber cell reflects the outcome of a rapid tapering of the nascent trichoblast, weeks of polarized diffuse growth, followed by a transition to persistent secondary cell wall synthesis. Highly conserved and dynamic microtubule and cellulose microfibril-based anisotropic growth control modules are central to all of these phases. In this paper, we developed novel quantitative phenotyping and computational modeling pipelines to analyze fiber growth behaviors at a daily resolution. We uncovered unexpected variability in growth rate, cell wall properties, and cell geometry across a critical window of fiber development. Finite element computational modeling of fiber growth was used to analyze the instability of cell diameter control and predict how spatial gradients of fiber and matrix material properties can interact to dictate the patterns of shape change. As an initial step toward gaining insight into the molecular orchestration of cellulose biosynthesis, expression profiles of a broad set of relevant genes were quantified across the same developmental timeline and correlated with fiber phenotypes. This analysis identified specific candidate genes that may serve as targets for fiber quality improvement.
Functional mapping of epigenetic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes
Authors: Tang Yuning J. , Xu Haiqing , Hughes Nicholas W. , Kim Samuel H. , Ruiz Paloma , Shuldiner Emily G. , Lopez Steven S. , Hebert Jess D. , Karmakar Saswati , Andrejka Laura , Dolcen D. Nesli , Boross Gabor , Chu Pauline , Detrick Colin , Pierce Sarah , Ashkin Emily L. , Greenleaf William J. , Voss Anne K. , Thomas Tim , van de Rijn Matt , Petrov Dmitri A. , Winslow Monte M.
Published: August 2024

Epigenetic dysregulation is widespread in cancer. However, the specific epigenetic regulators and the processes they control to drive cancer phenotypes are poorly understood. Here, we employed a novel, scalable and high-throughputin vivomethod to perform iterative functional screens of over 250 epigenetic regulatory genes within autochthonous oncogenic KRAS-driven lung tumors. We identified multiple novel epigenetic tumor suppressor and tumor dependency genes. We show that a specific HBO1 complex and the MLL1 complex are among the most impactful tumor suppressive epigenetic regulators in lung. The histone modifications generated by the HBO1 complex are frequently absent or reduced in human lung adenocarcinomas. The HBO1 and MLL1 complexes regulate chromatin accessibility of shared genomic regions, lineage fidelity and the expression of canonical tumor suppressor genes. The HBO1 and MLL1 complexes are epistatic during lung tumorigenesis, and their functional correlation is conserved in human cancer cell lines. Together, these results demonstrate the value of quantitative methods to generate a phenotypic roadmap of epigenetic regulatory genes in tumorigenesisin vivo.
Coping switches stress–evoked network disconnection to a new forebrain network state
Authors: Durieux Laura , Herbeaux Karine , Totah Nelson K , Lecourtier Lucas
Published: August 2024

Coping with stress is critical to maintaining mental and physical health. Acute stress is associated with changes in neuronal activity across many brain regions and with the reorganization of cross– region correlations in neurovascular coupling. How neuronal activity itself is coordinated across regions during stress, and how neuronal networks are modified during coping, are unknown. We recorded in rats local field potentials (LFPs) simultaneously from five stress–responsive regions during stress and stress–coping behavior. We characterized network activity by computing cross– region coherence, Granger causality, and phase–amplitude coupling on bipolar derivatives of LFPs in the lateral habenula, basolateral amygdala, dorsal hippocampus, prelimbic cortex, and anterior cingulate cortex. First, we established a stress–coping model in rats. We showed that the behavioral response to acute 10–minute restraint stress returned to baseline after a second restraint 3 hours later. The pre–stress state was characterized by robust global network interactions in the theta (6– 9 Hz) and gamma (45–65 Hz) bands. Stress exposure led to nearly complete loss of connectivity. During coping, the robust connectivity reemerged, but in a new pattern compared to the pre–stress state. Finally, we found that baseline, stressed, and coping states can be predicted with high accuracy (> 90 %) from network activity. Overall, we showed that the acutely stressed brain state was primarily a state of network disconnection, while coping was a new network state rather than a return to baseline.
Enhancing Variant Calling in Whole Exome Sequencing (WES) Data Using Population-Matched Reference Genomes
Authors: Guo Shuming , Huang Zhuo , Zhang Yanming , He Yukun , Chen Xiangju , Wang Wenjuan , Li Lansheng , Kang Yu , Gao Zhancheng , Yu Jun , Du Zhenglin , Chu Yanan
Published: August 2024

