bluuebunny/crossref_metadata_2025_split huggingface dataset:
Photosymbiont density is correlated with constitutive and induced immunity in the facultatively symbiotic coral,Astrangia poculata
Authors: Changsut Isabella V. , Borbee Erin M. , Womack Haley R. , Shickle Alicia , Sharp Koty H. , Fuess Lauren E. 
Published: March 2024

ABSTRACTScleractinian corals, essential ecosystem engineers that form the base of coral reef ecosystems, have faced unprecedented mortality in recent decades due climate-change related stressors, including disease outbreaks. Despite this emergent threat to corals, many questions still remain regarding mechanisms underlying observed variation in disease susceptibility. Emergent data suggests at least some degree of variation in disease response may be linked to variability in the relationship between host corals and their algal photosymbionts (Family Symbiodineaceae). Still, the nuances of connections between symbiosis and immunity in cnidarians, including scleractinian corals, remain poorly understood. Here we leveraged an emergent model species, the facultatively symbiotic, temperate, scleractinian coralAstrangia poculata, to investigate associations between symbiont density and both constitutive and induced immunity. We used a combination of controlled immune challenges with heat-inactivated pathogens and transcriptomic analyses. Our results demonstrate thatA. poculatamounts a robust initial response to pathogenic stimuli that is highly similar to responses documented in tropical corals. Furthermore, we document positive associations between symbiont density and both constitutive and induced immune responses, in agreement with recent preliminary studies inA. poculata. A suite of immune genes, including those coding for antioxidant peroxidoxin biosynthesis, are constitutively positively associated with symbiont density inA. poculata. Furthermore, variation in symbiont density is associated with distinct patterns of immune response; low symbiont density corals induce preventative immune mechanisms whereas high symbiont density corals mobilize energetic resources to fuel humoral immune responses. In summary, our study reveals the need for more nuanced study of symbiosis-immune interplay across diverse scleractinian corals, preferably including quantitative energy budget analysis for full disentanglement of these complex associations and their effects on pathogen susceptibility.
Metastable condensates suppress conversion to amyloid fibrils
Authors: Das Tapojyoti , Zaidi Fatima , Farag Mina , Ruff Kiersten M. , Messing James , Taylor J. Paul , Pappu Rohit V. , Mittag Tanja 
Published: March 2024

AbstractStress granules form via co-condensation of RNA binding proteins with prion-like low complexity domains (PLCDs) and RNA molecules released by stress-induced polysomal runoff. Homotypic interactions among PLCDs can drive amyloid fibril formation and this is enhanced by ALS-associated mutations. We find that homotypic interactions that drive condensation versus fibril formation are separable for A1-LCD, the PLCD of hnRNPA1. These separable interactions lead to condensates that are metastable versus fibrils that are globally stable. Metastable condensates suppress fibril formation, and ALS-associated mutations enhance fibril formation by weakening condensate metastability. Mutations designed to enhance A1-LCD condensate metastability restore wild-type behaviors of stress granules in cells even when ALS-associated mutations are present. This suggests that fibril formation can be suppressed by enhancing condensate metastability through condensate-driving interactions.One-Sentence SummaryIn PLCDs, fibril formation driven by zipper motifs is suppressed by condensation-driving interactions mediated by stickers.
Imaging of cellular dynamicsin vitroandin situ: from a whole organism to sub-cellular imaging with self-driving, multi-scale microscopy
Authors: Daetwyler Stephan , Mazloom-Farsibaf Hanieh , Zhou Felix Y. , Segal Dagan , Sapoznik Etai , Westcott Jill M. , Brekken Rolf A. , Danuser Gaudenz , Fiolka Reto 
Published: March 2024

