bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive Responses to PARP Inhibition Predict Response to Olaparib and Durvalumab: Multi-omic Analysis of Serial Biopsies in the AMTEC Trial
Authors: Mitri Zahi I. , Creason Allison L. , Stommel Jayne M. , Bottomly Daniel , Ozmen Tugba Y. , Rames Matthew J. , Ozmen Furkan , Jeong Boyoung , Lukashchuk Natalia , Ashton Jack , Lim Jeong Youn , Sivagnanam Shamilene , Betra Konjit , Lee Jinho , Labrie Marilyne ,   SMMART Clinical Trials Program, Coussens Lisa M. , Corless Christopher L. , McWeeney Shannon K. , Mills Gordon B. 
Published: August 2024

AbstractIn syngeneic murine breast cancer models, poly ADP-ribose polymerase inhibitor (PARPi) and anti-PD-L1 combinations induce deep, sustained responses independent ofBRCA1/2mutation status. We therefore investigated this combination in the AMTEC clinical trial, in which a one-month olaparib run-in was followed by combined olaparib and durvalumab in participants withBRCA1/2wild-type metastatic triple negative breast cancer. To characterize adaptive responses to olaparib monotherapy, paired biopsies taken before and during PARPi lead-in were deeply characterized by DNA, RNA, and protein multi-omic analyses, including spatially-resolved single cell proteomics for tumor and immune contexture. We identified multiple potential tumor-intrinsic and microenvironmental biomarkers from pre-treatment and on-olaparib biopsies that robustly predicted participant response to combined olaparib and durvalumab. Notably, the on-olaparib biopsy provided the greatest information content, suggesting that adaptation of malignant cells and the tumor ecosystem to PARPi can serve as a predictor of potential benefit from combined PARPi and anti-PD-L1 therapy.
Estimated morbimortality and costs attributable to child and adolescent obesity in Brazil from 2024 to 2060: a multistate life table study
Authors: Nilson Eduardo Augusto Fernandes , de Oliveira Ana Carolina Rocha , Gusmão Bruna , Barbosa Raphael Barreto da Conceição 
Published: August 2024

AbstractIntroductionChildhood obesity is a major global public health issue globally and in Brazil. The impacts of childhood obesity include higher risk of disease during childhood and of obesity and non-communicable diseases in adulthood and represent an important epidemiological and economic burden to countries.MethodsThis study is based on the multistate life table modeling of different scenarios of change3s in the child and adolescent obesity on the estimated costs attributable to obesity and the epidemiological burden of obesity-related diseases.ResultsAccording to this study, if the current trends in childhood and adolescent obesity in Brazil continue, the prevalence will significantly increase across different age subgroups and for both sexes by 2060 and obesity among adults will nearly double, resulting in R$3.84 billion costs attributable to childhood and adolescent obesity to the Brazilian Unified Health System during this period. Alternatively, if obesity prevalence among children and adolescents is reduced and remains constant these direct costs could be reduced by R$1.05 to R$1.27 billion by 2060 and up to 244,600 incident cases and 70,800 deaths from obesity-related diseases could be prevented.ConclusionThis study highlights that the costs of childhood obesity are not limited to the impacts on adult health and represent a relevant economic burden to the Brazilian National Health System and to families because of additional costs during childhood. Therefore, the prevention and control of childhood obesity is a public health priority that demands immediate and robust policies.
The NeuroBioBank Whole-Genome Catalog: Sequencing from human brain donors with central nervous system disorders
Authors: Hupalo Daniel , McCauley Jacob L. , Gomez Lissette , Griswold Anthony J. , Hoher Gabriela , Konidari Ioanna , Lorenzo Jose , Parker Griffin S. , Pascual Julianna , Sandford Amanda R. , Whitehead Patrice L. , Davis David A. , Garamszegi Susanna , Gultekin S. Humayun , Sun Xiaoyan , Vontell Regina T. , Chatigny Michael , Chernicky Darren , Constant Myrtha M. , Darling Isabelle G. , Ennulat David J. , Esposito John M. , Morris Kiely , Lawton Elisabeth S. , Morakabati Neda R. , Oduor Phyllis , Rodgers Allison P. , Sang Lorelle A. , Sullivan Kathleen M. , Tabit Catalina J. , Turpin Tori , Zeabi Aya , Zheng Tina , Berretta Sabina , Klengel Torsten , Oakley Derek H. , Ruzicka W. Brad , Blanchard Thomas , Ho Eric , Johnson Robert , LeFevre Alexandra , Bustamante Maxwell , Haroutunian Vahram , Katsel Pavel , Marino Christine , Panopoulos Stephen , Purohit Dushyant P. , Wysocki Michael , Glausier Jill R. , Lewis David .A. , Nagra Rashed M. , Alba Camille , Martin Julianna , Rice Elizabeth , Rosenberger John , Smith Grace , Sukumar Gauthaman , Tompkins Miranda , Wilkerson Matthew , Dalgard Clifton L. , Scott William K. 
Published: August 2024

