bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT
Authors: Bernabéu-Herrero Maria E. , Patel Dilipkumar , Bielowka Adrianna , Zhu JiaYi , Jain Kinshuk , Mackay Ian S. , Chaves Guerrero Patricia , Emanuelli Giulia , Jovine Luca , Noseda Michela , Marciniak Stefan J. , Aldred Micheala A. , Shovlin Claire L. 
Published: March 2024

Abstract
For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P &lt; .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of near-invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with &gt;11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.
IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation
Authors: Hong Lih En , Wechalekar Mihir D. , Kutyna Monika , Small Annabelle , Lim Kelly , Thompson-Peach Chloe , Li Joule J. , Chhetri Rakchha , Scott Hamish S. , Brown Anna , Hahn Christopher N. , Yeung David T. , Sajid Salvia , Robinson Nirmal , Thomas Ranjeny , Branford Susan , D’Andrea Richard J. , Samaraweera Saumya E. , Patnaik Mrinal , Proudman Susanna , Thomas Daniel , Kok Chung Hoow , Shah Mithun V. , Hiwase Devendra K. 
Published: March 2024

Abstract
High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.
Architecture and sedimentary evolution of the Ladinian Kobilji curek basin (External Dinarides, central Slovenia)
Authors: Rožič Boštjan , Kocjančič Anja , Gale Luka , Zupančič Nina , Popit Tomislav , Vodnik Primož , Kolar-Jurkovšek Tea , Brajkovič Rok , Žvab Rožič Petra 
Published: March 2024

AbstractThe study area is located in cental Slovenia, and geologically located at the junction between the Alps and the Dinarides. The Middle Triassic of this region is characterised by intense rifting manifested by differential subsidence and volcanism. This led to a major paleogeographic reorganisation of the region, where three paleogeographic domains formed in the Upper Triassic: The Julian Carbonate Platform in the north, the intermediate Slovenian Basin, both parts of the Southern Alps, and the Dinaric (Adriatic, Friuli) Carbonate Platform in the south, which today is a part of the External Dinarides that host the area of investigation. Prior to the installation of the Dinaric Carbonate Platfrom, i.e. in the Ladinian, the entire area of the preset-day External Dinarides broke up into numerous tectonic blocks that were exposed to either erosion or continental, shallow-marine, and deep-marine sedimentation. In this study, we analyse at small scale a complex transitional area between a local carbonate platform and the Kobilji curek basin (depositional area dominated by deeper marine sediments), located in the Rute Plateau in central Slovenia south of Ljubljana. During enhanced subsidence, the basin was filled with volcanic material (tuffs and volcanogenic clays and subordinate extrusive material), while the adjacent platform aggraded. The slope was positioned above active paleofaults. During relative sea level lowstand, the platform prograded across the basin. The study area is divided into four major tectonic paleoblocks. The NW paleoblock experienced the most enhanced subsidence, and the platform prograded twice in this area and was submerged again by the rejuvenated subsidence and/or sea-level rise. The second and third paleoblocks subsided only during discrete major subsidence events, and the carbonates of the platform and slope were soon reinstated therein. In the fourth paleoblock to the east the platform persisted during the Ladinian. In the Carnian, the entire study area became emerged, and continental clastics were deposited. These were then replaced by a uniform shallow marine/intertidal Hauptdolomit (Dolomia Principale) formation at the onset of the Norian. This study provides the first detailed reconstruction of the sedimentary evolution of small-scale Ladinian basin and platforms system in the northern External Dinarides.
Huntingtin HTT1a is generated in a CAG repeat-length-dependent manner in human tissues
Authors: Hoschek Franziska , Natan Julia , Wagner Maximilian , Sathasivam Kirupa , Abdelmoez Alshaimaa , von Einem Björn , Bates Gillian P. , Landwehrmeyer G. Bernhard , Neueder Andreas 
Published: March 2024

Abstract
Background
The disease-causing mutation in Huntington disease (HD) is a CAG trinucleotide expansion in the huntingtin (HTT) gene. The mutated CAG tract results in the production of a small RNA, HTT1a, coding for only exon 1 of HTT. HTT1a is generated by a block in the splicing reaction of HTT exon 1 to exon 2 followed by cleavage in intron 1 and polyadenylation. Translation of HTT1a leads to the expression of the highly toxic HTT exon 1 protein fragment. We have previously shown that the levels of HTT1a expression in mouse models of HD is dependent on the CAG repeat length. However, these data are lacking for human tissues.