AbstractMany biological processes span multiple time and length scales, including developmental processes and cancer metastasis. While light-sheet fluorescence microscopy (LSFM) has become a fast and efficient method for imaging of organisms, cells and sub-cellular dynamics, simultaneous observations across these scales have remained challenging. Moreover, continuous high-resolution imaging inside living organisms has mostly been limited to few hours as regions of interest quickly move out of view due to sample movement and growth. Here, we present a self-driving, multi-resolution light-sheet microscope platform controlled by a custom Python-based software, to simultaneous observe and quantify sub-cellular dynamics and entire organismsin vitroandin vivoover hours of imaging. We apply the platform to the study of developmental processes, cancer invasion and metastasis, and we provide quantitative multi-scale analysis of immune-cancer cell interactions in zebrafish xenografts.
The aging-induced long non-coding RNAMIRIALcontrols endothelial cell and mitochondrial function
Authors: Kohnle Caroline , Koziarek Susanne , Warwick Timothy , Theodorou Kosta , Fischer Ariane , Juni Rio Putra , Muhly-Reinholz Marion , Busscher Denise , Lam Frederike , Vetter Felix , Wagner Julian U. G. , Sommer Janina , Gimbel Anna Theresa , Stanicek Laura , Günther Stefan , Wittig Ilka , Maegdefessel Lars , Leisegang Matthias S. , Brandes Ralf P. , Dimmeler Stefanie , Boon Reinier A. 
Published: March 2024

AbstractAimsVascular aging is characterized by the progressive deterioration of endothelial function. Long non-coding RNAs (lncRNAs) are critical regulators of gene expression and protein function. However, their involvement in aging-related dysregulation of endothelial cell function remains largely unknown. Here, we aim to characterize the aging-regulated lncRNAMIRIALin endothelial cells.Methods + ResultsWe identifiedMirialas an aging-induced lncRNA in RNA-sequencing data of mouse cardiac endothelial cells. In human umbilical vein endothelial cells (HUVECs), gapmer-mediated knockdown ofMIRIALled to decreases in proliferation, migration and basal angiogenic sprouting. Additionally,MIRIALknockdown led to increased mitochondrial mass, spare respiratory capacity, and vascular endothelial growth factor (VEGF)-stimulated sprouting. Mechanistically, we demonstrate thatMIRIALforms anRNA·DNA:DNA triple helix (triplex) with a regulatory region of the quiescence-promoting Forkhead Box O1 (FOXO1) gene, thus inducing its expression. The formation of this triplex involves anAluelement within theMIRIALtranscript, representing a previously undescribed mechanism of action for a lncRNA. Further, we generated a globalMirialknockout mouse line of. Angiogenic sprouting of aortic rings fromMirialknockout mice was reduced under basal conditions, but increased after VEGF administration, validating thein vitroangiogenic phenotype. Importantly, cardiac contractile function after acute myocardial infarction is severely reduced inMirialknockout mice, as compared to wild-type littermates.ConclusionsThe lncRNAMIRIALis an aging-induced regulator of endothelial quiescence and metabolism.Translational PerspectiveLncRNAs often exhibit cell-type or tissue-specific expression and regulation, rendering them potentially druggable targets requiring lower doses and having fewer side effects compared to protein targets. Our current research highlights, that loss ofMirialcorrelates with adverse outcomes post-acute myocardial infarction in a murine model. Dysregulation ofMIRIALin various human pathological conditions, such as ischemic heart disease, abdominal aortic aneurysm, cancer, and aging, indicates its potential as a diagnostic marker. Mechanistically,MIRIALregulates endothelial quiescence by modulatingFOXO1expression, suggesting it as a promising therapeutic target to counteract the age-related decline in endothelial cell function.
Temporal Trends in Stroke Management and Outcomes between 2011 and 2020: Results from a Nationwide Multicenter Registry
Authors: Park Tai Hwan , Hong Keun-Sik , Cho Yong-Jin , Ryu Wi-Sun , Kim Dong-Eog , Park Man-Seok , Choi Kang-Ho , Kim Joon-Tae , Kang Jihoon , Kim Beom-Joon , Han Moon-Ku , Lee Jun , Cha Jae-Kwan , Kim Dae-Hyun , Kim Jae Guk , Lee Soo Joo , Kwon Jee-Hyun , Kim Wook-Joo , Shin Dong-Ick , Yum Kyu Sun , Sohn Sung Il , Hong Jeong-Ho , Choi Jay Chol , Lee Byung-Chul , Yu Kyung-Ho , Oh Mi-Sun , Park Jong-Moo , Kang Kyusik , Lee Kyungbok , Lee Sang-Hwa , Jeong Hae-Bong , Park Kwang-Yeol , Lee Ji Sung , Lee Juneyoung , Gorelick Philip B. , Bae Hee-Joon 
Published: March 2024

