bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Alzheimer’s disease genes and epistasis identified using machine learning GWAS platform
Authors: Lundberg Mischa , Sng Letitia M.F. , Szul Piotr , Dunne Rob , Bayat Arash , Burnham Samantha C. , Bauer Denis C. , Twine Natalie A. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2023

AbstractAlzheimer’s disease (AD) is a complex genetic disease, and variants identified through genome-wide association studies (GWAS) explain only part of its heritability. Epistasis has been proposed as a major contributor to this ‘missing heritability’, however, many current methods are limited to only modelling additive effects. We use VariantSpark, a machine learning (ML) approach to GWAS, and BitEpi, a tool for epistasis detection, to identify AD associated variants and interactions across two independent cohorts, ADNI and UK Biobank. By incorporating significant epistatic interactions, we captured 10.41% more phenotypic variance than logistic regression (LR). We validate the well-established AD loci,APOE, and identify two novel genome-wide significant AD associated loci in both cohorts,SH3BP4andSASH1, which are also in significant epistatic interactions withAPOE. We show that theSH3BP4SNP has a modulating effect on the known pathogenicAPOESNP, demonstrating a possible protective mechanism against AD.SASH1is involved in a triplet interaction with pathogenicAPOESNP andACOT11,where theSASH1SNP lowered the pathogenic interaction effect betweenACOT11andAPOE. Finally, we demonstrate that VariantSpark detects disease associations with 80% fewer controls than LR, unlocking discoveries in well annotated but smaller cohorts.
Egg Consumption and Bone Mass Density among the Elderly: A Scoping Review
Authors: Olagunju Mobolaji T. , Abodunrin Olunike R. , Omotoso Ifeoluwa O. , Adewole Ifeoluwa E. , Ola Oluwabukola M. , Abel Chukwuemeka , Akinsolu Folahanmi T. 
Published: October 2023

AbstractIntroductionEggs offer a range of essential nutrients that could potentially support skeletal health as individuals age. Maintaining bone density is crucial for reducing the risk of fractures and improving overall mobility and quality of life in later years. Understanding the potential benefits of habitual egg consumption on bone mass density among older people is essential, given that the natural decline in bone mass density occurs with age. This area of research has not garnered sufficient attention basically because of the mixed reactions and conflicting reports about the safety of egg consumption especially among the elderly hence the scoping review aims to systematically examine the existing literature to map the evidence regarding the association between habitual egg consumption and bone mass density in elderly individuals.MethodologyThe scoping review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines to ensure methodological rigor and transparency. Five electronic databases were searched for published pieces of literature. The review included letters, reviews, observational studies, and experimental studies, while the exclusion criteria were books, grey literature, and publications not in English.ResultsOut of an initial 315 studies found across five databases, 27 duplicates were removed. After screening, 283 studies were excluded as they did not meet the study eligibility criteria. Only two studies were finally included in the review, with two excluded due to focusing on eggshell powder’s impact on elderly bone mass and one involving children.ConclusionLimited research on the link between egg consumption and bone mass density in the elderly highlights the need for further investigation. Concerns about cholesterol have overshadowed potential benefits. Given aging populations and bone health challenges, exploring eggs’ role in preventing falls and fractures is essential for a proactive approach to elderly well-being.
Myocardial Characterization for Early Diagnosis, Treatment Response Monitoring, and Risk Assessment in Systemic Light-Chain Amyloidosis
Authors: Clerc Olivier F. , Cuddy Sarah A. M. , Jerosch-Herold Michael , Benz Dominik C , Katznelson Ethan , Canseco Neri Jocelyn , Taylor Alexandra , Kijewski Marie Foley , Bianchi Giada , Ruberg Frederick L. , Di Carli Marcelo F. , Liao Ronglih , Kwong Raymond Y. , Falk Rodney H. , Dorbala Sharmila 
Published: October 2023

