bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population genomics ofAspergillus sojaeis shaped by the food environment
Authors: Acevedo Kimberly L. , Eaton Elizabeth , Zhao Shu , Chacon-Vargas Katherine , McCarthy Colin M. , Choi Dasol , Yu Jae-Hyuk , Gibbons John G. 
Published: September 2023

AbstractTraditional fermented foods often contain specialized microorganisms adapted to the unique food environment. For example, the filamentous moldAspergillus oryzae, used in saké fermentation, has evolved to thrive in starch-rich conditions compared to its wild ancestor,Aspergillus flavus. Similarly,Aspergillus sojaeis used in soybean-based food fermentations (e.g.miso and shochu) and is closely related toAspergillus parasiticus. Here, we investigated the impact of long-termA. sojaeusage in soybean fermentation on population structure, genome variation, and phenotypic traits. We analyzed 12A. sojaeand 10A. parasiticusgenomes, along with phenotypic characteristics of 15 isolates. Our results revealed thatA. sojaeisolates formed a distinct population separate fromA. parasiticusand displayed remarkably low levels of genetic diversity, indicative of a recent clonal expansion. Genome comparisons revealed numerous loss-of-function mutations inA. sojae, notably in genes responsible for secondary metabolite production, including genes in the aflatoxin encoding gene cluster. Consequently,A. sojaelacked aflatoxin production, while it varied amongA. parasiticusisolates. No other significant differences were observed in growth rates or other measured phenotypic traits betweenA. sojaeandA. parasiticus. These findings suggest thatA. sojaemay have evolved from a population ofA. parasiticusand lost the ability to produce some secondary metabolites. To elucidate the phenotypic differences betweenA. sojaeandA. parasiticus, future work should focus on the influence of wild and food-associated strains on the sensory aspects and microbial community dynamics of fermented soy products.Significance StatementLike plants and animals, microbes were also domesticated by humans, however relatively little is known about how the process of domestication shapes microbial genomes and traits. We found that isolates ofAspergillus sojae, a mold used in the production of miso and soy sauce, makeup a less toxic group that is genetically distinct from its closely related wild ancestorAspergillus parasiticus. Our analyses shed new light on commonalities observed across filamentous molds adapted to the food environment.
OxLDL/LOX-1 Mediated Sex, Age, and Cell Dependent Alterations in Mouse Thoracic Aortic Vascular Reactivity
Authors: Wendt Trevor S. , Gonzales Rayna J. 
Published: September 2023

ABSTRACTElevated oxidized low-density lipoprotein (oxLDL) is a risk factor and component that worsens cardiovascular disease states. OxLDL can elicit its detrimental action, via lectin-like oxLDL receptor 1 (LOX-1) and has been shown to disrupt vascular function. In this study, we determined whether oxLDL, via LOX-1, alters aortic vascular reactivity and determined if sex differences exist. Thoracic aortic endothelium-intact or -denuded ring segments were isolated from intact C57BL/6J female and male mice and incubated with oxLDL ex vivo (50ug/dL; 2h). Using wire myography, cumulative concentration-response curves to phenylephrine (PE) were generated to determine contractile responses. From these curves, the EC50 was determined and used to contract rings to assess acetylcholine (ACh) dependent relaxation. Calculated aortic stiffness and remodeling, as well as mRNA expression of vasoactive and pro-inflammatory mediators were assessed. BI-0115 (10μM; selective LOX-1 inhibitor) was used to determine LOX-1 dependence. We observed differential sex, age, endothelial cell, and LOX-1 dependent alterations to the efficacy of PE-induced contractile responses and ACh-mediated vasorelaxation in the thoracic aortic rings following oxLDL exposure. Additionally, we observed a distinct sex and age effect on thoracic aortic stiffness following exposure to oxLDL. There was also a sex effect on calculated vessel diameter, as well as an age effect on oxLDL-mediated inward remodeling that was LOX-1 dependent. Thus, LOX-1 inhibition and the resulting attenuation of oxLDL/endothelial-mediated alterations in aortic function suggests that there are differential sex differences in the role of oxLDL/LOX-1 in the thoracic aorta of male and female mice.NEW & NOTEWORTHYWe investigated the effects of oxidized low-density lipoprotein (oxLDL) via the LOX-1 receptor on murine thoracic aortic vasoreactivity, stiffness, and remodeling across age and sex. Acute exposure to oxLDL led to altered vasoreactivity, endothelial dysfunction, and changes in aortic stiffness and remodeling. These effects were in-part age, sex, endothelial, and LOX-1 dependent. This study reveals potential complex interactions in oxLDL/LOX-1-mediated vascular responses that could serve as potential therapeutic intervention for vascular diseases such as atherosclerosis.
Deep Learning Model for Tumor Type Prediction using Targeted Clinical Genomic Sequencing Data
Authors: Darmofal Madison , Suman Shalabh , Atwal Gurnit , Chen Jie-Fu , Chang Jason C. , Toomey Michael , Vakiani Efsevia , Varghese Anna M , Rema Anoop Balakrishnan , Syed Aijazuddin , Schultz Nikolaus , Berger Michael , Morris Quaid 
Published: September 2023

AbstractTumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a dataset of 39,787 solid tumors sequenced using a clinical targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivalling performance of WGS-based methods. GDD-ENS can also guide diagnoses on rare type and cancers of unknown primary, and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows has enabled clinically-relevant tumor type predictions to guide treatment decisions in real time.
Pre-dominance of dengue non-cross-reacting SARS-CoV-2 spike antibodies during the Omicron era and their role in the ADE-mediated surge of Dengue virus serotype 3
Authors: Sarker Supratim , Dutta Chiroshri , Mallick Abinash , Das Sayantan , Chowdhury Chandrika Das , De Abhishek , Gorai Surajit , Biswas Subhajit 
Published: September 2023

ABSTRACTIn India, the SARS-CoV-2 Delta wave (2020-21) gradually faded away with the advent of the Omicron variants (2021-present). Dengue incidences were observably less in Southeast Asia during the active years of the pandemic (2020-21). However, Dengue virus type 3 (DV3) cases were increasingly reported in India and many other dengue-endemic countries concurrent with the progression of the Omicron wave since 2022. This observation prompted us to investigate the current state of cross-reactivity between prevalent SARS-CoV-2 variants and different DV serotypes.Fifty-five COVID-19 serum samples (collected between January-September, 2022) and three pre-pandemic healthy serum samples were tested for DV or SARS-CoV-2 Immunoglobulin G/Immunoglobulin M (IgG/IgM) using the lateral flow immunoassays (LFIAs). The SARS-CoV-2 antibody (Ab)-positive samples were further tested for their ability to cross-neutralize DV types 1-4 (DV1-4) in Huh7 cell lines.Cross-reactivity between SARS-CoV-2 and DV diminished with the shift from Delta to Omicron prevalence. COVID-19 serum samples that were DV cross-reactive neutralized all DV serotypes, including DV3. However, Omicron wave serum samples were predominantly DV non-cross-reactive (about 70%) in LFIAs and coincided with the prevalence of BA.2 Omicron variant. They also cross-neutralized DV1, 2 and 4 but enhanced DV3 infectivity as evident from increased DV3 titres in virus neutralization test (VNT) compared to control serum samples.In conclusion, DV non-cross-reactive COVID-19 serum samples are becoming increasingly prominent in the present times. These non-cross-reactive serums could neutralize DV1, 2 and 4 but they are contributing to the surge in DV3 cases worldwide by means of ADE.
Change in body weight of older adults before and during the COVID-19 pandemic: Longitudinal results from the Berlin Aging Study II
Authors: Vetter Valentin Max , Drewelies Johanna , Düzel Sandra , Homann Jan , Meyer-Arndt Lil , Braun Julian , Pohrt Anne , Kendel Friederike , Wagner Gert G. , Thiel Andreas , Bertram Lars , Regitz-Zagrosek Vera , Gerstorf Denis , Demuth Ilja 
Published: September 2023