Whole exon sequencing (WES) data are frequently used for cancer diagnosis and genome-wide association studies (GWAS), hinging upon high-coverage read mapping, informative variant calling, and high-quality reference genomes. The center position of the currently used genome assembly, GRCh38, is now challenged by two newly publicized telomere-to-telomere or T2T genomes, T2T-CHM13 and T2T-YAO, and it becomes urgent to have a comparative study to test population specificity using the three reference genomes based on real case WES data. We here report our analysis along this line for 19 tumor samples collected from Chinese patients. The primary comparison of the exon regions among the three references reveals that the sequences in up to ∼1% target regions in YAO are widely diversified from GRCh38 and may lead to off-target in sequence capture. However, YAO still outperforms GRCh38 genomes by obtaining 7.41% more mapped reads. Due to more reliable read-mapping and closer phylogenetic relationship with the samples than GRCh38, YAO reduces half of variant calls of clinical significance which are mostly benign while keeping sensitivity in identifying pathogenic variants. YAO also outperforms CHM13 in reducing calls of Chinese-specific variants. Our findings highlight the critical need for employing population-specific reference genomes in genomic analysis to ensure accurate variant analysis and the significant benefits of tailoring these approaches to the unique genetic backgrounds of each ethnic group.
Phylogeographic Insights into Lion Evolution: Unraveling the Genetic Diversity and Lineage Divergence ofPanthera leo
Authors: Afzali Yaser Amir
Published: August 2024

This study investigates the genetic diversity and phylogeographic structure of lion populations (Panthera leo) across Africa and Asia, revealing significant insights into their evolutionary history. Our analysis identifies two primary clades: the North Clade comprising Asian and northern African populations identified asPanthera leo leo, and the South Clade containing East and southern African populations identified asPanthera leo melanochaita. We estimate that the lion’s modern lineage originated approximately 320–280 Kya, with a divergence into the North Clade around 170–130 Kya. The South Clade exhibits a deeper divergence about 290–180 Kya, suggesting a longer history of geographic isolation driven by environmental changes. These dates are older than earlier estimates, owing to new information on the time of divergence betweenP. leoandP. spelaea. Most famous and referenced studies used 0.55 Mya as the split time betweenP. leoandP.spelaeaas the calibration point for their time calibrated trees but new studies demonstrated that split time betweenP. leoandP.spelaeais circa 1.89 Mya. Also, our findings indicate that the Indian lineage (Asian haplogroup) represents a genetically distinct group that should not be classified as a separate subspecies, as its genetic differentiation is trivial compared to that betweenP. l. leoandP. l. melanochaita. The results also indicate higher genetic diversity withinP. l. melanochaita, suggesting a stable population structure influenced by historical environmental conditions. In contrast,P. l. leoexhibits lower genetic variability, likely due to recent anthropogenic pressures, including habitat loss and fragmentation. Demographic analyses illustrate a dramatic decline in effective population size starting in the mid-20th century, correlating with the well-documented reduction in lion range. Phylogeographic patterns in lions reflect broader trends in savannah mammals, underscoring the role of historical climatic fluctuations in shaping modern populations. Crucially, our results contest the hypothesis that the Indian lion population was bolstered by sub-Saharan lion introductions, indicating its ancient lineage. These findings highlight the necessity for targeted conservation strategies that consider the genetic and evolutionary context of lion populations, as well as the unique challenges they face in a changing landscape. Overall, this research underscores the importance of integrating genetic data into lion conservation efforts to ensure the long-term survival of this iconic species.