ABSTRACTCentral nervous system diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors including genetic risk. Here we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered in 15 broad categories by ICD-10 coding. These donors were collected by six repositories comprising the NIH NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants detected by Whole-Genome Sequencing (WGS) were called genome-wide and annotated to describe their functional impact, resulting in 171,121,209 unique mutations and 1,078,774 non-silent mutations. This whole-genome resource has been made available in the NIMH Data Archive (nda.nih.gov) and accompanying deep demographic and phenotypic descriptions are available at the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate an application of this resource, we replicated the strong association observed in previous studies between pathogenic CAG repeat expansions in theHTTgene with the clinical diagnosis of Huntington’s disease.
Tentative analysis of biomarkers associated with filariasis in moungo division, littoral, cameroon
Authors: Hzounda Fokou Jean Baptiste , Teudem Biyong Syntiche , Kouemo Francine , Akumwah Fru Awah , Reine Ambassa , Fannang Véronique Simone , Koube Juliette , Assob Jules Clement 
Published: August 2024

AbstractFilariasis is a significant cause of morbidity and a public health concern in most tropical countries. These diseases are usually contracted in childhood and most often diagnosed in adulthood. This study aimed to identify biochemical markers associated with filariasis and the endobacteria present in microfilariae.This was a cross-sectional analytical study within a hospital setting. Persons aged from six years and above were included in the study. They were then clustered into asymptomatic and symptomatic. Data was collected from February to June 2023. Blood, urine, and skin samples were collected and analysed by microscopy to identify microfilariae. The plasmatic and urinary markers were evaluated by spectrophotometry and protein fraction was monitored by electrophoresis. The data was analysed using SPSS 25 with the significant threshold set at 0.005.A total of 55 persons were included in the study, representing 74,32% of the total population questioned. The sex ratio (F/M) was 2.66. The infection rate was 18.2%Onchocerca volvulus, 54.54%Mansonella perstans, 22.72%Loa loaand 4.54%Wuchereria bancrofti. Protein levels were 35% higher in the asymptomatic with no parasite, 80% in the asymptomatic with detected parasite and 91.67% in the symptomatic. The decrease in albumin fraction and increase in gamma fractions seem to be correlated with the presence of parasites in the blood.These results suggest that protidemia and serum protein are significant indicators in the diagnosis of filariasis.
Application of chaos and systems theories to explore health workforce re-organisation following district splitting in Uganda
Authors: Mutebi Aloysius , Mukuru Moses , Kiwanuka Suzanne , Makumbi Fredrick , Rutebemberwa Elizeus 
Published: August 2024

