bluuebunny/crossref_metadata_2025_split huggingface dataset:
mTOR signaling regulates aberrant epithelial cell proliferative and migratory behaviors characteristic of airway mucous metaplasia in asthma
Authors: Kudrna Katrina , Staab Elizabeth B. , Eilers Evan , Thomes Paul , Maurya Shailendra , Brody Steven L. , Wyatt Todd A. , Bailey Kristina L. , Dickinson John D. 
Published: February 2024

AbstractIn asthma, the airway epithelium is hyperplastic, hypertrophied, and lined with numerous large MUC5AC-containing goblet cells (GC). Furthermore, the normal epithelial architecture is disorganized with numerous, what we here describe as, ectopic goblet cells (eGC) deep within the thickened epithelial layer disconnected from the lumenal surface. mTOR is a highly conserved pathway that regulates cell size and proliferation. We hypothesized that the balance between mTOR and autophagy signaling regulates key features of the asthma epithelial layer. Airway histological sections from subjects with asthma had increased frequency of eGC and increased levels of mTOR phosphorylation target-Ribosomal S6. Using human airway epithelial cells (hAECs) with IL-13 stimulation and timed withdrawal to stimulate resolution, we found that multiple key downstream phosphorylation targets downstream from the mTOR complex were increased during early IL-13-mediated mucous metaplasia, and then significantly declined during resolution. The IL-13-mediated changes in mTOR signaling were paralleled by morphologic changes with airway epithelial hypertrophy, hyperplasia, and frequency of eGC. We then examined the relationship between mTOR and autophagy using mice deficient in autophagy protein Atg16L1. Despite having increased cytoplasmic mucins, mouse AECs from Atg16L1 deficient mice had no significant difference in mTOR downstream signaling. mTOR inhibition with rapamycin led to a loss of IL-13-mediated epithelial hypertrophy, hyperplasia, ectopic GC distribution, and reduction in cytoplasmic MUC5AC levels. mTOR inhibition was also associated with a reduction in aberrant IL-13-mediated hAEC proliferation and migration. Our findings demonstrate that mTOR signaling is associated with mucous metaplasia and is crucial to the disorganized airway epithelial structure and function characteristic of muco-obstructive airway diseases such as asthma.Graphical Abstract Key ConceptsThe airway epithelium in asthma is disorganized and characterized by cellular proliferation, aberrant migration, and goblet cell mucous metaplasia.mTOR signaling is a dynamic process during IL-13-mediated mucous metaplasia, increasing with IL-13 stimulation and declining during resolution.mTOR signaling is strongly increased in the asthmatic airway epithelium.mTOR signaling is associated with the development of key features of the metaplastic airway epithelium including cell proliferation and ectopic distribution of goblet cells and aberrant cellular migration.Inhibition of mTOR leads to decreased epithelial hypertrophy, reduced ectopic goblet cells, and cellular migration.
Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer
Authors: Lakatos Eszter , Gunasri Vinaya , Zapata Luis , Househam Jacob , Heide Timon , Trahearn Nicholas , Swinyard Ottilie , Cisneros Luis , Lynn Claire , Mossner Maximilian , Kimberley Chris , Spiteri Inmaculada , Cresswell George D. , Llibre-Palomar Gerard , Mitchison Miriam , Maley Carlo C. , Jansen Marnix , Rodriguez-Justo Manuel , Bridgewater John , Baker Ann-Marie , Sottoriva Andrea , Graham Trevor A. 
Published: February 2024