Methods
To answer this question, we developed highly sensitive digital PCR assays to determine HTT1a levels in human samples. These assays allow the absolute quantification of transcript numbers and thus also facilitate the comparison of HTT1a levels between tissues, cell types and across different studies. Furthermore, we measured CAG repeat sizes for every sample used in the study. Finally, we analysed our data with ANOVA and linear modelling to determine the correlation of HTT1a expression levels with CAG repeat sizes.

Results
In summary, we show that HTT1a is indeed expressed in a CAG repeat-length-dependent manner in human post mortem brain tissues as well as in several peripheral cell types. In particular, PBMCs show a statistically significant positive correlation of HTT1a expression with CAG repeat length, and elevated HTT1a expression levels even in the adult-onset CAG repeat range.

Conclusions
Our results show that HTT1a expression occurs throughout a wide range of tissues and likely with all CAG lengths. Our data from peripheral sample sources demonstrate that HTT1a is indeed generated throughout the body in a CAG repeat-length-dependent manner. Therefore, the levels of HTT1a might be a sensitive marker of disease state and/or progression and should be monitored over time, especially in clinical trials targeting HTT expression.
Differential association between physical activity behaviours and dynapenia by comorbid diseases in community-dwelling Korean older adults
Authors: Park Jae Hyeon , Nam Hyung Seok , Park Mina , Kim Yeo Hyung 
Published: March 2024

Abstract
Background
Physical activity (PA) behaviours and comorbid diseases are associated with muscle strength. However, the association between dynapenia and detailed PA behaviours, including participation in aerobic and resistance exercises and sedentary behaviour (SB), in relation to comorbid diseases has not yet been investigated. Using nationwide data, this study aimed to evaluate the independent association of dynapenia with detailed PA behaviour (participation in aerobic and resistance exercises and SB), and assess the differential associations of detailed PA behaviour with dynapenia according to comorbid diseases with prevalent sarcopenia.

Methods
A total of 7,558 community-dwelling older adults aged ≥ 65 years who were included in the Korea National Health and Nutrition Examination Survey from 2014 to 2019 were included in the present study. Cross-sectional associations between PA behaviours (participation in aerobic exercise, participation in resistance exercise, and SB) and dynapenia were analysed using complex-sample multivariable-adjusted logistic regression models according to the type of comorbid disease (cardiovascular disease [CVD], diabetes mellitus [DM], and chronic lung disease [CLD]).

Results
Sufficient aerobic exercise, sufficient resistance exercise, and low sedentary time of < 420 min/day showed independent negative associations with dynapenia (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.60–0.83; OR, 0.54; 95% CI, 0.42–0.69; and OR, 0.84; 95% CI, 0.72–0.97, respectively). Among the participants with CVD or CLD, the associations of sufficient resistance exercise (OR, 0.46; 95% CI, 0.26–0.82 and OR, 0.51; 95% CI, 0.35–0.75 for CVD and CLD, respectively) and low sedentary time (OR, 0.66; 95% CI, 0.45–0.98 and OR, 0.71; 95% CI, 0.55–0.93 for CVD and CLD, respectively) with dynapenia were significant, whereas the association of sufficient aerobic exercise with dynapenia was insignificant. Meanwhile, in participants with DM, sufficient aerobic exercise (OR, 0.70; 95% CI, 0.52–0.94) and sufficient resistance exercise (OR, 0.45; 95% CI, 0.29–0.70) were independently associated with dynapenia, whereas no association between SB and dynapenia was found.

Conclusion
We observed an independent inverse association between PA behaviours and dynapenia. Disease-specific associations between each PA behaviour (sufficient aerobic exercise, sufficient resistance exercise, and low sedentary time) and dynapenia differed in the older adults. Therefore, these differences should be acknowledged during interventions for this population.
Bayesian inference for identifying tumour-specific cancer dependencies through integration of ex-vivo drug response assays and drug-protein profiling
Authors: Xing Hanwen , Yau Christopher 
Published: March 2024

