bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning reveals diverging effects of altitude on aging
Authors: Teklu Amanuel Abraha , Heckenbach Indra , Petr Michael Angelo , Bakula Daniela , Keijzers Guido , Scheibye-Knudsen Morten 
Published: September 2024

SummaryAging is influenced by a complex interplay of multifarious factors, including an individual’s genetics, environment, and lifestyle. Notably, high altitude may impact aging and age-related diseases through exposures such as hypoxia and ultraviolet radiation. To investigate this, we mined summary exposure value as a measure of risk exposure levels, and disability-adjusted life years (DALYs) as a measure of disease burden from the Global Health Data Exchange (GHDx) for each subnational region of Ethiopia, a country with considerable differences in the living altitude. We conducted a cross-sectional clinical trial involving 227 highland and 202 lowland dwellers from the Tigray region in Northern Ethiopia to gain a general insight into the biological aging at high altitudes. Notably, we observed significantly lower risk exposure rates and a reduced disease burden in higher-altitude regions of Ethiopia. When assessing biological aging using facial photographs, we found a faster rate of aging with increasing elevation, likely due to greater UV exposure. Conversely, analysis of nuclear morphologies of peripheral blood mononuclear cells in blood smears (PBMCs) with five different senescence predictors revealed a significant decrease in DNA damage-induced senescence in both monocytes and lymphocytes with increasing elevation. Overall, our findings suggest that disease and DNA damage-induced senescence decreases with altitude in agreement with the idea that oxidative stress may drive aging.
Air cleaning reduces incident infections in day care - an interventional crossover study
Authors: Vartiainen Ville , Ehder-Gahm Inga , Hela Johanna , Luoto Anni , Juvela Jussi-Pekka , Nikuri Petra , Taipale Aimo , Lastovets Natalia , Saari Sampo , Kulmala Ilpo , Säämänen Arto , Sanmark Enni , Sormunen Piia 
Published: September 2024

AbstractBackgroundWhile possibility of airborne transmission in the spread of common respiratory infections, there is no consensus on the relative importance of airborne infection route in real-life. This study aimed to investigate the significance of the airborne transmissions and the effectiveness of air cleaning in reducing infections among children in daycare.MethodsA cross-over study was conducted in four daycare centers in Helsinki. All children attending the daycare were invited to participate (n = 262) and the sole inclusion criterion was that the children were expected to stay in the same day care center for the two-year duration of the study. 51 subjects were included in the final analysis. Clean air flow rate was increased by 2.1-2.9 times compared to baseline mechanical ventilation of the premises. The effect of intervention was assessed using negative binomial regression.ResultsThe intervention reduced incident infections from 0.95 to 0.78 infections per child per month among the children (primary outcome) in daycare. The reduction attributed to intervention in the statistical model was 18.0 % (95% CI 2.1-31.3 %, p = 0.028).ConclusionsWe observed a significant decrease in incident infections without implementing any other infection mitigation strategies but air cleaning. Our results challenge the current paradigm which emphasizes fomite and contact transmission and infection control measures that target these pathways. As ventilation and air cleaning can only affect particles able to float in the air stream, our results support the significance of airborne transmission among common respiratory pathogens as well as air cleaning as an infection control measure.
Gestational arsenite exposure alters maternal postpartum heart size and induces Ca2+handling dysregulation in cardiomyocytes
Authors: Taube Nicole , Steiner Morgan , Ebenebe-Kasonde Obialunanma V. , Kabir Raihan , Garbus-Grant Haley , Alam El Din Sarah-Marie , Illingworth Emily , Wang Nadan , Lin Brian L. , Kohr Mark J. 
Published: September 2024