ABSTRACTImmune system control is a major hurdle that cancer evolution must circumvent. The relative timing and evolutionary dynamics of subclones that have escaped immune control remain incompletely characterized, and how immune-mediated selection shapes the epigenome has received little attention. Here, we infer the genome- and epigenome-driven evolutionary dynamics of tumour-immune coevolution within primary colorectal cancers (CRCs). We utilise our existing CRC multi-region multi-omic dataset that we supplement with high-resolution spatially-resolved neoantigen sequencing data and highly multiplexed imaging of the tumour microenvironment (TME). Analysis of somatic chromatin accessibility alterations (SCAAs) reveals frequent somatic loss of accessibility at antigen presenting genes, and that SCAAs contribute to silencing of neoantigens. We observe that strong immune escape and exclusion occur at the outset of CRC formation, and that within tumours, including at the microscopic level of individual tumour glands, additional immune escape alterations have negligible consequences for the immunophenotype of cancer cells. Further minor immuno-editing occurs during local invasion and is associated with TME reorganisation, but that evolutionary bottleneck is relatively weak. Collectively, we show that immune evasion in CRC follows a “Big Bang” evolutionary pattern, whereby genetic, epigenetic and TME-driven immune evasion acquired by the time of transformation defines subsequent cancer-immune evolution.
Bisphenol A induces sex-dependent alterations in the dynamics of neuroendocrine seasonal adaptation in Djungarian hamsters
Authors: Moralia Marie-Azélie , Bothorel Béatrice , Andry Virginie , Simonneaux Valérie 
Published: February 2024

AbstractIn nature, species synchronize reproduction and energy metabolism with seasons to optimize survival and growth. While the effects of endocrine-disrupting chemicals (EDCs) exposure on conventional laboratory rodents are increasingly studied, their impacts on mammalian seasonal adaptation remain unexplored. This study investigates the effect of oral exposure to bisphenol A (BPA) on physiological and neuroendocrine seasonal adaptation in Djungarian hamsters. Adult female and male hamsters were orally exposed to BPA (5, 50, or 500 µg/kg/d) or vehicle during a 10-week transition from a long (LP) to short (SP) photoperiod (winter transition) or vice versa (summer transition). Changes in body weight, food intake, and pelage color were monitored weekly and, at the end of the exposure, gene expression of hypothalamic markers of photoperiodic, reproductive and metabolic integration, reproductive organ activity, and glycemia were assessed. Our results revealed sex-specific effects of BPA on acquiring SP and LP phenotypes. During LP to SP transition, females exposed to 500 µg/kg/d BPA exhibited delayed body weight loss and reduced feed efficiency associated with a lower expression ofsomatostatinin the arcuate nucleus (ARC), while males exposed to 5 µg/kg/d BPA showed an accelerated acquisition of SP-induced metabolic parameters. During SP to LP transition, females exposed to 5 µg/kg/d BPA displayed a faster LP adaptation in reproductive and metabolic parameters, along with quicker ARC kisspeptin downregulation and delayed ARCPomcupregulation, while males exposed to BPA exhibited decreased expression of central photoperiodic integrators without changes in the physiological LP acquisition. This pioneering study investigating EDC impacts on mammalian seasonal physiology shows that BPA alters the dynamic of metabolic adaptation to both SP and LP transitions with marked sex dimorphism, causing temporal discordance in seasonal adaptation between males and females. These findings emphasize the importance of investigating EDCs’ impact on non-conventional animal models, providing insights into wildlife physiology.HighlightsDjungarian hamster’s seasonal adaptation is disrupted by BPA oral exposureBPA delays in females and accelerates in males the metabolic adaptation to short daysBPA accelerates in females, not in males, metabolic/reproductive adaptation to long daysBPA affects the photoperiodic expression of central reproductive and metabolic genesGraphical abstract
Characterization of Reconstructed Human Epidermis in a Chemically-defined, Animal Origin-free Cell Culture System
Authors: Bajsert Julia , De Glas Valerie , Faway Emilie , de Rouvroit Catherine Lambert , Perez-Aso Miguel , Cook Paul W. , Poumay Yves 
Published: February 2024