AbstractBackgroundThere have been significant advancements in the treatment of ischemic stroke including stent retrievers for endovascular thrombectomy, new oral anticoagulants for atrial fibrillation, dual antiplatelet therapy for stroke prevention, and statins for atherosclerotic stroke. This study aims to evaluate temporal trends of these treatments and related clinical outcomes through a decade-long trend analysis, utilizing data from a comprehensive, national, multicenter stroke registry. We also seek to identify areas in need of improvement.MethodsThis analysis involved patients with ischemic stroke or transient ischemic attack registered prospectively in the Clinical Research Center for Stroke-Korea-National Institute of Health (CRCS-K-NIH) registry between 2011 and 2020. We examined temporal trends in risk factors, etiologic subtypes, acute management strategies, and outcomes for up to one year post-stroke. Generalized linear mixed models were employed to account for center clustering.ResultsAmong 77,662 patients over 10 years, the average age increased by 2.2 years in men and 2.4 years in women. Notably, in-hospital neurological deterioration, 3-month and 1-year mortality, and cumulative incidence of recurrent stroke within one year showed significant decreases over time after adjustments for age, sex, and initial stroke severity (Ptrend’s< 0.01). However, functional outcomes at 3 months and 1 year remained unchanged. The use of endovascular thrombectomy increased from 5.4% in 2011 to 10.6% in 2020. There was also an increase in the prescription of anticoagulants for atrial fibrillation, dual antiplatelet therapy, statins, and stroke unit care. Contrarily, the rate of intravenous thrombolysis showed a slight decline.ConclusionsThis study points to a reduction in mortality and risk of recurrent stroke over the past decade, paralleling enhancement in acute and preventive stroke management. Nevertheless, the decline in use of intravenous thrombolysis and the stagnation of functional outcomes may signal the need for further investigation to identify underlying causes of these trends and counterstrategies to mitigate risks.
Machine Learning for Predicting Therapeutic Outcomes in Acute Myeloid Leukemia Patients
Authors: Karathanasis Nestoras , Papasavva Panayiota , Oulas Anastasis , Spyrou George M 
Published: March 2024

AbstractBackground and ObjectiveThe standard of care inAcute Myeloid Leukemiapatients has remained essentially unchanged for nearly 40 years. Due to the complicated mutational patterns within and between individual patients and a lack of targeted agents for most mutational events, implementing individualized treatment for AML has proven difficult. We reanalysed theBeatAML datasetemployingMachine Learning algorithms. The BeatAML project entails patients extensively characterized at the molecular and clinical levels and linked to drug sensitivity outputs. Our approach capitalizes on the molecular and clinical data provided by theBeatAML datasetto predict theex vivodrug sensitivity for the 122 drugs evaluated by the project.MethodsWe utilized ElasticNet, which produces fully interpretable models, in combination with a two-step training protocol that allowed us to narrow down computations. We automated the genes’ filtering step by employing two metrics, and we evaluated all possible data combinations to identify the best training configuration settings per drug.ResultsWe report a Pearson correlation across all drugs of 0.36 when clinical and RNA sequencing data were combined, with the best-performing models reaching a Pearson correlation of 0.67. When we trained using the datasets in isolation, we noted that RNA Sequencing data (Pearson: 0.36) attained three times the predictive power of whole exome sequencing data (Pearson: 0.11), with clinical data falling somewhere in between (Pearson 0.26). Lastly, we present a paradigm of clinical significance. We used our models’ prediction as ahealth management scoreto rank an individual’s expected response to treatment. We identified 78 patients out of 89 (88%) that the proposed drug was more potent than the administered one based on theirex vivodrug sensitivity data.ConclusionsIn conclusion, our reanalysis of the BeatAML dataset using Machine Learning algorithms demonstrates the potential for individualized treatment prediction in Acute Myeloid Leukemia patients, addressing the longstanding challenge of treatment personalization in this disease. By leveraging molecular and clinical data, our approach yields promising correlations between predicted drug sensitivity and actual responses, highlighting a significant step forward in improving therapeutic outcomes for AML patients.HighlightsMachine learning can predict response to treatment in Acute Myeloid Leukemia patients.RNA sequencing data are more informative than whole exome sequencing and clinical data in predicting drug response in Acute Myeloid Leukemia patients.Drug response predictions could be used as a health management score to rank the individual’s expected response to treatment.We identified a more potent drug than the administered one for 88% (78 out of 89) of the patients examined.
Within-subjects ultra-short sleep-wake protocol for characterising circadian variations in retinal function
Authors: Heinrichs Hannah Sophie , Spitschan Manuel 
Published: March 2024