ABSTRACTCardiovascular disease is the leading cause of mortality in the US. Studies suggest a role for environmental exposures in the etiology of cardiovascular disease, including exposure to arsenic through drinking water. Arsenic exposure during pregnancy has been shown to have effects on offspring, but few studies have examined impacts on maternal cardiovascular health. While our prior work documented the detrimental effect of arsenic on the maternal heart during pregnancy, our current study examines the effect of gestational arsenic exposure on the maternal heart postpartum. Timed-pregnant wild-type (C57BL/6J) mice were exposed to 0, 100 or 1000 µg/L sodium arsenite (NaAsO2) via drinking water from embryonic day 2.5 (E2.5) until parturition. Postpartum heart structure and function was assessed via transthoracic echocardiography and gravimetric measurement. Hypertrophic markers were probed via qRT-PCR and western blot. Isolated cardiomyocyte Ca2+-handling and contraction were also assessed, and expression of proteins associated with Ca2+handling and contraction. Interestingly, we found that exposure to either 100 or 1000 µg/L sodium arsenite increased postpartum heart size at P12 vs. non-exposed postpartum controls. At the cellular level, we found altered cardiomyocyte Ca2+-handling and contraction. We also found altered expression of key contractile proteins, including α-Actin and cardiac myosin binding protein C (cMyBP-c). Together, these findings suggest that gestational arsenic exposure impacts the postpartum maternal heart, possibly inducing long-term cardiovascular changes. Furthermore, these findings highlight the importance of reducing arsenic exposure during pregnancy, and the need for more research on the impact of arsenic and other environmental exposures on maternal heart health and adverse pregnancy events.New & NoteworthyGestational exposure to sodium arsenite at environmentally relevant doses (100 and 1000 µg/L) increases postpartum heart size, and induces dysregulated Ca2+homeostasis and impaired shortening in isolated cardiomyocytes. This is the first study to demonstrate that gestational arsenic exposure impacts postpartum heart structure and function beyond the exposure period.
Learning Impairments inFmr1-/-mice on an Audio-Visual Temporal Pattern Discrimination Task
Authors: Mol William , Post Sam , Lee Megan , Goel Anubhuti 
Published: September 2024

AbstractEstimating time and making predictions is integral to our experience of the world. Given the importance of timing to most behaviors, disruptions in temporal processing and timed performance are reported in a number of neuropsychiatric disorders such as Schizophrenia, Autism Spectrum Disorder (ASD), Fragile X Syndrome (FXS), and Attention-deficit Hyperactivity Disorder (ADHD). Symptoms that implicitly include disruption in timing are atypical turn-taking during social interactions, unusual verbal intonations, poor reading, speech and language skills, inattention, delays in learning, and difficulties making predictions. Currently, there are no viable treatments for these symptoms, the reason being the underlying neural dysfunction that contributes to timing deficits in neuropsychiatric disorders is unknown. To address this unknown, we have designed a novel Temporal Pattern Discrimination Task (TPSD) for awake-behaving mice. Stimuli consist of audiovisual stimuli that differ in duration. Compared to Wild-Type (WT) mice,Fmr1-/-mice, a well-established mouse model of FXS, showed significant impairment in learning the TPSD task, as evidenced by reduced discriminability indices and atypical licking patterns. Often sensory information is multimodal and indeed studies show that learning in humans and rodents improves with multimodal stimuli than with unimodal stimuli. To test how the multimodal nature of stimuli impacted performance ofFmr1-/-mice, following training on the audiovisual stimuli, we tested mice on audio-only or visual-only stimuli. While WT mice showed significant disruption in performance when tested on unimodal stimuli,Fmr1-/-mice displayed equivalent performance on visual-only stimuli when compared to the multimodal task. Our novel task captures timing difficulties and multisensory integration issues inFmr1-/-mice and provides an assay to examine the associated neural dysfunction.
Identifying an optimal anti-gravity assistance level for select functional shoulder movements: A simulation study
Authors: Asgari Morteza , Crouch Dustin L. 
Published: September 2024