AbstractAimsIn systemic light-chain (AL) amyloidosis, cardiac involvement portends poor prognosis. Using myocardial characteristics on magnetic resonance imaging (MRI), this study aimed to detect early myocardial alterations, to analyze temporal changes with plasma cell therapy, and to predict risk of major adverse cardiac events (MACE) in AL amyloidosis.Methods and ResultsParticipants with recently diagnosed AL amyloidosis were prospectively enrolled. Presence of AL cardiomyopathy (AL-CMP vs. AL-non-CMP) was determined by abnormal cardiac biomarkers. MRI was performed at baseline and 6 months, with 12-month imaging in AL-CMP cohort. MACE was defined as all-cause death, heart failure hospitalization, or cardiac transplantation. Mayo AL stage was based on troponin T, NT-proBNP, and difference in free light chains. The study cohort included 80 participants (median age 62 years, 58% males). Median left ventricular extracellular volume (ECV) was significantly higher in AL-CMP (53% vs. 30%, p<0.001). ECV was abnormal (>32%) in all AL-CMP and in 47% of AL-non-CMP. ECV tended to increase at 6 months and decreased significantly from 6 to 12 months in AL-CMP (median -3%, p=0.011). ECV was strongly associated with MACE (p<0.001), and improved MACE prediction when added to Mayo AL stage (p=0.002). ECV≤32% identified a cohort without MACE, while ECV>48% identified a cohort with 74% MACE.ConclusionsIn AL amyloidosis, ECV detects subclinical cardiomyopathy. ECV tends to increase from baseline to 6 months and decreases significantly from 6 and 12 months of plasma cell therapy in AL-CMP. ECV provides excellent risk stratification and offers additional prognostic performance over Mayo AL stage.
Unveiling the antiviral capabilities of targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2
Authors: Purificação Aline D. , Mendonça Sabrina S. , Cruz Luiza V. , Sacramento Carolina Q. , Temerozo Jairo R. , Fintelman-Rodrigues Natalia , Souza de Freitas Caroline , Godoi Bruna F. , Vaidergorn Miguel M. , Leite Juliana Almeida , Salazar Alvarez Luis Carlos , Freitas Murillo V. , Silva Meryck F. B. , Martin Bianca A. , Lopez Renata F. V. , Neves Bruno J. , Costa Fabio T. M. , Souza Thiago M. L. , Emery Flavio da S. , Andrade Carolina Horta , Nonato M. Cristina 
Published: October 2023

ABSTRACTThe urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase (HsDHODH), one of the enzymes in charge of pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated quinone-based compounds, discovering potentHsDHODH inhibition (low nanomolar IC50) and promising in vitro anti-SARS-CoV-2 activity (low micromolar EC50). These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools like molecular docking and QSAR models to analyze protein-ligand interactions. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs.
Telomerase RNA structural heterogeneity in living human cells detected by DMS-MaPseq
Authors: Forino Nicholas M. , Woo Jia Zheng , Zaug Arthur J. , Jimenez Arcelia Gonzalez , Edelson Eva , Cech Thomas R. , Rouskin Silvi , Stone Michael D. 
Published: October 2023

