bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Distinct Inflammatory Milieu in Patients with Right Heart Failure
Authors: Yang Bin Q , Park Arick C , Liu Jason , Byrnes Kathleen , Javaheri Ali , Mann Douglas L , Schilling Joel D 
Published: April 2023

ABSTRACTBackground:Right heart failure (RHF) is associated with worse clinical outcomes. In addition to hemodynamic perturbations, the syndrome of RHF involves liver congestion and dysfunction. The mechanisms that underlie heart-liver interactions are poorly understood and may involve secreted factors. As a first step to understand the cardiohepatic axis, we sought to elucidate the circulating inflammatory milieu in patients with RHF.Methods:Blood samples were collected from the IVC and hepatic veins during right heart catheterization from 3 groups of patients: 1) controls with normal cardiac function, 2) patients with heart failure (HF) who did not meet all criteria of RHF, and 3) patients who met prespecified criteria for RHF defined by hemodynamic and echocardiographic parameters. We performed multiplex protein assay to survey levels of several circulating markers and analyzed their association with mortality and need for left ventricular assist device or heart transplant. Finally, we leveraged publicly available single cell RNA sequencing (scRNAseq) data and performed tissue imaging to evaluate expression of these factors in the liver.Results:In this study of 43 patients, RHF was associated with elevated levels of a subset of cytokines/chemokines/growth factors compared to controls. In particular, soluble CD163 (sCD163) and CXCL12 were higher in RHF and predicted survival in an independent validation cohort. Furthermore, scRNAseq and immunohistochemistry of human liver biopsies suggest that these factors are expressed by Kupffer cells and may be liver derived.Conclusions:RHF is associated with a distinct circulating inflammatory profile. sCD163 and CXCL12 are novel biomarkers that can prognosticate patient outcomes. Future studies to define how these molecules influence HF phenotypes and disease progression may lead to new approaches to management of patients with RHF.
Mixed-method evaluation of an expedited partner therapy take-home medication program: a pilot ED intervention to improve sexual health equity
Authors: Ager Emily E. , Sturdavant William , Curry Zoe , Ahmed Fahmida , DeJonckheere Melissa , Gutting Andrew , Merchant Roland C. , Kocher Keith E. , Solnick Rachel E. 
Published: April 2023

ABSTRACTBackgroundTreatment for partners of patients diagnosed with sexually transmitted infections (STIs), referred to as expedited partner therapy (EPT), is infrequently used in emergency departments (EDs). This was a pilot program to initiate and evaluate EPT through medication-in-hand (“take-home”) kits or paper prescriptions. This study aimed to assess the frequency of EPT prescribing, the efficacy of a randomized best practice advisory (BPA) on the uptake of EPT, perceptions of ED clinicians regarding the EPT pilot, and factors associated with EPT prescribing.MethodsThis pilot study was conducted at an academic ED in the midwestern US between August and October 2021. The primary outcome was EPT prescription uptake and the BPA impact was measured via chart abstraction and analyzed through summary statistics and Fisher’s exact test. The secondary outcome of barriers and facilitators to program implementation was analyzed through ED staff interviews (physicians, physician assistants, and nurses). A rapid qualitative assessment method for the analysis of the interviews was employed.ResultsFifty-two ED patients were treated for chlamydia/gonorrhea during the study period. EPT was offered to 25% (95% CI 15%-39%) of patients. EPT was prescribed twice as often (85% vs. 38%;p<0.01) when the interruptive pop-up alert BPA was shown. Barriers identified in the interviews included workflow constraints and knowledge of EPT availability. The BPA was viewed positively by the majority of participants.ConclusionsIn this pilot EPT program, EPT was provided to 25% of ED patients who appeared eligible to receive it. The interruptive pop-up alert BPA significantly increased EPT prescribing. Barriers identified to EPT prescribing can be the subject of future interventions to improve ED EPT provision.
Effect of Graft Fixation Angles in Double-Bundle Anterior Cruciate Ligament Reconstruction, a Systematic Review
Authors: Phadke Rohan , Song Bo 
Published: April 2023