AbstractThe level of assistance torque is one key design parameter for passive shoulder exoskeletons. High assistance levels may perturb arm movements, while low assistance may not provide functional benefits. This study aimed to use computational tools to identify an optimal anti-gravity assistance level for passive shoulder exoskeletons.We used the task space framework to perform biomechanical simulations of arm movements in OpenSim (Stanford, CA, USA). The simulated movements included shoulder elevation and lowering movements in frontal and scapular planes, as well as forward and lateral reaching movements. These movements were simulated across a range of assistance torque levels from 0% (no-assistance) to 100% of the maximum shoulder gravity torque, in increments of 10%. The optimal assistance level was identified based on analysis of hand kinematics, muscular response efficiency, and glenohumeral joint stability.As the assistance level increased from 10% to 40%, the variability of hand movements nearly doubled, and this trend continued for higher assistance levels. The total muscle effort rate was minimized at an assistance level ranging from 20% to 30%. While the stability of the glenohumeral joint was mostly maintained across assistance levels, it decreased slightly at higher assistance levels.The results of this study indicated that, for the simulated movements, an optimal assistance level lies within the range of 20-30% of the maximum gravity torque at the shoulder joint. Assistance levels above 40% could cause undesired effects such as greater variability of end-limb kinematics, reduced muscular efficiency, and compromised glenohumeral joint stability.
Replication of a GWAS signal nearHLA-DQA2with acute myeloid leukemia using a disease-only cohort and external population-based controls
Authors: Laflamme Rose , Lisi Véronique , Hébert Josée , Sauvageau Guy , Lemieux Sébastien , Lavallée Vincent-Philippe , Lettre Guillaume 
Published: September 2024

ABSTRACTAcute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Its risk factors include rare and highly penetrant somatic mutations. Genome-wide association studies (GWAS) have also identified four common inherited variants associated with AML risk, but these findings have not yet been confirmed in many independent datasets. Here, we performed a replication study with 567 AML cases from the Leucegene cohort and 1,865 controls from the population-based cohort CARTaGENE (CaG). Because genotypes were generated using different technologies in the two datasets (e.g. low- vs. high-coverage whole-genome sequencing), we applied stringent quality-control filters to minimize type I errors. We showed using data reduction methods (e.g. principal component analysis [PCA] and uniform manifold approximation and projection [UMAP]) that our approach successfully integrated the Leucegene and CaG genetic data. We replicated the association between cytogenetically normal (CN)-AML and rs3916765, a variant located nearHLA-DQA2(odds ratio [95% confidence interval] = 1.88 [1.21-2.93], P- value=0.005). The effect size of this association was stronger when we restricted the analyses to AML patients withNPM1mutations (odds ratios >2.35). We foundHLA- DOBto be the most significantly upregulated gene in Leucegene participants with the CN-AML protective A-allele at rs3916765. We further found that several HLA class II genes are also differentially expressed albeit at lower statistical significance. Our results confirm that a common genetic variant at the HLA locus associates with AML risk, providing new opportunities to improve disease prognosis and treatment.
Single-cell Transcriptome Profiling of Post-treatment and Treatment-naïve Colorectal Cancer: Insights into Putative Mechanisms of Chemoresistance
Authors: Puzanov Grigory A. , Astier Clémence , Yurchenko Andrey A. , Jules-Clement Gérôme , Andre Fabrice , Marabelle Aurélien , Hollebecque Antoine , Nikolaev Sergey I. 
Published: September 2024

AbstractDrug resistance remains a major clinical challenge in the treatment of colorectal cancer (CRC) with conventional chemotherapy. Analyzing changes within tumor cells and tumor microenvironment (TME) after treatment and in metastases is essential to understanding how resistance develops. In this study, we analyzed scRNA-seq data from 56 CRCs including treatment-naïve tumors and tumors treated with standard chemotherapy with the known response status (18 responders and 6 progressors). In our cohort, primary left-sided CRCs were associated with metastatic potential mesenchymal phenotype and with depleted B cells. In the post-treatment CRC, there was a high prevalence of dendritic cells (DC) in the TME in the response group. The DC-derived signature was associated with better survival in a large CRC cohort from the TCGA. In progressors there was an enrichment of pericyte-like fibroblasts, which appeared to be associated with poor survival in a CRC-TCGA cohort. Progressors also showed elevated fractions of exhausted CD8+ T memory cells suggesting a pro-inflammatory TME. In tumor cells of progressors group, we identified specific expression of chemo-protective markersMTRNR2L1andCDX1; and their co-expression with stemness-related immune-checkpointCD24. In summary, scRNA-seq provides a valuable information for the discovery of prognostic markers, and reveals distinct features potentially underlying response to chemotherapy or disease progression in CRC.
Regulation of tmTNF-α Processing by FRMD8 in Triple-Negative Breast Cancer Metastasis: Insights into Molecular Pathway Dynamics
Authors: Xu Jun , Yang Xiaoyu , Shu Peng , Wang Wei , Wu Haibo , Wang Zhe 
Published: September 2024