AbstractPrior studies suggest that visual functions undergo time-of-day variations. Under naturalistic entrainment, diurnal changes in physiology may be driven by circadian and/or homeostatic processes, and repeated measurements at different times of day are thus not suitable to draw unambiguous conclusions about circadian effects on visual function. In this study, we disentangle circadian and homeostatic effects on variations of retinal function. We examine the earliest stages of image-forming (temporal contrast sensitivity of the post-receptoral channels) and non-image forming visual functions (pupillary light response) by employing a short forced-desynchrony multiple-naps protocol lasting 40 hours. Participants (n=12, 50% female) will stay in a controlled time-isolating environment under dim light conditions and adhere to an ultra-short sleep-wake cycle, alternating between 2h30m of wake time in dim light and 1h15m hour of sleep in no light. During eleven intervals of wakefulness, participants will undergo psychophysical and pupillometric assessments with silent-substitution stimuli. We hypothesize that the sensitivity of retinal mechanisms undergoes circadian variations. This hypothesis will be investigated by separately determining psychophysical contrast thresholds to parafoveal silent-substitution stimuli targeting the postreceptoral pathways (isoluminant red-green, L − M; isoluminant blue-yellow, S; luminance, L+M+S). We will furthermore measure the pupillary light response to peripheral stimuli (annulus 10°–30°) in comparison to the response to stimuli isolating or including melanopsin stimulation. All stimuli will be delivered at constant retinal irradiance using a Maxwellian view system or artificially restricting pupil size. Additionally, we will quantify and report effects of our test stimuli on the circadian system by comparing the dim-light melatonin onset (DLMO) timing during two supplementary evening sessions, comparing dim-light conditions to such with experimental light exposure. Our work informs the fundamental biological mechanisms underlying the influence of light on the human circadian system. Based on our findings, current models about the sensitivity of the circadian system may need to be modified in order to account for the bidirectional influence of circadian function and photoreception.
Historical state compulsory schooling laws and pandemic-era mortality: A quasi-experimental study
Authors: Wells Whitney , Chen Yea-Hung , Charpignon Marie-Laure , Lee Ah-Reum , Chen Ruijia , Stokes Andrew C. , Torres Jacqueline M. , Glymour M. Maria 
Published: March 2024

AbstractIntroductionLow educational attainment is associated with increased risk of COVID-19 mortality, but it remains unclear whether the link between education and COVID-19 mortality is causal or due to confounding factors, such as childhood socio-economic status or cognitive skills. To address this question, we evaluated whether older adults’ risk of COVID-19 mortality was associated with historical state-level compulsory schooling laws (CSLs) applicable when they were school-aged. We also evaluated whether that impact was unique to COVID-19 mortality or also applied to all-cause mortality, both before and during the pandemic.MethodsWe defined mortality outcomes using US death certificate data from Mar 2019-Dec 2021 for people born in the US before 1964 in three time periods: the year prior to the pandemic (Mar 2019-Feb 2020), pandemic year 1 (Mar 2020-Feb 2021), and pandemic year 2 (Mar-Dec 2021). We determined the population at risk using 2019 American Community Survey PUMS data with population weights, representing 78.7 million individuals born in the US before 1964. We linked individuals to the number of mandatory years of education defined by CSLs specific to their state of birth and years when school age. We estimated intention-to-treat effects of CSLs on mortality using logistic regressions controlling for state-of-birth fixed effects, birth year (linear and quadratic), sex, race, ethnicity, and state-level factors including percent urban, Black, and foreign-born (at age 6) and manufacturing jobs per capita and average manufacturing wages (at age 14).ResultsWe identified a dose-response relationship between CSLs and mortality. In the first year of the pandemic, people mandated to receive 8 vs 9 (reference) years of education had higher odds of COVID-19 mortality (Odds Ratio [OR]: 1.15; 95% Confidence Interval [CI]: 1.10, 1.19), while those mandated to receive 10 vs 9 (reference) years of education had lower odds of COVID-19 mortality (OR: 0.96; 95% CI: 0.94, 0.98). The association of CSLs with COVID-19 mortality was similar in pandemic years 1 and 2; for all-cause mortality in pandemic years 1 and 2; and for all-cause mortality in the year prior to the pandemic. Results were robust to alternative model specifications.ConclusionsThese findings support a causal benefit of education for reduced mortality during the COVID-19 pandemic. State investments in children’s education may have reduced pandemic-era mortality decades later. Our research has implications beyond the pandemic context, as our results suggest the observed relationship mirrors a pre-existing relationship between CSLs and all-cause mortality.
GASTROINTESTINAL MUCOSAL DAMAGE AND SUBSEQUENT RISK OF PARKINSON’S DISEASE
Authors: Chang Jocelyn J. , Kulkarni Subhash , Pasricha Trisha S. 
Published: March 2024