AbstractContextRecent reviews have demonstrated a shift towards anatomical double bundle (DB) techniques for anterior cruciate ligament reconstruction (ACLR). However, to our knowledge, there are no reviews that have directly assessed the relationship between bone tunnel graft angle placement in DB ACLR and clinical outcomes.ObjectiveTo investigate the effect of bone tunnel graft angle on clinical outcomes in DB ACLR.Data SourcesWe performed a comprehensive search of the databases PubMed, Scopus, and Embase using the search terms (Fixation OR Angle) AND (ACL OR anterior cruciate ligament) AND (double-bundle OR DB OR double bundle) AND (Reconstruction OR surgery OR arthroscopy) across all time periods.Study SelectionTwo independent authors performed a systematic review of the literature. After removing duplicates and applying inclusion/exclusion criteria on a number of clinical outcomes and other factors, 5 eligible studies were recruited under PRISMA guidelines from the 1032 titles identified.Study DesignSystematic ReviewLevel of Evidence2aData ExtractionSystematic review of clinical trials and extraction of relevant surgical data.ResultsOur data did not support the original hypothesis and rather showed that increasing the PL bundle angle from 0° to 90° leads to better performance on the pivot-shift tests. Having a nonzero AM bundle graft fixation angle, more specifically at or above 20°, produces better performance on the ATT, Tegner, Lysholm and pivot-shift tests when compared to a 0° angle.ConclusionsA PL bundle angle at or above 45° as well as a nonzero AM bundle angle both yielded better clinical outcome scores. However, with respect to a specific combination, there is no consensus on an optimal graft angle combination in DB ACLR currently. Future randomized controlled trials on this topic are recommended to better understand the effects of greater ranges of graft fixation angles on clinical outcome heterogeneity.
Exact confidence intervals for population growth rate, longevity and generation time
Authors: Hernandez-Suarez Carlos M , Rabinovich Jorge 
Published: April 2023

AbstractBy quantifying key life history parameters in populations, such as growth rate, longevity, and generation time, researchers and administrators can obtain valuable insights into its dynamics. Although point estimates of demographic parameters have been available since the inception of demography as a scientific discipline, the construction of confidence intervals has typically relied on approximations through series expansions or computationally intensive techniques. This study introduces the first mathematical expression for calculating confidence intervals for the aforementioned life history traits when individuals are unidentifiable and data are presented as a life table. The key finding is the accurate estimation of the confidence interval forr, the instantaneous growth rate, which is tested using Monte Carlo simulations with four arbitrary discrete distributions. In comparison to the bootstrap method, the proposed interval construction method proves more efficient, particularly for experiments with a total offspring size below 400. We discuss handling cases where data are organized in extended life tables or as a matrix of vital rates.
Suppressed vascular Rho-kinase activation is a protective cardiovascular mechanism in obese female mice
Authors: Barbosa Gabriela Souza , Costa Rafael M , Awata Wanessa MC , Singh Shubhnita , Alves Juliano V , Bruder-Nascimento Ariane , Corrêa Camila Renata , Bruder-Nascimento Thiago 
Published: April 2023

AbstractBackgroundObesity is the number one cardiovascular risk factor for both men and women and is a complex condition. Although a sex dimorphism on vascular function has already been noted, the underlying processes remain unclear. The Rho-kinase pathway has a unique role in controlling vascular tone, and in obese male mice, hyperactivation of this system results in worsened vascular constriction. We investigated whether female mice exhibit decreased Rho-kinase activation as a protective mechanism in obesity.MethodsWe exposed male and female mice to a high-fat diet (HFD) for 12 weeks. At the end, energy expenditure, glucose tolerance, adipose tissue inflammation, and vascular function were investigated.ResultsMale mice were more sensitive to HFD-induced body weight gain, glucose tolerance, and inflammation than female mice. After establishing obesity, female mice demonstrated increase in energy expenditure, characterized by an increase in heat, whereas male mice did not. Interestingly, obese female mice, but not male, displayed attenuated vascular contractility to different agonists, such difference was blunted by inhibition of Rho-kinase. Finally, aortae from obese female mice, but not male, responded prematurely to Rho-kinase inhibitor, which was accompanied by a suppressed Rho-kinase activation, measured by western blot.ConclusionIn obesity, female mice demonstrate a vascular protective mechanism – suppression of vascular Rho-kinase – to minimize the cardiovascular risk associated with obesity, whereas male mice do not generate any adaptive response. Future investigations can help to understand how Rho-kinase becomes suppressed in female during obesity.
A tough nutlet to crack: resolving the phylogeny ofThesium(Thesiaceae), the largest genus in Santalales
Authors: García Miguel A. , Mucina Ladislav , Nickrent Daniel L. 
Published: April 2023