AbstractTelomerase is a specialized reverse transcriptase that uses an intrinsic RNA subunit as the template for telomeric DNA synthesis. Biogenesis of human telomerase requires its RNA subunit (hTR) to fold into a multi-domain architecture that includes the template-containing pseudoknot (t/PK) and the three-way junction (CR4/5). These two hTR domains bind the telomerase reverse transcriptase (hTERT) protein and are thus essential for telomerase catalytic activity. Here, we probe the structure of hTR in living cells using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and ensemble deconvolution analysis. Unexpectedly, approximately 15% of the steady state population of hTR has a CR4/5 conformation lacking features thought to be required for hTERT binding. The proportion of hTR CR4/5 that is folded into the primary functional conformation does not require hTERT expression and the fraction of hTR that assumes a misfolded CR4/5 domain is not refolded by overexpression of its hTERT binding partner. This result suggests a functional role for an RNA folding cofactor other than hTERT during telomerase biogenesis. Mutagenesis demonstrates that stabilization of the alternative CR4/5 conformation is detrimental to telomerase assembly and activity. Moreover, the alternative CR4/5 conformation is not found in telomerase RNP complexes purified from cells via an epitope tag on hTERT, supporting the hypothesis that only the major CR4/5 conformer is active. We propose that this misfolded portion of the cellular hTR pool is either slowly refolded or degraded. Thus, kinetic traps for RNA folding that have been so well-studied in vitro may also present barriers for assembly of ribonucleoprotein complexes in vivo.
A Mathematical Model Simulating the Adaptive Immune Response in Various Vaccines and Vaccination Strategies
Authors: Xu Zhaobin , Song Jian , Zhang Hongmei , Wei Zhenlin , Wei Dongqing , Demongeot Jacques 
Published: October 2023

AbstractVaccination is the most effective measure for preventing infectious diseases. Developing an appropriate mathematical model facilitates quantitative research into the activation of adaptive immune responses in the human body by vaccines, thereby providing better guidance for vaccine development. In this study, we have constructed a novel mathematical model to simulate the dynamics of antibody levels following vaccination. Based on principles from immunology, our model provides a concise and accurate representation of the kinetics of antibody response. We have compared the antibody dynamics within the body after administering several common vaccines, including traditional inactivated vaccines, mRNA vaccines, and future attenuated vaccines based on defective interfering viral particles (DVG). Our model explains the crucial role of booster shots in enhancing IgG antibody levels and provides a detailed discussion on the advantages and disadvantages of different vaccine types. From a mathematical standpoint, our model systematically proposes four essential approaches to guide vaccine design: enhancing antigenic T-cell immunogenicity, directing the production of high-affinity antibodies, reducing the rate of IgG decay, and lowering the peak level of vaccine antigen-antibody complexes. Our model contributes to the understanding of vaccine design and its application by explaining various phenomena and providing positive guidance in comprehending the interactions between antibodies and antigenic substances during the immune process.
Modelling the impact of population mobility, post-infection immunity and vaccination on SARS-CoV-2 transmission in the Dominican Republic
Authors: Finch Emilie , Nilles Eric J , Paulino Cecilia Then , Skewes-Ramm Ronald , Lau Colleen , Lowe Rachel , Kucharski Adam J 
Published: October 2023

AbstractCOVID-19 epidemic dynamics are driven by a complex interplay of factors including population behaviour, government interventions, new variants, vaccination campaigns and immunity from prior infections. We aimed to quantify the epidemic drivers of SARS-CoV-2 dynamics in the Dominican Republic, an upper-middle income country of 10.8 million people, and assess the impact of the vaccination campaign implemented in February 2021 in saving lives and averting hospitalisations.We used an age-structured, multi-variant transmission dynamic model to characterise epidemic drivers in the Dominican Republic and explore counterfactual scenarios around vaccination coverage and population mobility. We fit the model to reported deaths, hospital bed occupancy, ICU bed occupancy and seroprevalence data until December 2021 and simulated epidemic trajectories under different counterfactual vaccination scenarios.We estimate that vaccination averted 5040 hospital admissions (95% CrI: 4750 - 5350), 1500 ICU admissions (95% CrI: 1420 - 1590) and 544 deaths (95% CrI: 488 - 606) in the first 6 months of the campaign. We also found that early vaccination with Sinovac-CoronaVac was preferable to delayed vaccination using a product with higher efficacy. We investigated the trade-off between changes in vaccination coverage and population mobility to understand how much relaxation of social distancing measures vaccination was able to ‘buy’ in the later stages of a pandemic. We found that if no vaccination had occurred, an additional decrease of 10-20% in population mobility would have been required to maintain the same death and hospitalisation outcomes. We found SARS-CoV-2 transmission dynamics in the Dominican Republic were driven by substantial accumulation of immunity during the first two years of the pandemic but that, despite this, vaccination was essential in enabling a return to pre-pandemic mobility levels without incurring considerable additional morbidity and mortality.
Research Protocol for a Randomised Controlled Trial Comparing the Outcome of the 3D-Printed Patient-Specific-Instrument Assisted Lapidus Fusion vs Conventional Lapidus Fusion for Surgical Correction of Hallux Valgus Deformity
Authors: Ling Samuel Ka-Kin , Wei Rachel Xiaoyu , Chui Elvis Chun-Sing , Chong Boon Hor , Ong Michael Tim-Yun , Lui Pauline Po-Yee , Yung Patrick Shu-Hang 
Published: October 2023