AbstractBackgroundChange in body weight during the COVID-19 pandemic as an unintended side effect of lockdown measures has been predominantly reported for younger and middle-aged adults. However, information on older adults for which weight loss is known to result in adverse outcomes, is scarce.AimsDescribe body weight change in older adults before, during, and after the COVID-19 lockdown measures and explore putative associated factors with a focus on the period that includes the first six months of the COVID-19 containment measures.MethodsIn this study, we analyzed the longitudinal weight change of 472 participants of the Berlin Aging Study II (mean age of 67.5 years at baseline, average follow-up time 10 years). Additionally, differences between subgroups characterized by socio-economic, cognitive, and psychosocial variables as well as morbidity burden, biological age markers (epigenetic clocks, telomere length), and frailty were compared.ResultsOn average, women and men lost 0.87% (n=227) and 0.5% (n=245) of their body weight per year in the study period covering the first six months of the COVID-19 pandemic. Weight loss among men was particularly pronounced among groups characterized by change in physical activity due to COVID-19 lockdown, low positive affect, premature epigenetic age (7-CpG clock), diagnosed metabolic syndrome, and a more masculine gender score (all variables: p<0.05, n=245).ConclusionsOlder participants lost weight with a 2.5-times (women) and 2-times (men) higher rate than what is expected in this age.
A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing
Authors: Verma Renu , Esther da Silva Kesia , Rockwood Neesha , Wasmann Roeland E. , Yende Nombuso , Song Taeksun , Kim Eugene , Denti Paolo , Wilkinson Robert J. , Andrews Jason R. 
Published: September 2023

AbstractRationaleStandardized dosing of anti-tubercular (TB) drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic (PGx) assays that predict metabolism of anti-TB drugs have been lacking.ObjectivesTo develop a Nanopore sequencing panel and validate its performance in active TB patients to personalize treatment dosing.Measurements and Main ResultsWe developed a Nanopore sequencing panel targeting 15 single nucleotide polymorphisms (SNP) in 5 genes affecting the metabolism of isoniazid (INH), rifampin (RIF), linezolid and bedaquiline. For validation, we sequenced DNA samples (n=48) from the 1000 genomes project and compared variant calling accuracy with Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n=100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for INH and RIF.ResultsThe PGx panel achieved 100% concordance with Illumina sequencing in variant identification for the samples from the 1000 Genomes Project. In the clinical cohort, coverage was >100x for 1498/1500 (99.8%) amplicons across the 100 samples. One third (33%) of participants were identified as slow, 47% were intermediate and 20% were rapid isoniazid acetylators. Isoniazid clearance was significantly impacted by acetylator status (p<0.0001) with median (IQR) clearances of 11.2 L/h (9.3-13.4), 27.2 L/h (22.0-31.7), and 45.1 L/h (34.1-51.1) in slow, intermediate, and rapid acetylators. Rifampin clearance was 17.3% (2.50-29.9) lower in individuals with homozygousAADACrs1803155 G>A substitutions (p=0.0015).ConclusionTargeted sequencing can enable detection of polymorphisms influencing TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention.SummaryThis manuscript describes the development and validation of Nanopore sequencing panel to detect host pharmacogenomic markers to guide personalized drug dosing for treatment or prevention of tuberculosis.This article has an online data supplement, which is accessible from this issue’s table of content online atwww.atsjournals.org
Advancing Drug Development with aiHumanoid Simulations: A Virtual Phase 1 Comparative Study of Standard Chemotherapy versus Standard Chemotherapy plus COTI-2 for Pancreatic Adenocarcinoma
Authors: Danter WR 
Published: September 2023

AbstractBackgroundTraditional Phase 1 trials often provide important drug development insights, which can be limited by ethical issues, costs, and lengthy timelines. Advancements in AI based simulations offer a potential avenue for mitigating these challenges. The present study used the aiHumanoid platform, specifically the upgraded DeepNEU database v8.1, to design and conduct a virtual Phase 1 trial, to assess the comparative efficacy and toxicity of standard chemotherapy with gemcitabine plus Taxol vs a combination of standard chemotherapy plus COTI-2 for treating Pancreatic Adenocarcinoma (PAC).MethodsApplying the updated DeepNEU database of 7267 genotypic and phenotypic concepts linked through 67491 relationships, the study used aiHumanoid simulations to predict outcomes from 30 virtual patients. Data from the standard chemotherapy arm and the standard treatment plus COTI2 arm were analyzed at 25%, 50%, 75%, and 100% of maximal dose. Estimates of efficacy and potential toxicities were based on a combination of the paired 2 tailed T test and Cohen’s d values as a true estimate of treatment effects.ResultsThe novel combined treatment regimen, especially at 100% dosage, showed medium to large treatment effects on the entire Pancreatic Adenocarcinoma disease profile. Notably, a significant decrease was observed in all disease profile components, bolstered by p-values less than 8.68E-5 and Cohen’s d values >=0.335. While evidence hinted at an increased bone marrow toxicity in the novel treatment arm, no individual organoid toxicity exceeded one standard deviation above predicted values. Importantly, COTI-2 treatment demonstrated a dose-dependent increase in p53 levels, significant at p < 0.006.ConclusionThis aiHumanoid’s virtual Phase 1 trial emphasizes the potential of computational simulations in the drug development process. Our findings indicate a promising treatment pathway combining COTI-2 with standard chemotherapy for Pancreatic Adenocarcinoma. Ongoing development and validation of the aiHumanoid based virtual Phase 1 clinical trial methodology is warranted.
Characterizing spinal reflexes evoked by spinal cord stimulation to restore sensation in people with lower-limb amputation
Authors: Bose Rohit , Dalrymple Ashley N , Sarma Devapratim , Petersen Bailey A , Barra Beatrice , Nanivadekar Ameya C , Madonna Tyler J , Liu Monica F , Levy Isaiah , Helm Eric R , Miele Vincent J , Capogrosso Marco , Fisher Lee E , Weber Douglas J 
Published: September 2023