AbstractWith over 350 species,Thesiumis the largest genus in Santalales. It is found on all continents except Antarctica; however, its highest diversity is in the Cape Floristic Region of South Africa where approximately half the species occur.Thesiumsamples of ca. 590 collections from throughout its entire geographic range were obtained and nuclear ribosomal ITS sequenced from 396 accessions representing 196 named taxa and 30 currently unnamed taxa for a total of ca. 230 species. In addition, two chloroplast genome spacers (trnDTandtrnLF) were sequenced from 269 and 315 accessions, respectively. Maximum parsimony, maximum likelihood and Bayesian methods were employed to generate gene trees and infer phylogenies. The value of the morphological characters traditionally used in the taxonomy of the genus and previous infrageneric classifications are discussed. Broad scale relationships were generally congruent among the ITS and the chloroplast trees. For example, both the nuclear and chloroplast trees support the presence of Eurasian and African clades. In contrast, major incongruence was detected between nuclear and chloroplast trees for a number of taxa including the recently describedT. nautimontanumthat is sister to the entire African clade on the ITS tree. Although the causes of this incongruence are currently unknown, a novel form of chloroplast capture is hypothesized. A hypothesis of the biogeographical history of the genus based on our molecular phylogeny is presented.
A physiologically based pharmacokinetic model for CYP2E1 phenotyping via chlorzoxazone
Authors: Küttner Jonas , Grzegorzewski Jan , Tautenhahn Hans-Michael , König Matthias 
Published: April 2023

ABSTRACTThe cytochrome P450 (CYP) superfamily of enzymes plays a critical role in the metabolism of drugs, toxins, and endogenous and exogenous compounds. The activity of CYP enzymes can be influenced by a variety of factors, including genetics, diet, age, environmental factors, and disease. Among the major isoforms, CYP2E1 is of particular interest due to its involvement in the metabolism of various low molecular weight chemicals, including alcohols, pharmaceuticals, industrial solvents, and halogenated anesthetics. Metabolic phenotyping of CYPs based on the elimination of test compounds is a useful method for assessing in vivo activity, with chlorzoxazone being the primary probe drug for phenotyping of CYP2E1. The aim of this work was to investigate the effect of changes in CYP2E1 level and activity, ethanol consumption, ethanol abstinence, and liver impairment on the results of metabolic phenotyping with chlorzoxazone. To accomplish this, an extensive pharmacokinetic dataset for chlorzoxazone was established and a physiologically based pharmacokinetic (PBPK) model of chlorzoxazone and its metabolites, 6-hydroxychlorzoxazone and chlorzoxazone-O-glucuronide, was developed and validated. The model incorporates the effect of ethanol consumption on CYP2E1 levels and activity by extending the model with a core ethanol pharmacokinetic model and a CYP2E1 turnover model. The model accurately predicts pharmacokinetic data from several clinical studies and is able to estimate the effect of changes in CYP2E1 levels and activity on chlorzoxazone pharmacokinetics. Regular ethanol consumption induces CYP2E1 over two to three weeks, resulting in increased conversion of chlorzoxazone to 6-hydroxychlorzoxazone and a higher 6-hydroxychlorzoxazone/chlorzoxazone metabolic ratio. After ethanol withdrawal, CYP2E1 levels return to baseline within one week. Importantly, liver impairment has an opposite effect, resulting in reduced liver function via CYP2E1. In alcoholics with liver impairment who also consume ethanol, these factors will have opposite confounding effects on metabolic phenotyping with chlorzoxazone.
Anisotropic Subcutaneous Response During Fingertip Normal and Tangential Loadings
Authors: Duprez Guillaume H.C. , Delhaye Benoit P. , Laurent Delannay 
Published: April 2023

