bluuebunny/crossref_metadata_2025_split huggingface dataset:
Melanin-concentrating hormone promotes feeding through the lateral septum
Authors: Payant Mikayla A. , Shankhatheertha Anjali , Chee Melissa J. 
Published: May 2024

AbstractFeeding is necessary for survival but can be hindered by anxiety or fear, thus neural systems that can regulate anxiety states are key to elucidating the expression of food-related behaviors. Melanin-concentrating hormone (MCH) is a neuropeptide produced in the lateral hypothalamus that promotes feeding and anxiogenesis. The orexigenic actions of MCH that prolong ongoing homeostatic or hedonic feeding are context-dependent and more prominent in male than female rodents, but it is not clear where MCH acts to initiate feeding. The lateral septum (LS) promotes feeding and suppresses anxiogenesis when inhibited, and it comprises the densest projections from MCH neurons. However, it is not known whether the LS is a major contributor to MCH-mediated feeding. As MCH inhibits LS cells by MCH receptor (MCHR1) activation, MCH may promote feeding via the LS. We bilaterally infused MCH into the LS and found that MCH elicited a rapid and long-lasting increase in the consumption of standard chow and a palatable, high sugar diet in male and female mice; these MCH effects were blocked by the co-administration of a MCHR1 antagonist TC-MCH 7c. Interestingly, the orexigenic effect of MCH was abolished in a novel, anxiogenic environment even when presented with a food reward, but MCH did not induce anxiety-like behaviors. These findings indicated the LS as a novel region underlying orexigenic MCH actions, which stimulated and enhanced feeding in both sexes in a context -dependent manner that was most prominent in the homecage.
Epileptic encephalopathy linked to a DALRD3 missense variant impaired in tRNA modification function
Authors: Zhang Kejia , Löhner Katharina , Lemmink Henny H. , Boon Maartje , Lentini Jenna M. , de Silva Naduni , Fu Dragony 
Published: May 2024

AbstractEpileptic encephalopathies are severe epilepsy syndromes characterized by early onset and progressive cerebral dysfunction. A nonsense variant in theDALR Anticodon Binding Domain Containing 3(DALRD3) gene has been implicated in epileptic encephalopathy but no other disease-associated variants inDALRD3have been described. In human cells, the DALRD3 protein forms a complex with the METTL2 methyltransferase to generate the 3-methylcytosine (m3C) modification in specific arginine tRNAs. Here, we identify a patient with a homozygous missense variant in DALRD3 who displays developmental delay, cognitive deficiencies, and multifocal epilepsy. The missense variant substitutes an arginine residue to cysteine (R517C) within the DALR domain of DALRD3 that is required for binding tRNAs. Patient cells homozygous for the DALRD3-R517C variant exhibit reduced levels of m3C modification in arginine tRNAs, indicating that the R517C variant impairs DALRD3 function. Notably, the DALRD3-R517C variant displays reduced association with METTL2 and loss of interaction with substrate tRNAs. Our results uncover a novel pathogenic variant in DALRD3 that links DALRD3 loss-of-function to epileptic encephalopathy disorders. Importantly, these findings underscore DALRD3-dependent tRNA modification as a key contributor to proper brain development and function.
Kinetical analysis of D-alanine upon oral intake in humans
Authors: Kimura Tomonori , Sakai Shinsuke , Horio Masaru , Takahara Shiro , Ishigo Shoto , Nakane Maiko , Negishi Eiichi , Imoto Hiroshi , Mita Masashi , Hamase Kenji , Higa-Maekawa Yoko , Kakuta Yoichi , Mizui Masayuki , Isaka Yoshitaka 
Published: May 2024