AbstractPurposeBreast cancer remains the leading cause of cancer-related mortality among women worldwide, with late-stage diagnoses prevalent in China resulting in significantly lower survival rates. This study focuses on identifying genes implicated in breast cancer metastasis, highlighting the role of Tumor Necrosis Factor-alpha (TNF-α) and its forms—transmembrane (tmTNF-α) and soluble (sTNF-α).Experimental DesignTNF-α is crucial for activating NF-κB pathways that regulate genes involved in cell adhesion, migration, and immune evasion, all essential for cancer metastasis. We conducted comprehensive analyses of FRMD8, a member of the FERM domain-containing proteins, as a significant regulator of tmTNF-α. Through integrative multi-omics and cellular functional studies, the relationship between FRMD8, iRhom2, and ADAM17 was assessed in the context of breast cancer metastasis.ResultsOur findings reveal that FRMD8 forms a complex with iRhom2 and ADAM17, enhancing the stability and sheddase activity of ADAM17, which is vital for the release of TNF-α. The absence of FRMD8 leads to decreased ADAM17 activity, increasing the availability of tmTNF-α and potentially promoting metastasis. This effect suggests that FRMD8 is a key modulator of TNF-α processing.ConclusionsThis study explores how FRMD8 influences TNF-α processing and the metastatic behavior of breast cancer, providing insights into molecular dynamics that could guide future therapeutic strategies to improve outcomes in breast cancer patients.
Effect of pre-germination temperature conditions on germination characteristics of temperate grassland species
Authors: Kiss Réka , Lukács Katalin , Tóth Ágnes , Tóth Benedek , Samraoui Kenz Raouf , Engel Rita , Deák Balázs , Valkó Orsolya 
Published: September 2024

AbstractGermination characteristics of target species used for grassland restoration are often unknown, despite such information would be essential for designing restoration interventions. Filling this knowledge gap and improving our understanding about germination responses of grassland species to varying cold and warm treatments could be especially important in the face of climate change. Here we studied the effect of three different durations of warm dry stratification and three different durations of cold wet stratification, and their combinations in a full factorial design (in total 15 different pre-germination treatments), on the germination capacity of 48 grassland species native to Central Europe. Stratification treatments modelled present and forecasted summer (1-3 months warm period) and winter (1-3 months cold period) temperature conditions, while the study of the combined effect of these treatments is especially important in spring-germinating species. As response variables, we calculated relative response indexes and germination uncertainties of each species separately and applied general linear models to study the effect of treatments on these variables. We found clear effect of warm- or cold stratification on relative response indexes only in four species: strong positive response to warm stratification was found inSilene conica, while strong positive response to cold stratification was found inAgrimonia eupatoria, Echium vulgare, andPlantago lanceolata. The responses to treatment combinations were contradictory or lacked clear trends in most of the species. Germination uncertainty in general was high for all species, supporting the fact that Central European grassland species often rely on bet hedging as risk spreading strategy, to avoid unfavourable conditions during seedling establishment.
An empirical model of aminoacylation kinetics forE. coliclass I and II aminoacyl tRNA synthetases
Authors: Dykeman Eric Charles 
Published: September 2024