AbstractThe subcutaneous mechanical response of the fingertip is highly anisotropic due to the presence of a network of collagen fibers linking the outer skin layer to the bone. Yet, the impact of this anisotropy on the fingerpad deformation had not been studied until now. This issue is here tackled using a two-dimensional finite element model of a transverse section of the finger. Different hypotheses about the orientation of the fibers are considered: radial (physiologic), circumferential, and random (isotropic behavior). The three variants of the model are assessed using experimental observations of a finger leaning on a flat surface. Predictions relying on the physiological orientation of fibers align best with reality. Moreover, the orientation of fibers plays a crucial role in determining the distribution of internal strain and stress. These factors, combined with the abrupt shift in contact pressure during the transition from sticking to slipping, represent important sensory cues for partial slip detection. This is valuable information for the development of haptic devices.
Evaluation of mRNA-LNP and adjuvanted protein SARS-CoV-2 vaccines in a maternal antibody mouse model
Authors: England Ross N. , Drapeau Elizabeth M. , Hosseinzadeh Reihaneh , Weissman Drew , Hensley Scott E. 
Published: April 2023

AbstractMaternal antibodies (matAbs) protect against a myriad of pathogens early in life; however, these antibodies can also inhibitde novoimmune responses against some vaccine platforms. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) matAbs are efficiently transferred during pregnancy and protect infants against subsequent SARS-CoV-2 infections. It is unknown if matAbs inhibit immune responses elicited by different types of SARS-CoV-2 vaccines. Here, we established a mouse model to determine if SARS-CoV-2 spike-specific matAbs inhibit immune responses elicited by recombinant protein and nucleoside-modified mRNA-lipid nanoparticle (mRNA-LNP) vaccines. We found that SARS-CoV-2 mRNA-LNP vaccines elicited robustde novoantibody responses in mouse pups in the presence of matAbs. Recombinant protein vaccines were also able to circumvent the inhibitory effects of matAbs when adjuvants were co-administered. While additional studies need to be completed in humans, our studies raise the possibility that mRNA-LNP-based and adjuvanted protein-based SARS-CoV-2 vaccines have the potential to be effective when delivered very early in life.
Pleiotropic Influence of DNA Methylation QTLs on physiological and aging traits
Authors: Mozhui Khyobeni , Kim Hyeonju , Villani Flavia , Haghani Amin , Sen Saunak , Horvath Steve 
Published: April 2023

AbstractDNA methylation is influenced by genetic and non-genetic factors. Here, we chart quantitative trait loci (QTLs) that modulate levels of methylation at highly conserved CpGs using liver methylome data from mouse strains belonging to the BXD Family. A regulatory hotspot on chromosome 5 had the highest density of trans-acting methylation QTLs (trans-meQTLs) associated with multiple distant CpGs. We refer to this locus as meQTL.5a. The trans-modulated CpGs showed age-dependent changes, and were enriched in developmental genes, including several members of the MODY pathway (maturity onset diabetes of the young). The joint modulation by genotype and aging resulted in a more “aged methylome” for BXD strains that inherited the DBA/2J parental allele at meQTL.5a. Further, several gene expression traits, body weight, and lipid levels mapped to meQTL.5a, and there was a modest linkage with lifespan. DNA binding motif and protein-protein interaction enrichment analysis identified the hepatic nuclear factor,Hnf1a(MODY3 gene in humans), as a strong candidate. The pleiotropic effects of meQTL.5a could contribute to variation in body size and metabolic traits, and influence CpG methylation and epigenetic aging that could have an impact on lifespan.
A calibration and uncertainty quantification analysis of classical, fractional and multiscale logistic models of tumour growth
Authors: Dimitriou Nikolaos M. , Demirag Ece , Strati Katerina , Mitsis Georgios D. 
Published: April 2023

AbstractThe validation of mathematical models of tumour growth is frequently hampered by the lack of sufficient experimental data, resulting in qualitative rather than quantitative studies. Recent approaches to this problem have attempted to extract information about tumour growth by integrating multiscale experimental measurements, such as longitudinal cell counts and gene expression data. In the present study, we investigated the performance of several mathematical models of tumour growth, including classical logistic, fractional and novel multiscale models, in terms of quantifyingin-vitrotumour growth in the presence and absence of therapy. We further examined the effect of genes associated with changes in chemosensitivity in cell death rates. State-of-the-art Bayesian inference, likelihood maximisation and uncertainty quantification techniques allowed a thorough evaluation of model performance. The results suggest that the classical single-cell population model (SCPM) was the best fit for the untreated and low-dose treatment conditions, while the multiscale model with a cell death rate symmetric with the expression profile of OCT4 (SymSCPM) yielded the best fit for the high-dose treatment data. Further identifiability analysis showed that the multiscale model was both structurally and practically identifiable under the condition of known OCT4 expression profiles. Overall, the present study demonstrates that model performance can be improved by incorporating multiscale measurements of tumour growth.
Combinatorial genetic strategy accelerates the discovery of cancer genotype-phenotype associations
Authors: Li Shan , Wong Alicia , Sun Huiyun , Bhatia Vipul , Javier Gerardo , Jana Sujata , Montgomery Robert B. , Wright Jonathan L. , Lam Hung-Ming , Hsieh Andrew C. , Faltas Bishoy M. , Haffner Michael C. , Lee John K. 
Published: April 2023