AbstractIntroductionHallux valgus (HV) affects up to 30% of the population. Lapidus surgery with 1st tarsal-metatarsal joint arthrodesis is one of the most common surgical options for HV. Despite its popularity, the current procedure is not without complications. This investigation will be the world’s first Lapidus arthrodesis surgery utilising patient-specific instruments (PSI) as an assistive tool. We hypothesise that the PSI will enhance surgical precision, accelerate fusion rates, decrease non-unions, and reduce the need to use bone grafts.Methods and analysisThis is a single-blinded, parallel-group, randomised controlled trial comparing the outcome of the 3D-Printed PSI Assisted Lapidus Fusion (n=27) vs Conventional Lapidus Fusion (n=27) for HV deformity. Both groups will receive an identical postoperative rehabilitation of protected weight bearing and splinting. Outcomes will include foot function scores, radiological alignment and arthrodesis site assessment with X-ray and High-Resolution Peripheral Quantitative-Computed Tomography, and foot pressure analysis.Strengths and LimitationsStrengthsThis will be the world’s first randomised control trial utilising PSI for hallux valgus surgery.Surgeries are done by a team of experienced foot and ankle surgeons.LimitationsA single-centre study with a follow-up of only 1 year. However, the authors believe that traditional Lapidus surgery has known term results, and the chief hypothetical benefit of PSI-assisted surgery is faster bony fusion and less surgical complications, which will be evident within 1 year.
Surviving on limited resources: effects of caloric restriction on growth, gene expression and gut microbiota in a species with male pregnancy (Hippocampus erectus)
Authors: Pappert Freya Adele , Wüst Vincent Alexander , Eguiguren Carmen Fontanes , Roth Olivia 
Published: October 2023

AbstractThe positive health effects of caloric restriction (CR) have been widely studied in a few conventional model species, displaying typically conventional reproductive roles, with females investing more in parental care. This creates a bias in the current literature about the impact of CR between males and females in species with unconventional reproductive strategies. In this study, we investigated the effects of CR on growth, gene expression, and intestinal microbiota in the lined seahorseHippocampus erectus.Juvenile seahorses were subjected to ad libitum (AL) or every other day fasting for 5 months. Total mRNA sequencing of liver, head kidney and gonad tissue, along with 16SrRNA amplicon sequencing of hind intestine samples was done to investigate sex-adverse effects of fasting in a species with male pregnancy and thus distinct life-history strategies leading to sex-specific trade-offs in resource allocation. Our results indicate that fasting caused a general stunting effect and delayed brood pouch development in males, reflecting its energetic demands and possibly delaying reproduction till more resources are available. We found both organ and sex-specific gene expression responses to CR, with liver and ovaries displaying the strongest variation. In the liver of CR female seahorses, numerous genes linked to energy and lipid synthesis were upregulated, and in the ovaries of the same, we found downregulation of inflammatory markers. These results reflect the fasted female’s need to allocate more resources to eggs to increase reproductive chances earlier in life compared to males. There was no sex-specific response to CR in the microbiota, rather both fasted males and females displayed similar higher alpha-diversity and increased abundance of Proteobacteria and Bacteroidetes compared to AL fed seahorses. Our research suggests that male and female reactions to nutrient scarcity may depend on their resource allocation to reproduction and parental investment, rather than directly on their biological sex. Our findings highlight the importance of using species displaying a broader range of reproductive strategies, sex role, mating system and life-history strategies when studying the sex-specific effects of CR.
The role of promiscuous molecular recognition in the evolution of RNase-based self-incompatibility
Authors: Erez Keren , Jangid Amit , Feldheim Ohad Noy , Friedlander Tamar 
Published: October 2023