ABSTRACTThe Reconstructed Human Epidermis (RHE) model derived from epidermal keratinocytes offers an ethical and scientifically valid alternative to animal experimentation, particularly in cutaneous toxicology and dermatological research, where elimination of animal cruelty is of paramount importance. Moreover, safer cell- and tissue-based cutaneous therapies are also possible, where the removal of animal-originated products from the RHE culture media lessens the risk of adverse clinical events. Thus, we compared chemically-define animal origin-free (cdAOF) supplements and the historically utilized supplement (HKGS), which contains growth factors and bovine pituitary extract. Herein we present the first extended characterization of RHE using cdAOF culture systems with newborn, adult, and immortalized N/TERT keratinocytes. Culture of RHE in the cdAOF media produced histological features that were nearly identical to that produced using HKGS, with the exception that the basal keratinocytes were less cylindrical, and with some immunolocalization of involucrin in the basal layer. Additionally, increased mRNA expression of several inflammatory-proliferative markers was observed in the cdAOF RHEs as well. Importantly, in RHEs cultured in cdAOF media, expression and immunolocalization of other expected markers of keratinization, as well as monitoring of barrier function revealed results equal or close to those observed in RHE cultured in HKGS.
Unique growth and morphology properties of Clade 5Clostridioides difficilestrains revealed by single-cell time-lapse microscopy
Authors: Ribis John W. , Nieto César , DiBenedetto Nicholas V. , Mehra Anchal , Dong Qiwen , Nagawa Irene , Meouche Imane El , Aldridge Bree B. , Dunlop Mary J. , Tamayo Rita , Singh Abhyudai , Shen Aimee 
Published: February 2024

AbstractClostridioides difficileis a major One Health threat as a gastrointestinal pathogen of both humans and agricultural animals. TheC. difficilespecies consists of five main clades, with Clade 5 currently undergoing speciation from Clades 1-4. Notably, Clade 5 strains are highly prevalent in agricultural animals and can cause zoonotic infections, suggesting that Clade 5 strains have evolved phenotypes that distinguish them from Clade 1-4 strains. Here, we compare the growth properties of Clade 5 strains to Clade 1, 2, and 4 strains using anaerobic time-lapse microscopy coupled with automated image analysis. These analyses reveal that Clade 5 strains grow faster than Clade 1, 2, and 4 strains and are more likely to form long chains of cells. Comparative genomic analyses revealed that the orientation of the invertiblecmrswitch sequence likely drives the cell chaining phenotype of Clade 5 strains during growth in rich media. Interestingly, during murine infection, Clade 5 strains with a high frequency of thecmrswitch in the ON orientation shifted to a largelycmrOFF state, suggesting that thecmrOFF state may be positively selected during infection. Taken together, our data suggest that Clade 5 strains have distinct growth properties that allow them to inhabit diverse ecological niches.ImportanceThe Clade 5 strains of theClostridioides difficilespecies are so phylogenetically divergent that they almost meet the threshold of being a distinct species. Although these strains are ubiquitously isolated from agricultural and environmental settings and an important source of zoonotic and community-acquired infections, it is unclear whether they have distinct phenotypic properties that allow them to efficiently colonize diverse hosts or persist in the environment. By combining a novel anaerobic time-lapse microscopy method with automated image analysis, we discovered that Clade 5 strains grow faster than strains from otherC. difficileclades and that they frequently form long chains. These chaining properties appear to be driven by the environmentally responsive expression of a non-canonical signal transduction system, which we also found is likely selected against during growth in mice. Collectively, our analyses reveal that Clade 5 strains have distinct growth properties that may promote their persistence in the environment.
Differential associations between SARS-CoV-2 infection, perceived burden of the pandemic and mental health in the German population-based cohort for digital health research
Authors: Steinmann Lavinia A. , Claaß Luise V. , Rau Moritz , Massag Janka , Diexer Sophie , Klee Bianca , Gottschick Cornelia , Binder Mascha , Sedding Daniel , Frese Thomas , Girndt Matthias , Hoell Jessica , Moor Irene , Rosendahl Jonas , Gekle Michael , Mikolajczyk Rafael , Opel Nils 
Published: February 2024