AbstractBackgroundDistrict splitting (DS) began in 1962 and intensified in 1997 during implementation of decentralization. This legislative process focuses on geographical demarcation. The health system, organized along local government structures, was re-organized as a result of DS. However, this study explored how the health workforce, as a component of the local government health system, re-organized following district splitting.MethodsConducted between June and December 2018, the qualitative study involved 22 key informant interviews in eight districts, representing four broader regions (North, Western, Eastern and Central) of Uganda. Participants included district political leaders, local government staff, district service commission members, district health team officials, and district senior management. Data was collected using an interview guide and four themes were identified for deductive thematic analysis.ResultsFindings reveal that district splitting led to an involuntary division of the health system between old and new districts, triggering multidirectional reorganization of the health workforce. Health workers were systematically allocated to districts based on the geographical location of their health facilities during the splitting process. Subsequently, inter-district migration occurred through health workforce secondment or appointment, while intra-health system migration involved vertical movement of health workers within districts during recruitment. This reorganization resulted in workforce shortages in health facilities vacated by migrating health workers.ConclusionsThe study concludes that district splitting caused unintended consequences as a result of chaotic occurrences that led to reorganization of the health workforce in both new and old districts, and caused gaps in service delivery capabilities. Adopting a systems and chaos perspective, the study emphasizes the importance of considering frontline service delivery systems as subsystems of the overall district system when evaluating the impact of district splitting. Such an approach provides a comprehensive framework for understanding the disruptive effects of district splitting on health system organization and service delivery.
Quantitative Multi-pathway Assessment of Exposure to Fecal Contamination for Infants in Rural Ethiopia
Authors: Wang Yuke , Yang Yang , Slanzi Crystal M. , Li Xiaolong , Ojeda Amanda , Paro Fevi , Deblais Löıc , Yakubu Habib , Hassen Bahar Mummed , Game Halengo , Roba Kedir Teji , Schieber Elizabeth , Ibrahim Abdulmuen Mohammed , Wolyie Jeylan , Hassen Jemal Yusuf , Rajashekara Gireesh , McKune Sarah L. , Havelaar Arie H. , Moe Christine L. , Liang Song 
Published: August 2024

AbstractIn low- and middle-income countries (LMICs), enteric infections pose a significant threat to children’s health. However, understanding the specifics of when, where, and how young children in LMICs are exposed to enteric pathogens and the roles of animal reservoirs, environmental media, and human hosts play during exposure remains limited. This study systematically evaluates infants’ exposure toE. colithrough various pathways in the rural Haramaya woreda of Ethiopia. Between June 2021 and June 2022, we conducted over 1300 hours of structured behavioral observations on 79 infants when aged 4–8 months (Timepoint 1) and 11–15 months (Timepoint 2). Enumerators recorded the infant’s behavior related to exposure, including when and where it occurred, using the Countee © application. Concurrently, we collected 1338 environmental samples from key contact interfaces between infants, other people, and the environment to test forE. coli. We used a competing hazard model for duration-based behaviors, an inhomogeneous Poisson point process model for frequency-based behaviors, and a left-censored lognormal distribution model forE. colicontamination levels. The behavioral and environmental information was then integrated into an agent-based exposure model framework to quantify the exposure toE. colithrough different pathways.The infant behavior, which altered the relative importance of different exposure pathways, changed as children grew older. Notably, we observed increased rates of touching behavior (e.g., touching fomites) and soil-pica, increased consumption of solid food, and more time spent on the bare ground at Timepoint 2. The major sources of exposure toE. coliwere food and breastfeeding at Timepoint 1 and food and soil at Timepoint 2. This study provides insights for interventions to minimize infants’ risk of exposure to fecal contamination and subsequent risk of enteric infections, including improved food handling practices, enhanced personal hygiene for breastfeeding caregivers, and education on the risk of soil-pica.
Can Place-Based Modifications Make a Difference to Local Health Inequalities in Urban Essex: An Evaluation Protocol
Authors: Cusimano K. , Freeman P. , Pettican A. , Brinkley A. J. 
Published: August 2024