ABSTRACTBackgroundPeople with lower-limb amputations lack sensory inputs from their missing limb, which increases their risk of falling. We recently demonstrated that spinal cord stimulation (SCS) can restore sensation in the missing lower limb. Previous studies have shown that SCS can affect motor control by exciting spinal reflex pathways after stroke or spinal cord injury. The effects of SCS on spinal reflex activation have not been studied in people with lower-limb amputation. Furthermore, it is unknown if SCS-evoked spinal reflex activation would perturb walking. Therefore, the goal of this study was to characterize SCS-evoked spinal reflexes in people with lower-limb amputation and quantify effects on gait parameters, including step cycle duration and limb alternation symmetry.MethodsWe implanted percutaneous SCS electrodes over the lumbosacral enlargement in 3 people with trans-tibial amputation (2 diabetic neuropathy; 1 traumatic) for 28 or 84 days. SCS was delivered to restore sensation in the missing limb during walking based on signals from a pressure-sensing insole in the shoe under the prosthesis. We used electromyography (EMG) to record posterior root-muscle (PRM) reflexes in the residual limb while participants were seated, standing, or walking. We characterized rate-dependent depression and recruitment properties of the PRM reflexes. We used pressure data from instrumented insoles to measure the step cycle duration and limb alternation symmetry with and without SCS.ResultsSCS evoked PRM reflexes in the residual limb muscles in all participants, which was confirmed by the presence of rate-dependent depression at stimulation frequencies ≥2Hz. Overall, there was broad activation of residual limb muscles with SCS that varied with the position of the stimulating electrode relative to the lumbar spinal cord. PRM reflexes were also activated during walking, as confirmed by the presence of rate-dependent depression. However, SCS-evoked PRM reflexes did not disrupt gait, with similar step cycle duration or limb alternation symmetry with and without SCS.ConclusionsRestoring sensation in the missing limb using SCS excites spinal reflexes according to the expected rostral-caudal myotomes but does not disrupt the step cycle duration or limb alternation symmetry in people with trans-tibial amputation.
Polygenic Scores for Longitudinal Prediction of Incident Type 2 Diabetes in an Ancestrally and Medically Diverse Primary Care Network
Authors: Mandla Ravi , Schroeder Philip , Porneala Bianca , Florez Jose C. , Meigs James B. , Mercader Josep M. , Leong Aaron 
Published: September 2023

ABSTRACTOBJECTIVEThe clinical utility of genetic information for type 2 diabetes (T2D) prediction with polygenic score (PGS) in ancestrally diverse, real-world US healthcare systems is unclear, especially for those at low clinical phenotypic risk for T2D.RESEARCH DESIGN AND METHODSWe tested the association of PGS with T2D incidence in patients followed within a primary care practice network over 16 years in four hypothetical scenarios that varied by clinical data availability (N = 14,712): 1) age and sex, 2) age, sex, BMI, systolic blood pressure, and family history of diabetes; 3) all variables in (2) and random glucose; 4) all variables in (3), HDL, total cholesterol, and triglycerides, combined in a clinical risk score (CRS). To determine whether genetic effects differed by baseline clinical risk, we tested for interaction with the CRS.RESULTSPGS was associated with incident diabetes in all models. Adjusting for age and sex only, the Hazard Ratio (HR) per PGS standard deviation (SD) was 1.76 (95% CI 1.68, 1.84) and the HR of top 5% of PGS vs interquartile range (IQR) was 2.80 (2.39, 3.28). Adjusting for the CRS, the HR per SD was 1.48 (1.40, 1.57) and HR of top 5% of PGS vs IQR was 2.09 (1.72, 2.55). Genetic effects differed by baseline clinical risk [(PGS-CRS interactionp=0.05; CRS below the median: HR 1.60 (1.43, 1.79); CRS above the median: HR 1.45 (1.35, 1.55)].CONCLUSIONSGenetic information can help identify high-risk patients even among those perceived to be low risk in a clinical evaluation.
Use of SGLT2i and ARNi in patients with atrial fibrillation and heart failure in 2021-2022: an analysis of real-world data
Authors: Alonso Alvaro , Morris Alanna A. , Naimi Ashley I. , Alam Aniqa B. , Li Linzi , Subramanya Vinita , Chen Lin Yee , Lutsey Pamela L. 
Published: September 2023