AbstractHow do biological networks evolve and expand and which parameters determine their size? We study these questions in the context of the plant collaborative-non-self recognition self-incompatibility system. Self-incompatibility evolved to avoid self-fertilization among hermaphroditic plants. It relies on specific molecular recognition between highly diverse proteins of two families: female and male determinants, such that the combination of alleles an individual possesses determines its mating partners. Though highly diverse, previous models struggled to pinpoint the evolutionary trajectories by which new alleles evolved. Here, we construct a novel theoretical frame-work, that crucially affords interaction promiscuity and multiple distinct partners per protein, empirical findings disregarded by previous models. We demonstrate a dynamic long-term balance between allele emergence and extinction, where their equilibrium number depends on population parameters. Our work highlights the importance of molecular recognition promiscuity to network evolvability. Promiscuity was found in additional systems suggesting that our framework could be more broadly applicable.
Antimicrobial resistance in Arctic soils is mediated by competition and facilitation
Authors: Roy Shamik , Dawson Robin , Bradley James A. , Hernández Marcela 
Published: October 2023

AbstractAntimicrobial resistance (AMR) is widespread in terrestrial ecosystems. However, the natural processes shaping the spatial and temporal dissemination of AMR in soils are not well understood. We aimed to determine whether, how, and why AMR varies in recently deglaciated pioneer and developing Arctic soils. We showed that antibiotic-resistant genes (ARGs), mobile genetic elements (MGEs), and antibiotic-resistant bacteria (ARB) are abundant, exhibit a non-uniform distribution, and generally increase with soil age. Our analyses suggest a strong positive relationship between soil age and ARG and ARB, which we attribute to increased competition between microbes in older soils. We also observed a weak negative relationship between soil age and ARG diversity mediated by soil organic matter – suggesting facilitation due to the alleviation of nutrient limitation. The microbial processes regulating the spread of AMR in Arctic soils may be further susceptible to the effects of future climate change and human activities.TeaserThe spatial and temporal spread of antimicrobial resistance in Arctic soils is dependent on microbial interactions for nutrients
Yeast Heterochromatin Only Stably Silences Weak Regulatory Elements by Altering Burst Duration
Authors: Wu Kenneth , Dhillon Namrita , Bajor Antone , Abrahamson Sara , Kamakaka Rohinton T. 
Published: October 2023

AbstractThe interplay between nucleosomes and transcription factors leads to programs of gene expression. Transcriptional silencing involves the generation of a chromatin state that represses transcription and is faithfully propagated through DNA replication and cell division. Using multiple reporter assays, including directly visualizing transcription in single cells, we investigated a diverse set of UAS enhancers and core promoters for their susceptibility to heterochromatic gene silencing. These results show that heterochromatin only stably silences weak and stress induced regulatory elements but is unable to stably repress housekeeping gene regulatory elements and the partial repression did not result in bistable expression states.Permutation analysis of different UAS enhancers and core promoters indicate that both elements function together to determine the susceptibility of regulatory sequences to repression. Specific histone modifiers and chromatin remodellers function in an enhancer specific manner to aid these elements to resist repression suggesting that Sir proteins likely function in part by reducing nucleosome mobility. We also show that the strong housekeeping regulatory elements can be repressed if silencer bound Sir1 is increased, suggesting that Sir1 is a limiting component in silencing.Together, our data suggest that the heterochromatic locus has been optimized to stably silence the weak mating type gene regulatory elements but not strong housekeeping gene regulatory sequences which could help explain why these genes are often found at the boundaries of silenced domains.