AbstractThe identification of tumor-specific molecular dependencies is essential for the development of effective cancer therapies. Genetic and chemical perturbations are powerful tools for discovering these dependencies. Even though chemical perturbations can be applied to primary cancer samples at large scale, the interpretation of experiment outcomes is often complicated by the fact that one chemical compound can affect multiple proteins. To overcome this challenge, Batzilla et al. (PLoS Comput Biol 18(8): e1010438, 2022) proposed DepInfeR, a regularized multi-response regression model designed to identify and estimate specific molecular dependencies of individual cancers from their ex-vivo drug sensitivity profiles. Inspired by their work, we propose a Bayesian extension to DepInfeR. Our proposed approach offers several advantages over DepInfeR, including e.g. the ability to handle missing values in both protein-drug affinity and drug sensitivity profiles without the need for data pre-processing steps such as imputation. Moreover, our approach uses Gaussian Processes to capture more complex molecular dependency structures, and provides probabilistic statements about whether a protein in the protein-drug affinity profiles is informative to the drug sensitivity profiles. Simulation studies demonstrate that our proposed approach achieves better prediction accuracy, and is able to discover unreported dependency structures.
scFSNN: a feature selection method based on neural network for single-cell RNA-seq data
Authors: Peng Minjiao , Lin Baoqin , Zhang Jun , Zhou Yan , Lin Bingqing 
Published: March 2024

AbstractWhile single-cell RNA sequencing (scRNA-seq) allows researchers to analyze gene expression in individual cells, its unique characteristics like over-dispersion, zero-inflation, high gene-gene correlation, and large data volume with many features pose challenges for most existing feature selection methods. In this paper, we present a feature selection method based on neural network (scFSNN) to solve classification problem for the scRNA-seq data. scFSNN is an embedded method that can automatically select features (genes) during model training, control the false discovery rate of selected features and adaptively determine the number of features to be eliminated. Extensive simulation and real data studies demonstrate its excellent feature selection ability and predictive performance.
Genome-wide analysis of acid tolerance genes of Enterococcus faecalis with RNA-seq and Tn-seq
Authors: Chen Zhanyi , Niu Chenguang , Wei Lifan , Huang Zhengwei , Ran Shujun 
Published: March 2024

AbstractEnterococcus faecalis, a formidable nosocomial and community-acquired opportunistic pathogen, can persist a wide range of extreme environments, including low pH and nutrient deficiency. Clarifying the survival mechanism of E. faecalis in low-pH conditions is the key to combating the infectious diseases caused by E. faecalis. In this study, we combined transcriptome profiling (RNA-seq) and transposon insertion sequencing (TIS) to comprehensively understand the genes that confer these features on E. faecalis. The metadata showed that genes whose products are involved in cation transportation and amino acid biosynthesis were predominantly differentially expressed under acid conditions. The products of genes such as opp1C and copY reduced the hydrion concentration in the cell, whereas those of gldA2, gnd2, ubiD, and ubiD2 mainly participated in amino metabolism, increasing matters to neutralize excess acid. These, together with the folE and hexB genes, which are involved in mismatch repair, form a network of E. faecalis genes necessary for its survival under acid conditions.
Childbirth experiences of women with a history of physical, sexual, and child abuse: a cross-sectional study of 2,575 Russian women
Authors: Suarez Anna , Yakupova Vera 
Published: March 2024

Abstract
Background
A substantial number of women who subsequently become pregnant and give birth have a history of physical, sexual, and/or child abuse. This study investigated the associations of these types of traumas and their cumulative effect with childbirth experiences, namely, mode of birth, maternal and child complications during pregnancy/childbirth, preterm birth, medical procedures, and obstetric violence during labour.

Methods
A group of Russian women (n = 2,575) who gave birth within the previous 12 months, completed a web-based survey, where they provided demographic information, details about their childbirth experiences, and a history of trauma.

Results
Women with any type of past abuse were at higher risk for maternal complications during pregnancy/childbirth (exp(β) < 0.73, p < 0.010 for all). More specific to the type of trauma were associations of physical abuse with caesarean birth, child abuse with complications during pregnancy/childbirth for the baby, and physical and child abuse with obstetric violence (exp(β) < 0.54, p < 0.022 for all). There was a cumulative effect of trauma for all the outcomes except for medical procedures during childbirth and preterm birth.

Conclusion
This study provides insights into potential different individual effects of physical, sexual, and/or child abuse as well as their cumulative impact on the childbirth experiences. The robust findings about maternal complications during pregnancy/childbirth and obstetric violence highlight the importance of trauma-informed care, supportive policies, and interventions to create safe and empowering birthing environments that prioritise patient autonomy, dignity, and respectful communication.
Regulation of metastatic potential by drug repurposing and mitochondrial targeting in colorectal cancer cells
Authors: Mathur Shashank , Srivastava Pransu , Srivastava Anubhav , Rai Neeraj Kumar , Abbas Sabiya , kumar Ashok , Tiwari Meenakshi , Sharma Lokendra Kumar 
Published: March 2024

Abstract
Background
Increased mitochondrial activities contributing to cancer cell proliferation, invasion, and metastasis have been reported in different cancers; however, studies on the therapeutic targeting of mitochondria in regulating cell proliferation and invasiveness are limited. Because mitochondria are believed to have evolved through bacterial invasion in mammalian cells, antibiotics could provide an alternative approach to target mitochondria, especially in cancers with increased mitochondrial activities. In this study, we investigated the therapeutic potential of bacteriostatic antibiotics in regulating the growth potential of colorectal cancer (CRC) cells, which differ in their metastatic potential and mitochondrial functions.