ABSTRACTIntroductionUnderstanding the potential adverse effects of the Covid-19-pandemic remains a challenge for public mental health. In this regard, the differentiation between potential consequences of actual infection with SARS-CoV-2 and the subjective burden of the pandemic due to measures and restrictions to daily life remains elusive.MethodsHere we investigated the differential association between infection with SARS-Cov-2 and subjective burden of the pandemic in a study cohort of 7601 participants from the German population-based cohort for digital health research (DigiHero), who were recruited between March 4thand April 25th2022. Data was collected using the online survey tool LimeSurvey® between March and October 2022 in consecutive surveys, which included questionnaires on infection status and symptoms following COVID-19 as well as retrospective assessment of the subjective burden of the pandemic.ResultsWe observed an association of a past SARS-CoV-2 infection on deteriorated mental health related symptoms, whereas no association or interaction with burden of the pandemic occurred. The association was driven by participants with persistent symptoms 12 weeks after acute infection. On a symptom specific level, neuropsychiatric symptoms such as exhaustion and fatigue, concentration deficits as well as problems with memory function were the primary drivers of the association.ConclusionOur findings underscore the impact of SARS-CoV-2 infections on mental health in patients suffering from ongoing symptoms 12 weeks after infection. As the association between SARS-CoV-2 infection and mental health appeared more pronounced in populations with higher vulnerability for mental disorders, increased attention should be dedicated towards these subgroups regarding the prevention of infection.
Changes in diet quality across life transitions from adolescence to early adulthood: a latent growth analysis
Authors: Tao Yinhua , Wall Melanie , Larson Nicole , Neumark-Sztainer Dianne , Winpenny Eleanor M 
Published: February 2024

AbstractBackgroundAdolescence to early adulthood is a period of multiple education-, employment- and family-related life transitions. Changing resources and food environments within the context of these transitions could contribute to significant changes in diet, which persist into later adulthood. This study investigated diet quality trajectories from age 15 to 31 years and changes in diet quality associated with life transitions, by sex.MethodsData from the Project EAT (Eating and Activity in Teens and Young Adults) study were used to examine diet quality among a longitudinal cohort (n=2,524) across four waves (mean ages of 15, 19, 25 and 31 years). Diet quality was evaluated using the DASH (Dietary Approaches to Stop Hypertension) index. Life transitions were assessed by changes in life circumstances between pairs of waves, including leaving the parental home, leaving full-time education, beginning full-time employment, cohabitating with a partner, and becoming a parent. Average within-person changes in DASH scores were analysed by sex-specific latent growth models, incorporating underlying growth trajectories, five life transitions and baseline socio-demographic characteristics.ResultsBoth sexes followed a quadratic trajectory of DASH scores, showing decreases in diet quality from waves 1 to 2 followed by increases until wave 4. Compared to females, males had worse diet quality at wave 1, and this sex difference widened at wave 4. Leaving the parental home between waves 1 and 2 was associated with transient decreases in diet quality at wave 2 only for males. For females, cohabitating with a partner and becoming a parent between waves 3 and 4 were respectively related to decreases and increases in diet quality at wave 4. Leaving full-time education and starting full-time employment respectively had long-term negative and positive associations with diet quality for both sexes.ConclusionsDiet quality remained suboptimal throughout adolescence but to some extent improved across early adulthood. A sex-sensitive approach in public health policy is welcome for addressing sex differences in diet quality and dietary changes associated with family-related life transitions. Targeted dietary interventions are beneficial for young people who leave their parental home early or who do not enter into a structured school or workplace environment.
Feasibility and acceptability of collecting dried blood spots (DBS) from children after vaccination during Supplementary Immunization Activities to estimate measles and rubella seroprevalence
Authors: Carcelen Andrea C. , Prosperi Christine , Hamahuwa Mutinta , Kapungu Kelvin , Chongwe Gershom , Mwansa Francis D. , Ndubani Phillimon , Simulundu Edgar , Bwalya Innocent C. , Matakala Kalumbu H. , Musukwa Gloria , Mutale Irene , Betha Evans , Chaavwa Nchimunya , Kampamba Lombe , Matoba Japhet , Munachoonga Passwell , Mufwambi Webster , Situtu Ken , Thuma Philip E. , Sakala Constance , Kayeye Princess , Truelove Shaun A. , Winter Amy K. , Ferrari Matthew J , Moss William J. , Mutembo Simon 
Published: February 2024

