bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiotherapy resistance driven by Asparagine endopeptidase through ATR pathway modulation in breast cancer
Authors: Morillo-Huesca Macarena , G. López-Cepero Ignacio , Conesa-Bakkali Ryan , Tomé Mercedes , Watts Colin , Huertas Pablo , Moreno-Bueno Gema , Durán Raúl V. , Martínez-Fábregas Jonathan 
Published: February 2025

Abstract

Background
Tumor resistance represents a major challenge in the current oncology landscape. Asparagine endopeptidase (AEP) overexpression correlates with worse prognosis and reduced overall survival in most human solid tumors. However, the underlying mechanisms of the connection between AEP and reduced overall survival in cancer patients remain unclear.

Methods
High-throughput proteomics, cellular and molecular biology approaches and clinical data from breast cancer (BC) patients were used to identify novel, biologically relevant AEP targets. Immunoblotting and qPCR analyses were used to quantify protein and mRNA levels. Flow cytometry, confocal microscopy, chemical inhibitors, siRNA- and shRNA-silencing and DNA repair assays were used as functional assays. In-silico analyses using the TCGA BC dataset and immunofluorescence assays in an independent cohort of invasive ductal (ID) BC patients were used to validate the clinical relevance of our findings.

Results
Here we showed a dual role for AEP in genomic stability and radiotherapy resistance in BC patients by suppressing ATR and PPP1R10 levels. Reduced ATR and PPP1R10 levels were found in BC patients expressing high AEP levels and correlated with worst prognosis. Mechanistically, AEP suppresses ATR levels, reducing DNA damage-induced cell death, and PPP1R10 levels, promoting Chek1/P53 cell cycle checkpoint activation, allowing BC cells to efficiently repair DNA. Functional studies revealed AEP-deficiency results in genomic instability, increased DNA damage signaling, reduced Chek1/P53 activation, impaired DNA repair and cell death, with phosphatase inhibitors restoring the DNA damage response in AEP-deficient BC cells. Furthermore, AEP inhibition sensitized BC cells to the chemotherapeutic reagents cisplatin and etoposide. Immunofluorescence assays in an independent cohort of IDBC patients showed increased AEP levels in ductal cells. These analyses showed that higher AEP levels in radioresistant IDBC patients resulted in ATR nuclear eviction, revealing AEPhigh/ATRlow protein levels as an efficient predictive biomarker for the stratification of radioresistant patients.

Conclusion
The newly identified AEP/ATR/PPP1R10 axis plays a dual role in genomic stability and radiotherapy resistance in BC. Our work provides new clues to the underlying mechanisms of tumor resistance and strong evidence validating the AEP/ATR axis as a novel predictive biomarker and therapeutic target for the stratification and treatment of radioresistant BC patients.
Probing locus coeruleus functional network in healthy aging and its association with Alzheimer’s disease biomarkers using pupillometry
Authors: Wu Junjie , Toporek Aaron , Lin Qixiang , Goldstein Felicia C. , Loring David W. , Kelberman Michael A. , Weinshenker David , Levey Allan I. , Lah James J. , Qiu Deqiang 
Published: February 2025

Abstract

Background
Alzheimer’s disease (AD) is the leading cause of dementia, and the early detection of the disease-associated changes allows early interventions. The locus coeruleus (LC) has been reported to be the first brain region to develop tau pathology in AD. However, the functional brain network of the LC in both healthy aging and AD pathology is largely unknown due to technical difficulties associated with the small size of the LC. In this study, we used the measurement of spontaneous pupil constriction/dilation as a surrogate for LC activity to study LC brain network changes during healthy aging.

Methods
Thirty-seven healthy younger and thirty-nine healthy older adults were included from the Emory Healthy Brain Study and underwent resting-state functional MRI while simultaneously tracking pupil diameter. The measurements of pupil diameter dynamics were used as reference signals in brain connectivity analysis. The connectivity of the identified networks was then compared between younger and older participants. Correlations of the identified regions with neuropsychological assessments and cerebrospinal fluid (CSF) biomarkers were also evaluated.