AbstractAvailable genetically-defined cancer models are limited in genotypic and phenotypic complexity and underrepresent the heterogeneity of human cancer. Herein, we describe a combinatorial genetic strategy applied to an organoid transformation assay to rapidly generate diverse, clinically relevant bladder and prostate cancer models. Importantly, the clonal architecture of the resultant tumors can be resolved using single-cell or spatially resolved next-generation sequencing to uncover polygenic drivers of cancer phenotypes.
A mouse-specific model to detect genes under selection in tumors
Authors: Chen Hai , Shu Jingmin , Liu Li 
Published: April 2023

AbstractMouse is a widely used model organism in cancer research. However, no computational methods exist to identify cancer driver genes in mice due to a lack of labeled training data. To address this knowledge gap, we adapted the GUST (genes under selection in tumors) model, originally trained on human exomes, to mouse exomes using transfer learning. The resulting tool, called GUST-mouse, can estimate long-term and short-term evolutionary selection in mouse tumors, and distinguish between oncogenes, tumor suppressor genes, and passenger genes using high throughput sequencing data. We applied GUST-mouse to analyze 65 exomes of mouse primary breast cancer models, leading to the discovery of 24 driver genes. The GUST-mouse method is available as an open-source R package on github (https://github.com/liliulab/gust.mouse).
Spatial Multi-omics of Arterial Regions from Cardiac Allograft Vasculopathy Rejected Grafts
Authors: Nevarez-Mejia Jessica , Pickering Harry C. , Sosa Rebecca A. , Fishbein Gregory A. , Baldwin William M. , Fairchild Robert L. , Reed Elaine F. 
Published: April 2023

2. AbstractBackgroundCardiac allograft vasculopathy (CAV) is a major cause of late-graft failure and mortality following heart transplantation. The mechanisms underlying vascular remodeling are poorly understood. A major immune risk factor associated with the development of CAV is the presence of donor-specific antibodies (DSA) that induce chronic endothelial cell (EC) injury, leukocyte recruitment and inflammation resulting in thickening of arterial intima. Here, we molecularly characterized innate and adaptive immune cells present in the arteries of rejected cardiac allografts with DSA and identified protein and transcriptomic signatures distinguishing early and late CAV lesions.MethodsArterial areas of interest (AOIs) from CAV+DSA+ rejected cardiac allografts (N=3; 2 females, 1 male) were subjected to GeoMx digital spatial profiling (DSP). AOIs were scored on the level of CAV progression/neointimal thickening (22 AOIs total; 11 high and 11 low neointima) and were subjected to whole transcriptome and protein profiling.ResultsAOIs with low neointima significantly increased markers for activated inflammatory infiltrates, transcripts of EC activation and gene modules involved in activating metalloproteinases and TP53 regulation of caspases. Inflammatory and apoptotic protein markers significantly correlated with inflammatory modules in AOIs with low neointima. AOIs with high neointima increased TGFβ-regulated transcripts and modules enriched for platelet activation/aggregation. Proteins encoding SMCs and growth factors/survival correlated with modules enriched for proliferation/repair in AOIs with high neointima. Key transcripts in promoting proliferation, migration, and EndoMT were significantly associated with increasing neointima scores.ConclusionOur results reveal new protein and transcriptomic signatures associated with CAV progression. Lesions exhibiting inflammatory profiles appear to be early lesions that transition to later proliferative/pro-fibrotic phenotype CAV lesions. These findings should form the foundation for the identification of improved biomarkers to guide CAV treatment.