ABSTRACTObjectiveTo evaluate utilization of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor neprilysin inhibitors (ARNi) in patients with atrial fibrillation (AF) and heart failure (HF).MethodsWe analyzed the MarketScan databases for the period 1/1/2021 to 6/30/2022. Validated algorithms were used to identify patients with AF and HF, and to classify patients into HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). We assessed the prevalence of SGLT2i and ARNi use overall and by HF type. Additionally, we explored correlates of lower utilization, including demographics and comorbidities.ResultsThe study population included 60,927 patients (mean age 75, 43% female) diagnosed with AF and HF (85% with HFpEF, 15% with HFrEF). Prevalence of ARNi use was 11% overall (30% in HFrEF, 8% in HFpEF), while the corresponding figure was 6% for SGLT2i (13% in HFrEF, 5% in HFpEF). Use of both medications increased over the study period: ARNi from 9% to 12% (from 22% to 29% in HFrEF, from 6% to 8% in HFpEF), and SGLT2i from 3% to 9% (from 6% to 16% in HFrEF, from 2% to 7% in HFpEF). Female sex, older age, and specific comorbidities were associated with lower utilization of these two medication types overall and by HF type.ConclusionUse of ARNi and SGLT2i in patients with AF and HF is suboptimal, particularly among females and older individuals, though utilization is increasing. These results underscore the need for understanding reasons for these disparities and developing interventions to improve adoption of evidence-based therapies among patients with comorbid AF and HF.
Antibiotic pharmacokinetics in infected pleural effusions
Authors: Arnold David T , Read Liam , Waddington Oliver , Hamilton Fergus W , Patole Sonia , Hughes Jessica , Milne Alice , Noel Alan , Bayliss Mark , Maskell Nick A , MacGowan Alasdair 
Published: September 2023

AbstractPleural infection is usually treated with empirical broad-spectrum antibiotics but limited data exists around their penetrance into the infected pleural space. We performed a pharmacokinetic study analysing the concentration of 5 intravenous antibiotics across 146 separate timepoints in 35 patients (amoxicillin, metronidazole, piperacillin-tazobactam, clindamycin and cotrimoxazole). All antibiotics tested, apart from co-trimoxazole, reach pleural fluid levels equivalent to levels within blood, and well above the relevant minimum inhibitory concentrations. The results demonstrate that concerns around the penetration of commonly used antibiotics, apart from co-trimoxazole, into the infected pleural space are unfounded.
LVING Reveals the Intracellular Structure of Cell Growth
Authors: Pradeep Soorya , Zangle Thomas A. 
Published: September 2023

ABSTRACTThe continuous balance of growth and degradation inside cells maintains homeostasis. Disturbance of the balance by internal or external factors cause state of disease. Effective disease treatments seek to restore this balance. Here, we present a method based on quantitative phase imaging (QPI) based measurements of cell mass and the velocity of mass transport to quantify the balance of growth and degradation within intracellular control volumes. The result, which we call Lagrangian velocimetry for intracellular net growth (LVING), provides high resolution maps of intracellular biomass production and degradation. We use LVING to quantify the growth in different regions of the cell during phases of the cell cycle. LVING can also be used to quantitatively compare the effect of range of chemotherapy drug doses on subcellular growth processes. Finally, we applied LVING to characterize the effect of autophagy on the growth machinery inside cells. Overall, LVING reveals both the structure and distribution of basal growth within cells, as well as the disruptions to this structure that occur during alterations in cell state.