Results
A brain network of 20 clusters associated with pupil diameter dynamics was identified, including the LC as well as brain regions functionally connected to the LC. The pupil diameter network was found to positively correlate with the salience network and negatively correlate with the central executive network. Functional connectivity decreased within the pupil diameter network with healthy aging. The pupil diameter connectivity was associated with memory, executive, and visuospatial functioning. CSF total tau closely correlated with pupil diameter network.

Conclusions
Pupil diameter dynamics provide valuable insights into LC-related processes. While they are not solely influenced by LC activity, spontaneous pupil constrictor/dilatory activity shows promise as a non-invasive approach to probe the LC network and warrants further studies to evaluate its value as an early biomarker of AD.
Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice
Authors: Pantiru Andreea D. , Van de Sompele Stijn , Ligneul Clemence , Chatelain Camille , Barrea Christophe , Lerch Jason P. , Filippi Beatrice M. , Alkan Serpil , De Baere Elfride , Johnston Jamie , Clapcote Steven J. 
Published: February 2025

Abstract

Background
Intellectual developmental disorder with autism and dysmorphic facies (IDDADF) is a rare syndromic intellectual disability (ID) caused by homozygous disruption of PDZD8 (PDZ domain-containing protein 8), an integral endoplasmic reticulum (ER) protein. All four previously identified IDDADF cases exhibit autistic behavior, with autism spectrum disorder (ASD) diagnosed in three cases. To determine whether autistic behavior is a common outcome of PDZD8 disruption, we studied a third family with biallelic mutation of PDZD8 (family C) and further characterized PDZD8-deficient (Pdzd8

tm1b
) mice that exhibit stereotyped motor behavior relevant to ASD.

Methods
Homozygosity mapping, whole-exome sequencing, and cosegregation analysis were used to identify the PDZD8 variant responsible for IDDADF, including diagnoses of ASD, in consanguineous family C. To assess the in vivo effect of PDZD8 disruption on social responses and related phenotypes, behavioral, structural magnetic resonance imaging, and microscopy analyses were conducted on the Pdzd8

tm1b
mouse line. Metabolic activity was profiled using sealed metabolic cages.

Results
The discovery of a third family with IDDADF caused by biallelic disruption of PDZD8 permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism. In addition to impairments in social recognition and social odor discrimination, Pdzd8

tm1b
mice exhibit increases in locomotor activity (dark phase only) and metabolic rate (both lights-on and dark phases), and decreased plasma triglyceride in males. In the brain, Pdzd8

tm1b
mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis.

Limitations
The total number of known cases of PDZD8-related IDDADF remains low. Some mouse experiments in the study did not use balanced numbers of males and females. The assessment of ER stress and mitochondrial fusion markers did not extend beyond mRNA levels.

Conclusions
Our finding that the Pdzd8

tm1b
mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice. Other abnormalities exhibited by Pdzd8

tm1b
mice suggest that the range of comorbidities associated with PDZD8 deficiency may be wider than presently recognized.
Integrating multi-source data for life-cycle risk assessment of bridge networks: a system digital twin framework
Authors: Geng Ziheng , Zhang Chao , Jiang Yishuo , Pugliese Dora , Cheng Minghui 
Published: February 2025

Abstract
Bridges are critical infrastructure assets that face a variety of stressors throughout their service life, requiring a life-cycle approach to assess their risk profile. Recent advancements in sensing and monitoring technologies provide a powerful data foundation to improve the accuracy of life-cycle risk assessment (LCRA). However, existing works that incorporate data for probabilistic risk assessment typically focus on individual bridges and rely on single-source data, limiting their scope and applicability. To this end, a system digital twin (SDT) framework based on Bayesian network (BN) is proposed to integrate multi-source data for LCRA of bridge networks. Specifically, the SDT can capture correlations and interdependencies across various scales, including within individual components (e.g., multiple failure modes), between components within a system (e.g., bridges along a route), and across interconnected systems (e.g., bridge and hydraulic systems). It integrates data from various sources including bridge inspections, traffic monitoring facilities, and water watch stations. A coastal bridge network in Miami-Dade County, FL, is used as an illustrative example to demonstrate how the SDT integrates multi-source data for risk assessment. Additionally, several future scenarios are hypothesized to showcase the applicability and flexibility of the proposed framework in supporting risk management for infrastructure systems.
The Current State of Pediatric Cardiac Anesthesiology Staffing in the United States
Authors: Deutsch Nina , Grant Stephanie , Zabala Luis , Staffa Steven J. , Lau Jennifer , Andropoulos Dean , Geiduschek Jeremy , Kurth C. Dean , Nasr Viviane G. 
Published: February 2025