AbstractD-Alanine, a rare enantiomer of alanine in life, can potentially alleviate the worsening of viral infections and maintain circadian rhythm. This study aimed to analyze the kinetics of D-alanine upon oral intake. Five healthy volunteers were administered D-alanine as a single oral dose at 12,366 or 33,708 μmoL. Upon intake of the lower dose, the plasma level of D-alanine reached its peak concentration of 588.4 ± 40.9 μM with a peak time of 0.60 ± 0.06 h. The plasma level of D-alanine became close to the endogenous level after 24 h. The compartment model estimated the clearance of D-alanine at 12.5 ± 0.3 L/h, or 208 ± 5 mL/min, distribution volume of 8.3 ± 0.7 L and half-life of 0.46 ± 0.04 h. The peak concentration and area under the curve increased proportionally upon intake of the higher dose, while the clearance, distribution volume and half-life did not. The urinary ratio of D-alanine reached its peak of nearly 100%, followed by a slow decline. The peak time of the urinary ratio was 1.15 ± 0.15 h, showing a time lag of blood to urine excretion. Fractional excretion of D-alanine increased from 14.0 ± 5.8% to 64.5 ± 10.3%; the latter corresponded to the urinary clearance of D-alanine as about 77 mL/min for an adult, with a peak time of 1.90 ± 0.56 h. D-Alanine was quickly absorbed and appeared in blood, followed by urinary excretion. This kinetic analysis increases our fundamental knowledge of the oral intake of D-alanine.
Simultaneous assessment of genetic and epigenetic contributions to plasma lipid levels with respect to cardiovascular risk
Authors: Takeuchi Fumihiko , Yamamoto Masaya , Nakatochi Masahiro , Takano Kozue , Okazaki Atsuko , Emoto Sakurako , Tabara Yasuharu , Katsuya Tomohiro , Yamamoto Ken , Isono Masato , Mori Kotaro , Matsubara Tatsuaki , Ichihara Sahoko , Yokota Mitsuhiro , Hara Hisao , Hiroi Yukio , Kato Norihiro 
Published: May 2024

AbstractBackgroundThis study aims to develop a model for simultaneously assessing genetic and epigenetic contributions to plasma lipid levels.MethodsThe predictive model was developed using two cardiovascular risk groups, i.e., individuals with high low-density lipoprotein cholesterol (LDL-C) levels (≥160 mg/dl,N= 296) and coronary artery disease (CAD) (N= 315), in contrast to reference (maxN= 3,801) and non-CAD individuals (N= 164). For genetic predisposition, rare pathological variants in five target genes related to familial hypercholesterolemia (FH) were screened, while common variants were characterized to calculate a polygenic risk score (PRS). The methylation risk score (MRS) was also calculated for epigenetic profiles based on DNA methylation levels at 13 CpG sites. A relationship between these variables and lipid levels was analyzed in regression and quantile models.ResultsA total of 17 rare FH-related gene variants were identified in patients with high LDL-C or CAD, significantly more prevalent than in the general Japanese population (2.8% vs. 0.2%,P<1×10−15). For the rare variants plus PRS, the predictability of individual LDL-C increased (correlation coefficient between predicted and measured values,r= 0.261,P= 1.7×10−11) compared to PRS alone (r= 0.151,P= 1.2×10−4). PRS and MRS had the most significant impact on high-density lipoprotein cholesterol and triglycerides, respectively. The two risk scores had additive effects on these traits.ConclusionsOur results provide proof-of-concept that assessing the relative contribution of genetic predisposition and DNA methylation levels (reflecting past environmental exposures) may help individuals refine their dyslipidemia treatment.
Using a Quality Improvement Approach to improve reporting of malaria deaths in Namutumba District, Eastern Uganda, 2022–2023
Authors: Zalwango Marie Gorreti , Migisha Richard , Kwesiga Benon , Bulage Lilian , Kadobera Daniel , Ario Alex Riolexus 
Published: May 2024

AbstractBackgroundReporting malaria deaths is critical for assessing prevention and case management interventions. In Uganda, malaria mortality is recorded in inpatient registers and reported through weekly and monthly surveillance reports. During a data quality assessment in Namutumba District in October 2022, we found more malaria deaths in health facility registers than were reported. We conducted a continuous quality improvement initiative to improve the accuracy of reported malaria deaths in Namutumba District.MethodsWe purposively selected 2 high-level health centers (HC) in Namutumba District that reported malaria deaths during September 2021–October 2022. We formed quality improvement teams (QIT) comprising clinical and statistical staff at the HC. We held focus group discussions with QITs to identify challenges with reporting malaria deaths, prioritized areas for improvement, and conducted root cause analysis. Using the plan, do, study, act (PDSA) cycle, we identified change ideas to address root causes.InterventionsChallenges included knowledge gaps on malaria death definitions, lack of consequences for failing to document deaths, and unclear guidance on how to document deaths. Sustainable interventions identified included continuous medical education on malaria death definition, one-on-one mentorship of staff on documentation in inpatient registers, and weekly verification of inpatient register data, all implemented during November 2022–February 2023.ResultsOf the 36 malaria deaths that occurred during the baseline period (September 2021– October 2022), 25 (69%) were included in the weekly report, and four (11%) in the monthly report. Following the intervention implementation, all 7 malaria deaths recorded at the 2 health facilities during November 2022–February 2023 were reported in the weekly and monthly reports.ConclusionContinuous medical education, supervision and mentoring of HC staff, and clear and comprehensive guidance on documenting malaria deaths could facilitate improved malaria death reporting from HC in Uganda, enabling more accurate resource allocation for malaria control.
Gut microbiome alterations precede graft rejection in kidney transplantation patients
Authors: Holle Johannes , Reitmeir Rosa , Behrens Felix , Singh Dharmesh , Schindler Daniela , Potapenko Olena , McParland Victoria , Anandakumar Harithaa , Kanzelmeyer Nele , Sommerer Claudia , Hartleif Steffen , Andassy Joachim , Heemann Uwe , Neuenhahn Michael , Forslund-Startceva Sofia K. , Gerhard Markus , Oh Jun , Wilck Nicola , Löber Ulrike , Bartolomaeus Hendrik ,   members of the German Center of Infection Research Transplant Cohort
Published: May 2024