AbstractIntroductionThe gut-first hypothesis of Parkinson’s Disease (PD) has gained traction, yet the inciting events triggering PD from gut-related factors remain unclear. While H. pylori infection is linked to peptic injury and is 1.47 times more prevalent in PD individuals, it is unknown how gastrointestinal mucosal damage (MD) may increase the risk of PD. We aimed to study the association between upper endoscopy findings of MD and subsequent PD development.MethodsIn our retrospective study of 18,305 adults without prior PD, undergoing upper endoscopy between 2000 and 2005, patients with MD were matched with non-MDs. PD risk in MDs versus non-MDs was assessed using incidence rate ratio (IRR) and multivariate Cox analysis, controlling for covariates.ResultsIn the matched cohort, MD patients were significantly more likely to develop PD (IRR 3.00, p<0.0001), even after covariate adjustment (HR 2.42, p<0.001). Covariates including constipation, dysphagia, older age, and male sex were also associated with higher PD risk. Among MDs, H. pylori presence (AOR 5.38, p=0.04) and chronic NSAID use (AOR 3.28, p=0.04) increased PD odds, while chronic smoking decreased PD odds (AOR 0.19, p<0.05).ConclusionMD elevates PD risk, with H. pylori increasing risk only in the presence of MD, suggesting a closer link between PD and gastric mucosa disruption. Furthermore, chronic NSAID use significantly raises PD odds in MD, while chronic smoking reduces PD risk in this context. Increased vigilance among MD patients for future PD risk is warranted, with further studies needed to elucidate precise pathophysiology.
Identifying Appropriate Height Exponents and the Impact on Diagnosis and Prognosis of Left Ventricular Hypertrophy: the REMODEL Study
Authors: Lee Clement , Chan Ryan , Toh Desiree-Faye , Kui Michelle , Lee Vivian , Bryant Jennifer A , Bourbetakh Redha , Lee Chi-Hang , Ping Chai , Le Thu-Thao , Chin Calvin WL 
Published: March 2024

ABSTRACTBACKGROUNDLeft ventricular hypertrophy (LVH) is a strong predictor of adverse outcomes. Although normalizing LV mass (LVM) to height exponents reduced variability from body size, specific recommendations for height exponents are lacking due to a scarcity of normal cohorts to define appropriate height exponents. We aimed to demonstrate the diagnostic and prognostic implications of establishing height exponents specific to sex, ethnicity and imaging modality.METHODSNon-overweight/non-obese Asian healthy volunteers (n=416) were used to establish appropriate height exponents. The impact of these height exponents was examined in a separate cohort of Asians with hypertension (n=878). All individuals underwent standardized cardiovascular magnetic resonance. Primary outcome was a composite of acute coronary syndrome, heart failure hospitalization, stroke, and cardiovascular mortality.RESULTSThe height exponents for healthy females and males were 1.57 and 2.33, respectively. LVH was present in 27% of individuals with hypertension when indexed to body surface area (BSA) and 47% when indexed to sex-specific height exponents. Most individuals reclassified to LVH with height exponents were overweight or obese. There were 37 adverse events over 60 (37-73) months of follow-up. Regardless of indexing method, LVH was independently associated with increased adverse events (height exponent hazard ratio (HR): 2.8 [1.25-6.29], P=0.013;BSA HR: 5.43 [2.49-11.8], P<0.001).CONCLUSIONSReference ranges specific to ethnicity, sex and imaging modality are necessary to establish appropriate height exponents. Although utilising height exponents resulted in more LVH reclassification, this did not translate to a notable improvement in event prediction.Graphical AbstractIn this cardiovascular magnetic resonance study, the appropriate height exponents were 1.57 in Asian females and 2.33 in Asian males. Normalizing to height exponents increased the diagnosis of hypertensive left ventricular hypertrophy (LVH), predominantly in those who were overweight and obese. Regardless of the method of indexing, LVH was associated with adverse primary and secondary outcomes.