AbstractStemming from a complex picture of compositional, contextual and wider determinants, health inequalities are presented at the level in which people reside (i.e., their place). Examples of this exist within Essex, England, where despite seeming affluence, pockets of high multiple deprivation exist. Programmes delivered across the system representing each place may provide a solution to these complex challenges. For this reason, Epping Forest District Council commissioned the evaluation of a programme representing two place-based projects within their district (i.e., Limes Farm and Oakwood Hill). This paper provides the evaluation protocol for this programme. Broadly, the evaluation seeks to investigate the design, implementation, mechanisms and effectiveness of both projects. Our evaluation is underpinned by the Medical Research Council (MRC) guidelines for the design, evaluation and implementation for complex interventions, and takes inspiration from a realist approach. We aim to understandwhereeach project works,whodoes the projects work for,whatimpact do the projects have, andhowandwhydoes the projects work. This will be achieved through a mixed-methods approach which utilises a cohort study, ripple-effects mapping, focus groups, and secondary data analysis. Quantitative data will be analysed using descriptive, general linear and multi- level models, while qualitative data will be understood using visualisation (ripple-effects maps) and reflexive thematic analysis. Data will be triangulated to create programme theory configurations, which explain the outcomes which stemming from the programme, and how these are shaped by mechanisms within a given context. We anticipate our novel and robust approach to contribute to policy surrounding the adoption and implementation of place-based approaches.
A bifunctional antibody conjugate marks the location of DNA binding proteins on deproteinized DNA fibers
Authors: Pokharel Durga , Shaik Althaf , Gali Himabindu , Ling Chen , Bellani Marina A. , Seidman Michael M 
Published: August 2024

ABSTRACTImmunofluorescent foci of DNA Damage Response (DDR) proteins serve as surrogates for DNA damage and are frequently interpreted as denoting specific lesions. For example, Double Strand Breaks (DSBs) are potent inducers of the DDR, whose best-known factor is the phosphorylated histone variant H2AX (γ-H2AX). The association with DSBs is so well established that the reverse interpretation that γ-H2AX invariably implies DSBs is routine. However, this conclusion is inferential and has been challenged. The resolution of this question has been hampered by the lack of methods for distinguishing the location of DDR proteins relative to DSBs caused by sequence indifferent agents. Here, we describe an approach for marking the location of DDR factors in relation to DSBs on DNA fibers. We synthesized a two-arm “Y” conjugate containing biotin and trimethylpsoralen (TMP) coupled to a secondary antibody. After exposure to a DNA breaker, permeabilized mammalian cells were incubated with a primary antibody against the DDR factor followed by binding of the secondary antibody in the conjugate to the primary antibody. Exposure to longwave UV light covalently linked the psoralen to the DNA. DNA fibers were spread, and the immunofluorescence of the biotin tag denoted the location of the target protein.Abstract FigureGraphical abstract
Metabolic engineering of stomatal precursor cells enhances photosynthetic water-use efficiency and vegetative growth under water-deficit conditions inArabidopsis thaliana
Authors: Bouvier Jacques W. , Kelly Steven 
Published: August 2024

AbstractStomata are epidermal pores that control the exchange of gaseous CO2and H2O between plants and their environment. Modulating stomatal density can alter this exchange, and thus presents a target for engineering improved crop productivity and climate resilience. Here, we show that stomatal density inArabidopsis thalianacan be decreased by the expression of a water-forming NAD(P)H oxidase targeted to stomatal precursor cells. We demonstrate that this reduction in stomatal density occurs irrespective of whether the expressed enzyme is targeted to the cytosol, chloroplast stroma, or chloroplast intermembrane space of these cells. We reveal that this decrease in stomatal density occurs in the absence of any measurable impact on stomatal dynamics, or the efficiency or thermal sensitivity of photosynthesis. Consequently, overexpression plants exhibit a higher intrinsic water use efficiency due to an increase in CO2fixed per unit water transpired. Finally, we demonstrate that this enhanced water-use efficiency translates to an improvement in vegetative growth and biomass accumulation under water-deficit conditions. Together, these results thus provide a novel approach for enhancing plant productivity through metabolic engineering of stomatal density.
Exploiting XAI maps to improve MS lesion segmentation and detection in MRI
Authors: Spagnolo Federico , Molchanova Nataliia , Ocampo Pineda Mario , Melie-Garcia Lester , Bach Cuadra Meritxell , Granziera Cristina , Andrearczyk Vincent , Depeursinge Adrien 
Published: August 2024