AbstractEfficient functioning of the prokaryotic translational system depends on a steady supply of aminoacylated tRNAs to be delivered to translating ribosomes via ternary complex. As such, tRNA synthetases play a crucial role in maintaining efficient and accurate translation in the cell, as they are responsible for aminoacylating the correct amino acid to its corresponding tRNA. Moreover, the kinetic rate at which they perform this reaction will dictate the overall rate of supply of aminoacylated tRNAs to the ribosome and will have consequences for the average translational speed of ribosomes in the cell. In this work, I develop an empirical kinetic model for the 20 aminoacyl tRNA synthetase enzymes inE. colienabling the study of the effects of tRNA charging dynamics on translational efficiency. The model is parametrised based onin vitroexperimental measurements of substrateKmandkcatvalues for both pyrophosphate exchange and aminoacylation. The model also reproduces the burst kinetics observed in class I enzymes and the transfer rates measured in single turnover experiments. Stochastic simulation ofin vivotranslation shows the kinetic model is able to support the tRNA charging demand resulting from translation in exponentially growingE. colicells at a variety of different doubling times. This work provides a basis for the theoretical study of the amino acid starvation and the stringent response, as well as the complex behaviour of tRNA charging and translational dynamics in response to cellular stresses.Author summaryElucidating the complex interplay between tRNA charging by aminoacyl tRNA synthetases and the overall ribosomal demand for tRNAs will have important consequences for understanding the effects of amino acid starvation and the stringent response. Here I introduce an empirical kinetic model of the 20E. colitRNA synthetases and examine tRNA charging dynamics during exponential growth. The results show that the model is in good agreement with a variety of experimental observations, such as tRNA charging fractions, average translational speed of the ribosome, and measured total cellular tRNA abundances.
Intranasal therapies for neonatal hypoxic-ischemic encephalopathy: Systematic review, synthesis, and implications for global accessibility to care
Authors: Cavanagh Andrew S. , Kuter Nazli , Sollinger Benjamin I. , Aziz Khyzer , Turnbill Victoria , Martin Lee J. , Northington Frances J. 
Published: September 2024

AbstractNeonatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of neurodevelopmental morbidity in term infants worldwide. Incidence of HIE is highest in low and middle-income communities with minimal access to neonatal intensive care and an underdeveloped infrastructure for advanced neurologic interventions. Moreover, therapeutic hypothermia, standard of care for HIE in high resourced settings, is shown to be ineffective in low and middle-income communities. With their low cost, ease of administration, and capacity to potently target the central nervous system, intranasal therapies pose a unique opportunity to be a more globally accessible treatment for neonatal HIE. Intranasal experimental therapeutics have been studied in both rodent and piglet models, but no intranasal therapeutics for neonatal HIE have undergone human clinical trials. Additional research must be done to expand the array of treatments available for use as intranasal therapies for neonatal HIE thus improving the neurologic outcomes of infants worldwide.
CRISPR activation ofTfeb, a master regulator of autophagy and lysosomal biogenesis, in osteoblast lineage cells increases bone mass and strength
Authors: James Alicen , Hendrixson James , Kadhim Ilham , Marques-Carvalho Adriana , Laster Jacob , Crawford Julie , Thostenson Jeff , Sato Amy , Almeida Maria , Onal Melda 
Published: September 2024

ABSTRACTAutophagy is a recycling pathway in which damaged or dysfunctional proteins, protein aggregates, and organelles are delivered to lysosomes for degradation. Insufficiency of autophagy is thought to contribute to several age-related diseases including osteoporosis. Consistent with this, elimination of autophagy from the osteoblast lineage reduces bone formation and causes low bone mass. However, whether increasing autophagy would benefit bone health is unknown. Here, we increased expression of the endogenous Transcription Factor EB gene (Tfeb) in osteoblast lineage cells in vivo via CRISPR activation.Tfeboverexpression stimulated autophagy and lysosomal biogenesis in osteoblasts.Tfeboverexpressing male mice displayed a robust increase in femoral and vertebral cortical thickness at 4.5 months of age. Histomorphometric analysis revealed that the increase in femoral cortical thickness was due to increased bone formation at the periosteal surface.Tfeboverexpression also increased femoral trabecular bone volume. Consistent with these results, bone strength was increased inTfeboverexpressing mice. FemaleTfeboverexpressing mice also displayed a progressive increase in bone mass over time and at 12 months of age had high cortical thickness and trabecular bone volume. This increase in vertebral trabecular bone volume was due to elevated bone formation. Osteoblastic cultures showed thatTfeboverexpression increased proliferation and osteoblast formation. Overall, these results demonstrate that stimulation of autophagy in osteoblast lineage cells promotes bone formation and strength and may represent an effective approach to combat osteoporosis.