AbstractBackgroundKidney transplantation (KT) is the optimal treatment for end-stage kidney disease, with graft survival critically affected by the recipient’s immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might associate with allograft rejection.MethodsWe analyzed existing biomaterials of a multicenter prospective study involving 217 KT recipients and 28 kidney donors from the German Center for Infection Research. Changes in the gut microbiome were analyzed using 16S rRNA gene amplicon sequencing and functional predictions (PICRUSt2) and quantitative PCRs for the production potential of propionate and butyrate. Propensity score matching was utilized to compare patients who experienced graft rejection with those who did not.ResultsThe gut microbiome showed gradual recovery post-KT, marked by an increase of Shannon diversity and SCFA-producing bacterial taxa. However, prior to graft rejection, significant alterations were noted in microbiome composition, characterized by a decrease in microbial diversity and SCFA-producing taxa. Post-rejection analysis revealed normalization of these microbiome features. Functional analysis highlighted a decreased potential for SCFA production in patients prior to rejection. Comparison to published microbiome signatures from chronic kidney disease (CKD) patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD.ConclusionsOur findings suggest that alterations in the gut microbiome composition and function may precede and influence KT rejection, suggesting potential for use as biomarker and early therapeutic microbiome-targeting interventions to improve transplant outcomes.Key points– CKD-related microbiome alterations recover over time after transplantation mirroring CKD-to-health transition– Microbiome alterations with lowered production potential of short-chain fatty acids precede graft rejection, likely influencing graft immunity– The persistence of CKD-associated microbiome characteristics in rejection patients opens avenues for innovative treatment strategies.
STRchive: a dynamic resource detailing population-level and locus-specific insights at tandem repeat disease loci
Authors: Hiatt Laurel , Weisburd Ben , Dolzhenko Egor , VanNoy Grace E. , Kurtas Edibe Nehir , Rehm Heidi L. , Quinlan Aaron , Dashnow Harriet 
Published: May 2024

AbstractApproximately 3% of the human genome consists of repetitive elements called tandem repeats (TRs), which include short tandem repeats (STRs) of 1–6bp motifs and variable number tandem repeats (VNTRs) of 7+bp motifs. TR variants contribute to several dozen mono- and polygenic diseases but remain understudied and “enigmatic,” particularly relative to single nucleotide variants. It remains comparatively challenging to interpret the clinical significance of TR variants. Although existing resources provide portions of necessary data for interpretation at disease-associated loci, it is currently difficult or impossible to efficiently invoke the additional details critical to proper interpretation, such as motif pathogenicity, disease penetrance, and age of onset distributions. It is also often unclear how to apply population information to analyses.We present STRchive (S-T-archive,http://strchive.org/), a dynamic resource consolidating information on TR disease loci in humans from research literature, up-to-date clinical resources, and large-scale genomic databases, with the goal of streamlining TR variant interpretation at disease-associated loci. We apply STRchive —including pathogenic thresholds, motif classification, and clinical phenotypes—to a gnomAD cohort of ∼18.5k individuals genotyped at 60 disease-associated loci.Through detailed literature curation, we demonstrate that the majority of TR diseases affect children despite being thought of as adult diseases. Additionally, we show that pathogenic genotypes can be found within gnomAD which do not necessarily overlap with known disease prevalence, and leverage STRchive to interpret locus-specific findings therein. We apply a diagnostic blueprint empowered by STRchive to relevant clinical vignettes, highlighting possible pitfalls in TR variant interpretation. As a living resource, STRchive is maintained by experts, takes community contributions, and will evolve as understanding of TR diseases progresses.
Deep Learning Enhances Detection of Extracapsular Extension in Prostate Cancer from mpMRI of 1001 Patients
Authors: Khosravi Pegah , Saikali Shady , Alipour Abolfazl , Mohammadi Saber , Boger Max , Diallo Dalanda M. , Smith Christopher , Moschovas Marcio Covas , Hajirasouliha Iman , Hung Andrew J. , Venkataraman Srirama S. , Patel Vipul 
Published: May 2024