AbstractTo date, several methods have been developed to explain deep learning algorithms for classification tasks. Recently, an adaptation of two of such methods has been proposed to generate instance-level explainable maps in a semantic segmentation scenario, such as multiple sclerosis (MS) lesion segmentation. In the mentioned work, a 3D U-Net was trained and tested for MS lesion segmentation, yielding an F1 score of 0.7006, and a positive predictive value (PPV) of 0.6265. The distribution of values in explainable maps exposed some differences between maps of true and false positive (TP/FP) examples. Inspired by those results, we explore in this paper the use of characteristics of lesion-specific saliency maps to refine segmentation and detection scores. We generate around 21000 maps from as many TP/FP lesions in a batch of 72 patients (training set) and 4868 from the 37 patients in the test set. 93 radiomic features extracted from the first set of maps were used to train a logistic regression model and classify TP versus FP. On the test set, F1 score and PPV were improved by a large margin when compared to the initial model, reaching 0.7450 and 0.7817, with 95% confidence intervals of [0.7358, 0.7547] and [0.7679, 0.7962], respectively. These results suggest that saliency maps can be used to refine prediction scores, boosting a model’s performances.
Developmental control of E-cadherin junctions by mechanical contractility inDrosophilaembryos
Authors: Zhang Na , Liu Wangfang , Lu Huiying , Häring Matthias , Wolf Fred , Großhans Jörg , Lv Zhiyi , Kong Deqing 
Published: August 2024

ABSTRACTAdherens junctions are very plastic structures that change their composition and structure depending on the state of the epithelial tissue, involving mechanical stress and tissue dynamics. InDrosophilaembryos, adherens junctions mature only during gastrulation following their formation a few minutes before during cellularization. Although the developmental maturation is obvious during gastrulation, the factors and conditions controlling it have remained unclear. Here, we assay the levels, distribution pattern, and mobility of E-cadherin duringDrosophilagastrulation. Indicating a maturation, we find an increase in total levels at junctions and a drop in the mobile fraction of E-cadherin molecules. Both developmental changes depend on Myo-II contractility. Consistent with stereotypic Myo-II regulation, we find that interference with Rho signaling leads to corresponding changes in E-cadherin levels and mobility, at least in part. Besides Rho signaling, Src42A contributes to junction maturation, as tested by both loss-function and gain-of-function situations. Together, we demonstrate developmental maturation of adherens junctions and identify Rho signaling and Src42A as upstream regulatory pathways.
Sodalis praecaptivussubsp.spalangiaesubsp. nov., a nascent bacterial endosymbiont isolated from the parasitoid wasp,Spalangia cameroni
Authors: Teh Li Szhen , James Ian , Dolgova Anna , Chiel Elad , Dale Colin 
Published: August 2024

AbstractAn endosymbiotic bacterium of the genusSodalis,designated as strain HZT, was cultured from the parasitoid waspSpalangia cameroni, that develops on pupae of various host flies. The bacterium was detected inS. cameronithat developed on house flies,Musca domestica, in a poultry facility in Hazon, northern Israel. Following culture, this bacterium displayed no surface motility on LB agar, is rod-shaped and irregular in size, approximating 10-30 nm in diameter and 5-20 μm in length. Phylogenetic analyses revealed that strain HZTis closely related toSodalis praecaptivusstrain HST, a free-living species of the genusSodalisthat includes many insect endosymbionts. Although these bacteria maintain >98% sequence identity in shared genes, genomic characterization revealed that strain HZThas undergone substantial reductive evolution, such that it lacks many gene functions that are maintained inS. praecaptivusstrain HST. Based on the results of phylogenetic, genomic and chemotaxonomic analyses, we propose that this endosymbiont should be classified in a new subspecies asSodalis praecaptivussubsp. spalangiaesubsp. nov. The type strain for this new subspecies is HZT(=ATCC TSD-398T=NCIMB 15482T). The subspeciesSodalis praecaptivussubsp.praecaptivusstrain HSTis created automatically with the type strain ATCC BAA-2554T(=DSMZ 27494T).