BACKGROUND:
The population of patients with congenital heart disease has grown, but the supply of pediatric cardiac anesthesiologists has not kept pace. The Pediatric Anesthesia Leadership Council (PALC) and the Congenital Cardiac Anesthesia Society (CCAS) formed a task force to evaluate the current state of the specialty of pediatric cardiac anesthesia, including staffing, work environment, education, compensation, and career development.

METHODS:
Five task force working groups developed survey questions that explored 5 different aspects of a pediatric cardiac anesthesiologist’s career. Surveys were completed by CCAS member faculty volunteers, division chiefs/directors of pediatric cardiac anesthesia programs, program directors of pediatric cardiac anesthesia fellowships, and fellowship graduates from the past 10 years.

RESULTS:
Survey completion rates were 77% (n = 86) for CCAS faculty, 52% (n = 58) for pediatric cardiac anesthesiology directors/division chiefs, 91% (n = 21) for pediatric cardiac anesthesiology fellowship directors, and 53% (n = 65) for 2013–2022 pediatric cardiac anesthesia fellowship graduates. Of CCAS faculty respondents, 31.4% (n = 27) are considering leaving pediatric cardiac anesthesia for a less stressful field. While most respondents reported being involved in academic activities, 34% (n = 29) do not receive nonclinical time. Only 35.3% (n = 30) of respondents receive formal mentorship and 44.7% (n = 38) of participants have been sponsored for leadership positions, research opportunities, or speaking engagements. The total number of anticipated hires in the next 5 years is 129; that number goes up to 194 in 10 years. The challenge in hiring was graded as 8/10 with 10 being the most challenging.

CONCLUSIONS:
This survey provides important data about the current state of pediatric cardiac anesthesiology and the need to address staffing and academic support. With nearly one-third of those practicing in the field considering leaving the pediatric cardiac subspecialty and with the decreasing number of fellows per year, there is a significant cause for concern for staffing, especially when the demand for practitioners in this field is increasing. In addition, even though the majority of faculty reported being involved in academic activities, many do not receive academic time for these activities and less than half receive formal mentorship or have been sponsored for leadership positions, publications, research opportunities, or speaking engagements. Further work to recruit, retain, and develop pediatric cardiac anesthesiologists is warranted.
First morphological and genetic report of the hard tick, Amblyomma tigrinum (Acari: Ixodidae) in the Andean cat, Leopardus jacobita
Authors: Beltrán-Saavedra L. Fabián , Arteaga-Voigt Daniela A. , Poquechoque-Buezo Georgia E. 
Published: February 2025

El gato andino (Leopardus jacobita Cornalia 1865) es una de las especies felinas más raras del mundo y de las más amenazadas de América, además de no conocerse la ixodofauna que parasita a estos pequeños felinos. Aquí se describen morfológica y genéticamente ejemplares de garrapatas duras en un gato andino. Se recolectaron 4 especímenes de garrapatas duras (2 hembras y 2 machos) de 1 gato andino de la localidad de Patacamaya en el departamento de La Paz, Bolivia. Los ejemplares fueron identificados por sus características morfológicas y genéticas. El ADN se extrajo utilizando 1 o 2 patas de las garrapatas con un daño mínimo a los ejemplares. Las características morfológicas y genéticas correspondieron a Amblyomma trigrinum, con un porcentaje de identidad del 99.43 %. Esta investigación constituye el primer reporte morfológico y genético de garrapatas duras en estado adulto de la especie A. tigrinum parasitando a un gato andino, ampliando la distribución de esta garrapata a la región biogeográfica boliviana de alta montaña y altiplano en el departamento de La Paz, y enfatiza la circulación de este parásito zoonótico en el país.
Prediction and validation of anoikis-related genes in neuropathic pain using machine learning
Authors: He Yufeng , Wei Ye , Wang Yongxin , Ling Chunyan , Qi Xiang , Geng Siyu , Meng Yingtong , Deng Hao , Zhang Qisong , Qin Xiaoling , Chen Guanghui 
Published: February 2025