AbstractNested serosurveys within routine service delivery platforms such as planned supplemental immunization activities (SIAs) provide an opportunity to collect information that can be used to answer valuable questions on the effectiveness and efficiency of the delivery model to inform future activities. However, integrating research data collection in SIAs is rarely done due to concerns it will negatively impact the program.We conducted a serosurvey nested within the November 2020 measles-rubella SIA integrated with the Child Health Week activities in Zambia to evaluate this approach. In-depth interviews with the study teams and vaccination campaign staff at the vaccination sites were conducted. Recorded interviews were transcribed, transcripts were coded and then grouped into themes based on a process evaluation framework. A multi-methods analytical approach was used to assess the feasibility and acceptability of collecting dried blood spots from children during the SIA. This included a quantitative assessment of participant enrollment.The serosurvey successfully enrolled 90% of children from Child Health Week due to close coordination and teamwork between the vaccination teams and serosurvey team, in addition to substantial social mobilization efforts. Continually adjusting the sampling interval that was used to select eligible children allowed us to enroll throughout the SIA and capture a representative sample of children in attendance although it was challenging for the staff involved.As vaccination programs aim to tailor their approaches to reach the hardest-to-reach children, embedding research questions in SIAs will allow evaluation of the successes and challenges and compare alternative approaches. Lessons learned from this experience collecting data during an SIA can be applicable to future research activities embedded in SIAs or other delivery platforms.
Gene Discovery and Biological Insights into Anxiety Disorders from a Multi-Ancestry Genome-wide Association Study of >1.2 Million Participants
Authors: Friligkou Eleni , Løkhammer Solveig , Cabrera-Mendoza Brenda , Shen Jie , He Jun , Deiana Giovanni , Zanoaga Mihaela Diana , Asgel Zeynep , Pilcher Abigail , Di Lascio Luciana , Makharashvili Ana , Koller Dora , Tylee Daniel S. , Pathak Gita A. , Polimanti Renato 
Published: February 2024

ABSTRACTWe leveraged information from more than 1.2 million participants to investigate the genetics of anxiety disorders across five continental ancestral groups. Ancestry-specific and cross-ancestry genome-wide association studies identified 51 anxiety-associated loci, 39 of which are novel. Additionally, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, Admixed-American, and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, the cerebral cortex, the cerebellum, the metencephalon, the entorhinal cortex, and the brain stem. Transcriptome- and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. We also observed global and local genetic correlations with depression, schizophrenia, and bipolar disorder and putative causal relationships with several physical health conditions. Overall, this study expands the knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information.
Inhibition of epithelial Na+transport: novel mechanism ofUreaplasma-driven lung disease
Authors: Glaser Kirsten , Rieger Carl-Bernd , Paluszkiewicz Elisabeth , Thome Ulrich H. , Laube Mandy 
Published: February 2024

AbstractBackgroundRespiratory tract colonisation withUreaplasmaspecies has been associated with the development of acute and long-term pulmonary morbidity in preterm infants. Apart from inflammation, the underlying mechanisms ofUreaplasma-driven lung disease are mainly unknown. The present investigation is the first to examine the influence of acuteUreaplasmainfection on critical mechanisms of alveolar fluid clearance in the immature lung.MethodsPrimary rat fetal distal lung epithelial (FDLE) cells were incubated with viableUreaplasmain the absence or presence of the urease inhibitor flurofamide. Na+transport and activity of the epithelial Na+channel (ENaC) and the Na,K-ATPase were determined in Ussing chambers. Barrier integrity, metabolic activity, gene expression, and kinase signalling were also assessed.ResultsWe found a 30-90% decrease of epithelial Na+transport upon 24 hours ofUreaplasmainfection resulting from significant inhibition of ENaC and Na,K-ATPase activities. Notably,Ureaplasmainduced phosphorylation of Erk1/2 – a well-known inhibitor of ENaC activity. Moreover,Ureaplasma-driven NH3production - and not the accompanying pH shift - inhibited the epithelial Na+transport. Co-incubation with flurofamide entirely restored Na+transport inUreaplasma-infected FDLE cells.ConclusionOur data demonstrate thatUreaplasmainfection significantly impairs epithelial Na+transport and subsequent fluid clearance in fetal alveolar cells – most likely by Erk1/2 phosphorylation. We identified NH3as the mediating virulence factor and were able to restore Na+transport by inhibiting theUreaplasma-specific urease. This is the first study to show a functional impairment of pulmonary epithelial cells uponUreaplasmainfection, revealing a potential mechanism ofUreaplasma-driven preterm lung disease.Take HomeWe reportUreaplasma-induced inhibition of epithelial Na+transport as a potential mechanism ofUreaplasma-driven preterm lung disease. NH3is identified as a virulence factor offering a potential therapeutic role for urease inhibitors in colonised infants.