AbstractExtracapsular extension (ECE) is detected in approximately one-third of newly diagnosed prostate cancer (PCa) cases at stage T3a or higher and is associated with increased rates of positive surgical margins and early biochemical recurrence following radical prostatectomy (RP). This study presents the development of AutoRadAI, an end-to-end, user-friendly artificial intelligence (AI) pipeline designed for the identification of ECE in PCa through the analysis of multiparametric MRI (mpMRI) fused with prostate histopathology. The dataset consists of 1001 patients, including 510 pathology-confirmed positive ECE cases and 491 negative ECE cases. AutoRadAI integrates comprehensive preprocessing followed by a sequence of two novel deep learning (DL) algorithms within a multi-convolutional neural network (multi-CNN) strategy. The pipeline exhibited strong performance during its evaluation. In the blind testing phase, AutoRadAI achieved an area under the curve (AUC) of 0.92 for assessing image quality and 0.88 for detecting the presence of ECE in individual patients. Additionally, AutoRadAI is implemented as a user-friendly web application, making it ideally suited for clinical applications. Its data-driven accuracy offers significant promise as a diagnostic and treatment planning tool. Detailed instructions and the full pipeline are available athttps://autoradai.anvil.appand on our GitHub page athttps://github.com/PKhosravi-CityTech/AutoRadAI.
Prevalence of Obesity According to Body Mass Index, Waist Circumference, and Waist-to-Height Ratio in Peru: A Systematic Review and Meta-Analysis
Authors: Vásquez-Romero Luisa Erika Milagros , Zuzunaga-Montoya Fiorella E. , Loayza-Castro Joan A. , Vigil-Ventura Enrique , Ramos Willy , Vera-Ponce Víctor Juan 
Published: May 2024

ABSTRACTIntroductionObesity is a global public health issue with significant health implications. However, studies on the prevalence of obesity in Peru have yielded varied results, highlighting the need for updated data to inform effective public health policies.ObjectiveThe primary objective of this study is to determine the prevalence of obesity in Peru using three anthropometric measures: body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR).MethodsBetween March and April 2024, a systematic review of published studies reporting the prevalence of obesity in Peru was conducted. The databases Scopus, Web of Science, Embase, PubMed, LILACS, and Scielo were Searched.ResultsOverall, the prevalence of obesity was 23.23%, 38.90%, and 81.53% according to BMI, WC, and WHtR, respectively. However, these figures show wide variability, ranging from 13.10% to 37.4% according to BMI and from 19.4% to 51.6% according to WC. The highest reported prevalence of obesity by WHtR was 85.4%. Nonetheless, only a fraction of these studies were published in the last five years, and few specifically focused on obesity as the primary objective.ConclusionsThe prevalence of obesity in Peru varies significantly depending on the anthropometric measure used. To improve the collection and frequency of data on obesity in Peru, it is recommended that cut-off points be standardized to be suitable for the country and that annual national surveys specifically designed for this purpose be implemented.
Epigenetic Biomarkers of Socioeconomic Status are Associated with Age-Related Chronic Diseases and Mortality in Older Adults
Authors: Schmitz Lauren L. , Opsasnick Lauren A. , Ratliff Scott M. , Faul Jessica D. , Zhao Wei , Hughes Timothy M. , Ding Jingzhong , Liu Yongmei , Smith Jennifer A. 
Published: May 2024