Background
Neuropathic pain (NP) can be induced by a variety of clinical conditions, such as spinal cord injury, lumbar disc herniation (LDH), lumbar spinal stenosis, diabetes, herpes zoster, and spinal cord tumors, and inflammatory stimuli. The pathogenesis of NP is extremely complex. Specifically, in LDH, the herniated nucleus pulposus exerts mechanical pressure on nerve roots, triggering local inflammation and consequent NP. Anoikis, a special form of programmed cell death, is closely related to the progression of NP. In this study, we sought to clarify the molecular characteristics of anoikis-related genes in NP, providing novel insights for the diagnosis and treatment of NP.

Methods
We screened NP-related genes based on the GSE124272 dataset and obtained 439 anoikis-related genes from the GeneCards database. Through Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) machine learning algorithms, six key hub genes were identified: hepatocyte growth factor (HGF), matrix metalloproteinase 13 (MMP13), c-abl oncogene 1, non-receptor tyrosine kinase (ABL1), elastase neutrophil expressed (ELANE), fatty acid synthase (FASN), and long non-coding RNA (Linc00324). Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), alongside Gene Set Enrichment Analysis (GSEA) and immune infiltration analysis, were performed on these hub genes. Additionally, transcription factors and potential therapeutic drugs were predicted. We also used rats to construct an NP model and validated the analyzed hub genes using hematoxylin and eosin (H&E) staining, real-time polymerase chain reaction (PCR), and Western blotting assays.

Results
Our data indicated that anoikis-related genes have diagnostic value in NP patients, as confirmed by experimental results. Moreover, this study elucidated the role of these genes in immune infiltration during the pathogenesis of NP and identified potential therapeutic drugs targeting these key genes.

Conclusion
This study further explores the pathogenesis of NP and provides certain reference value for developing targeted therapeutic strategies, thereby improving NP management.
Predominance of extensively-drug resistant Acinetobacter baumannii carrying bla
OXA-23
in Jordanian patients admitted to the intensive care units
Authors: Ababneh Qutaiba , Aldaken Neda’a , Jaradat Ziad , Al-Rousan Ekhlas , Inaya Zeina , Alsaleh Dua’a , Alawneh Dua’a , Al Sbei Sara , Saadoun Ismail 
Published: February 2025

Background and Aim
The global emergence of Acinetobacter baumannii is of great concern, especially inside intensive care units (ICUs). This study investigated the prevalence, antibiotic resistance, biofilm formation and genetic relatedness of A. baumannii recovered from ICU patients in three major hospitals in Jordan.

Methods
The A. baumannii isolates included in this study were identified by the detection of the blaOXA-51 gene, and a multiplex PCR assay. Antibiotic susceptibility testing was performed using the disk diffusion and broth microdilution methods, and the ability of the isolates to form biofilms was tested using the 96-well plate assay. All isolates were tested for the presence of carbapenemases-encoding genes by PCR. Clonal relatedness was assessed by Rep-PCR and dendrogram analysis.

Results
Overall, 148 A. baumannii isolates were identified, with 96.7% of the isolates recognized as carbapenem resistant A. baumannii. Based on their resistance patterns, 90% of the isolates were extensively resistant (XDR). The highest prevalence of carbapenemases-encoding genes was for blaOXA-23-like (96.7%), followed by blaADC (93.9.2%), blaVIM (56.8%) and blaNDM-1 (7.4%). Almost 80% of the isolates were able to form biofilms, with 63.2% classified as strong biofilm former. Rep-PCR and clustering analysis revealed 26 different clusters and the circulation of hospital-specific clones.