Methods
A combination of viability, cell migration, and spheroid formation assays was used to measure the effect on metastatic potential. The effect on mitochondrial mechanisms was investigated by measuring mitochondrial DNA copy number by qPCR, biogenesis (by qPCR and immunoblotting), and functions by measuring reactive oxygen species, membrane potential, and ATP using standard methods. In addition, the effect on assembly and activities of respiratory chain (RC) complexes was determined using blue native gel electrophoresis and in-gel assays, respectively). Changes in metastatic and cell death signaling were measured by immunoblotting with specific marker proteins and compared between CRC cells.

Results
Both tigecycline and tetracycline effectively reduced the viability, migration, and spheroid-forming capacity of highly metastatic CRC cells. This increased sensitivity was attributed to reduced mtDNA content, mitochondrial biogenesis, ATP content, membrane potential, and increased oxidative stress. Specifically, complex I assembly and activity were significantly inhibited by these antibiotics in high-metastatic cells. Significant down-regulation in the expression of mitochondrial-mediated survival pathways, such as phospho-AKT, cMYC, phospho-SRC, and phospho-FAK, and upregulation in cell death (apoptosis and autophagy) were observed, which contributed to the enhanced sensitivity of highly metastatic CRC cells toward these antibiotics. In addition, the combined treatment of the CRC chemotherapeutic agent oxaliplatin with tigecycline/tetracycline at physiological concentrations effectively sensitized these cells at early time points.

Conclusion
Altogether, our study reports that bacterial antibiotics, such as tigecycline and tetracycline, target mitochondrial functions specifically mitochondrial complex I architecture and activity and would be useful in combination with cancer chemotherapeutics for high metastatic conditions.
PErspective and current status of Radiotherapy Service in IRan (PERSIR)-1 study: assessment of current external beam radiotherapy facilities, staff and techniques compared to the international guidelines
Authors: Saeedian Arefeh , Tabatabaei Fatemeh-sadat , Azimi Amirali , Babaei Mohammad , Lashkari Marzieh , Esmati Ebrahim , Abiar Zeinab , Moadabshoar Leila , Sandoughdaran Saleh , Kamrava Mitchell , Amini Arya , Ghalehtaki Reza 
Published: March 2024

Abstract
Background and purpose
Radiotherapy (RT) is an essential treatment modality against cancer and becoming even more in demand due to the anticipated increase in cancer incidence. Due to the rapid development of RT technologies amid financial challenges, we aimed to assess the available RT facilities and the issues with achieving health equity based on current equipment compared to the previous reports from Iran.

Materials and methods
A survey arranged by the Iran Cancer Institute's Radiation Oncology Research Center (RORC) was sent to all of the country's radiotherapy centers in 2022. Four components were retrieved: the reimbursement type, equipment, human resources, and patient load. To calculate the radiotherapy utilization rate (RUR), the Lancet Commission was used. The findings were compared with the previous national data.

Results
Seventy-six active radiotherapy centers with 123 Linear accelerators (LINACs) were identified. The centers have been directed in three ways. 10 (20 LINACs), 36 (50 LINACs), and 30 centers (53 LINACs) were charity-, private-, and public-based, respectively. Four provinces had no centers. There was no active intraoperative radiotherapy machine despite its availability in 4 centers. One orthovoltage X-ray machine was active and 14 brachytherapy devices were treating patients. There were 344, 252, and 419 active radiation oncologists, medical physicists, and radiation therapy technologists, respectively. The ratio of LINAC and radiation oncologists to one million populations was 1.68 and 4.10, respectively. Since 2017, 35±5 radiation oncology residents have been trained each year.

Conclusion
There has been a notable growth in RT facilities since the previous reports and Iran's situation is currently acceptable among LMICs. However, there is an urgent need to improve the distribution of the RT infrastructure and provide more facilities that can deliver advanced techniques.