AbstractLater-life health is patterned by socioeconomic influences across the lifecourse. However, the pathways underlying the biological embedding of socioeconomic status (SES) and its consequences on downstream morbidity and mortality are not fully understood. Epigenetic markers like DNA methylation (DNAm) may be promising surrogates of underlying biological processes that can enhance our understanding of how SES shapes population health. Studies have shown that SES is associated with epigenetic aging measures, but few have examined relationships between early and later-life SES and DNAm sites across the epigenome. In this study, we trained and tested DNAm-based surrogates, or “biomarkers,” of childhood and adult SES in two large, multi-racial/ethnic samples of older adults—the Health and Retirement Study (HRS) (N=3,527) and the Multi-Ethnic Study of Atherosclerosis (MESA) (N=1,182). Both biomarkers were associated with downstream morbidity and mortality, and these associations persisted after controlling for measured SES, and in some cases, epigenetic aging clocks. Both childhood and adult SES biomarker CpG sites were enriched for genomic features that regulate gene expression (e.g., DNAse hypersensitivity sites and enhancers) and were implicated in prior epigenome-wide studies of inflammation, aging, and chronic disease. Distinct patterns also emerged between childhood CpGs and immune system dysregulation and adult CpGs and metabolic functioning, health behaviors, and cancer. Results suggest DNAm-based surrogate biomarkers of SES may be useful proxies for unmeasured social exposures that can augment our understanding of the biological mechanisms between social disadvantage and downstream health.Significance StatementInformation on DNA methylation (DNAm)—an epigenetic modification that plays a central role in regulating gene expression—is increasingly available in large epidemiological studies. Since DNAm is relatively stable but responsive to environmental influences, genome-wide signatures are promising surrogates or biomarkers of exposure that may both shed light on biological mechanisms between adverse environments and downstream health and/or act as proxies for unmeasured exposures. To better understand the biological embedding of social disadvantage, this study trained and tested DNAm-based surrogates of childhood and adult socioeconomic status (SES) in two US-based cohorts of older adults. Findings reveal distinct DNAm signatures of SES that connect social adversity across the lifecourse with dysregulated immune system responses, inflammatory pathways, poorer metabolic functioning, chronic diseases, and cancer.
An International Longitudinal Natural History Study of Danon Disease Patients: Unique Cardiac Trajectories Identified Based on Sex and Heart Failure Outcomes
Authors: Hong Kimberly N. , Eshraghian Emily , Khedro Tarek , Argirò Alessia , Attias Jennifer , Storm Garrett , Tsotras Melina , Bloks Tanner , Jackson Isaiah , Ahmad Elijah , Graw Sharon , Mestroni Luisa , Bui Quan M. , Schwartz Jonathan , Turner Stuart , Adler Eric D. , Taylor Matthew 
Published: May 2024

ABSTRACTIntroductionDanon disease (DD) is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 gene. Though the severe morbidity of disease in males is well established, longitudinal studies describing the trajectory of cardiovascular disease in both sexes have not been performed. Herein we performed an analysis using the International Danon Disease Registry, a retrospective dataset that includes longitudinal data from a cohort of males and females with DD.MethodsData were from the International Danon Disease Registry and includes patients from 2005 to 2022. Records were obtained from the first episode of care to the date of enrollment and included demographics, clinical characteristics, echocardiographic and laboratory values, and outcomes. The primary outcome in this study was a heart failure (HF) composite defined as either transplant (TXP), left ventricular assist device (LVAD) or death.ResultsThe analysis included 116 DD patients: female (n=64, 55%) and male (n=52, 45%). Median age of diagnosis for the entire cohort was 15.2 years (10.0-25.2 years), and 21.9 years (15.0-34.9 years) and 12.4 years (7.1-15.6 years) for females and males respectively. The incidence of HF outcome was higher in males compared to females (p<0.001). Regarding trends in echocardiographic parameters over time, LVEF decreased and LVEDD increased regardless of sex and HF outcome, however, rate of change was increased in patients who experienced a HF outcome in both sexes. Increasing LV mass occurs in males but not females. Consistent with this, LV wall hypertrophy continues in males who have not yet experienced a HF outcome and stabilizes prior to HF outcome, while females have progressive LV thinning regardless of HF outcome. Analyses stratified by age of HF outcome in females found two distinct groups of females, one who experienced HF outcome prior to 26 years of age and another after.ConclusionsIn this largest longitudinal natural history study of DD to date, we confirmed that males present on average a decade earlier and demonstrate more progressive cardiac hypertrophy and heart failure than females. Of note, there may be a subset of females who are phenotypically similar to males with profound LV hypertrophy that appears to stabilize or regress prior to HF outcome. Correlations between structural changes including LV hypertrophy, dilation and dysfunction and disease progression may allow for risk stratification of Danon patients and refinement of treatment algorithms while also informing therapeutic trial design.