Conclusions
Our study revealed an alarming high prevalence of XDR, blaOXA-23-carrying and strong biofilm-producing A. baumannii among ICU patients. These findings call for continuous epidemiological surveillance and implementation of prevention strategies to reduce infections and dissemination of such a problematic pathogen inside the ICUs.
Addressing information and credit barriers to making India open defecation free and improving child health: Evidence from a cluster randomized trial in rural India
Authors: Seth Payal , Pingali Prabhu 
Published: February 2025

Background
Open defecation (OD) remains a significant public health challenge in India, contributing to adverse child health outcomes. Eliminating OD and improving child health necessitates both universal access and adoption of toilets. Despite the success of removing credit constraints and enhancing access to subsidized toilets through national sanitation campaigns, the adoption of these toilets is still lagging in India. This is because households might also be lacking information about the benefits of using toilets (information constraint).

Methods
In this paper, we test for the joint efficacy of the removal of information and credit constraints versus solely addressing the credit constraint at eliminating OD, based on a cluster randomized control trial in rural India. We implemented two interventions: a universal community-led behavior change campaign along with subsidized construction of individual household toilets for every household that opted for subsidy (cluster A) and only subsidized construction of individual household toilet construction for every household that opted for the subsidy (cluster B). No behavior change was provided in cluster B. The control group did not receive any intervention.

Results
We find that the removal of information and credit constraints at a near-universal level in cluster A resulted in improved toilet access and adoption, eliminating OD at the community level, with a significant gain in child weight-for-age z-scores (WAZ scores). There was an increase in the percentage of households that owned individual household toilets from 2% to 98% and a decline in female respondents practicing OD from 98% to 4% in cluster A. In cluster B, ownership of individual household toilets improved by 78 percentage points (from 6% to 84%), but OD decreased by only 45 percentage points (from 95% to 50%) for the respondents. The control group saw no significant changes. For children under five, there was a statistically significant increase in WAZ scores by 0.68-0.69 standard deviations in cluster A, while cluster B showed insignificant changes when compared to the control group.

Conclusions
The study implies that supplementing universal financial support with community-level information intervention enhances sustainable adoption of improved sanitation facilities, aiding India’s progress towards an open defecation-free nation and improving child health outcomes.
Protocol for a theory-based, mixed methods evaluation of Cynnau|Ignite: an active learning programme to foster positive research culture through leadership development at Cardiff University
Authors: Hennah Charlotte , Rizwan Maleeha , Edwards Nicola , Beckett Hayley , Convery Michele , Dawson Heidi , Morris Jonathan , Rigby Mair , Vilares James , Wahl-Jorgensen Karin , Williams Rebecca , Gameiro Sofia 
Published: February 2025

A recent UKRI call for training programmes to improve research culture at Higher Education Institutions led Cardiff University to design Cynnau|Ignite. This active learning programme intends to foster positive research culture practices through empowering staff towards leadership on this agenda, and by embedding learners in environments where these practices are highly valued. Cynnau|Ignite will be implemented within Cardiff University as three tailored programmes, dependant on job roles: Teaching and Research (64 learners), Research-Only (32 learners), and Professional Services, Technicians and Specialists (32 learners). This protocol details a theory-based, mixed methods evaluation of Cynnau|Ignite’s effectiveness, acceptability, and feasibility as a tool to improve research culture practices and perceptions within Cardiff University. This knowledge will help inform future iterations of Cynnau|Ignite and similar initiatives, while advancing methods for the evaluation of positive research culture practices, and has potential to inform choices regarding funding and evaluation of research culture initiatives at other Higher Education Institutions. Here, we outline the Cynnau|Ignite Theory of Change used to inform our primary outcomes and describe our plan to evaluate the programme’s effectiveness by measuring learners’ self-reported positive research culture practices (intentions and behaviours) before and after taking part in Cynnau|Ignite, in comparison to a control group of staff who were not involved in the programme. Additionally, data monitoring, sessions observation, and semi-structured interviews will be conducted to establish programme acceptability and feasibility for stakeholders including learners, the delivery team, and university management. We hypothesise Cynnau|Ignite will be largely acceptable and effective in boosting learners’ positive research culture intentions compared to a control group, but believe behavioural implementation may be adversely affected by common barriers such as insufficient time and resources. Overall, we expect Cynnau|Ignite to improve short-term positive research culture practices and perceptions at Cardiff University, but its potential long-term impact is unclear.

Study registration
Number: ISRCTN15575518