bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bayesian network modelling to identify on-ramps to childhood obesity
Authors: Zhu Wanchuang , Marchant Roman , Morris Richard W , Baur Louise A , Simpson Stephen J , Cripps Sally 
Published: November 2022

AbstractBackgroundWhen tackling complex public health challenges such as childhood obesity, interventions focused on immediate causes, such as poor diet and physical inactivity, have had limited success, largely because upstream root causes remain unresolved. A priority is to develop new modelling frameworks to infer the causal structure of complex chronic disease networks, allowing disease “on-ramps” to be identified and targeted.MethodsThe system surrounding childhood obesity was modelled as a Bayesian Network, using data from The Longitudinal Study of Australian Children. The existence and direction of the dependencies between factors represent possible causal pathways for childhood obesity and were encoded in directed acyclic graphs (DAGs). The posterior distribution of the DAGs was estimated using Partition Markov chain Monte Carlo.ResultsWe have implemented structure learning for each dataset. For each wave and cohort, socio-economic status was central to the DAGs, implying that socio-economic status drives the system regarding childhood obesity. Furthermore, the causal pathway socio-economic status and/or parental high school levels → parental body mass index (BMI) → child’s BMI existed in over 99.99% of posterior DAG samples across all waves and cohorts. For children under the age of 8y, the most influential proximate causal factors explaining child BMI were birth weight and parents’ BMI. After age 8y, free time activity became an important driver of obesity, while the upstream factors influencing free time activity for boys compared with girls were different.ConclusionsChildhood obesity is largely a function of socio-economic status, which is manifest through numerous downstream factors. Parental high school levels entangle with socio-economic status, hence are on-ramp to childhood obesity. The strong and independent causal relationship between birth weight and childhood BMI suggests a biological link. Our study implies that interventions that improve socio-economic status, including through increasing high school completion rates, may be effective in reducing childhood obesity prevalence.
Plasmodium vivaxrelapse, reinfection and recrudescence estimation using genetic data
Authors: Taylor Aimee R , Foo Yong See , White Michael T 
Published: November 2022

AbstractMalaria is a major public health concern. Among the two most important causes of human malaria,Plasmodium vivaxis the hardest to eliminate, owing largely to its ability to relapse (cause recurrent blood-stage infection following the activation of dormant liver-stage parasites called hypnozoites). Recurrent vivax malaria can also follow a failure to treat a preceding blood-stage infection (recrudescence) and, in endemic settings, a new infectious mosquito bite (reinfection). Understanding the cause of recurrent vivax malaria is critical for disease control efforts, e.g., to estimate the efficacy of a hypnozoiticidal drug, relapse needs to be separated from reinfection and recrudescence. In this report we describe the Pv3R statistical model designed to estimate usingP. vivaxgenetic data the probability that a recurrentP. vivaxblood-stage infection is a relapse, reinfection or recrudescence (thePv3Rs).
Vitamin D and the preclinical Alzheimer cognitive composite cognition (PACC) score: a two-sample mendelian randomization study
Authors: Ilboudo Yann , Yoshiji Satoshi , Lu Tianyuan , Butler-Laporte Guillaume , Zhou Sirui , Richards J. Brent 
Published: November 2022

ABSTRACTObjectiveObservational studies on cognition found that vitamin D supplementation is associated with improved cognition. Further, recent Mendelian randomization (MR) studies have shown that increased vitamin D levels, as measured by 25-hydroxyvitamin D [25(OH)D], may protect against Alzheimer’s disease. Thus, it is possible that 25OHD may protect against Alzheimer’s disease by improving cognition.MethodsTo evaluate this hypothesis, we began by performing an observational study by testing the association of 25OHD levels with 5 cognitive outcomes related to memory and executive function, adjusting for age, sex, BMI, smoking status and nutritional risk index in 26,787 older individuals (median age 62). Since such observational analyses can be biased by confounding, we next performed two-sample mendelian randomization (MR) analyses testing the effect of 25(OH)D on cognitive outcomes, since this method helps to protect against bias from confounding.ResultsObservational studies suggested a strong protective association between 25(OH)D and cognitive measures. However, in MR analyses, we found no estimated effect of 25(OH)D on these outcomes.ConclusionThese findings suggest that associations between 25(OH)D levels and cognition are likely to be biased by confounding and that the relationship between 25(OH)D levels and Alzheimer’s disease is not due to the effect of 25(OH)D on cognition.
Substance use, psychiatric symptoms, personal mastery, and social support among COVID-19 long haulers: A compensatory model
Authors: Tam Cheuk Chi , Qiao Shan , Garrett Camryn , Zhang Ran , Aghaei Atefeh , Aggarwal Abhishek , Li Xiaoming 
Published: November 2022

AbstractBackgroundSubstance use has become a critical health concern during the COVID-19 pandemic, and emerging attention has been paid to people with the persistent symptoms of COVID-19 (COVID-19 long haulers) due to their high vulnerability. However, scant research has investigated their substance use and relevant psychosocial factors. The current study was to (1) examine substance use behaviors (i.e., legal drug use, illicit drug use, and non-medical use of prescription drugs); and (2) assessed their associations with psychiatric symptoms (i.e., depression, anxiety, and post-traumatic stress disorder) and psychosocial factors (i.e., personal mastery and social support) among COVID-19 long haulers.MethodsIn January – March 2022, 460 COVID-19 long haulers (50% female), with an average age of 32, completed online surveys regarding their demographics, substance use, psychiatric symptoms, and psychosocial factors.ResultsIn the past three months, the most commonly used or non-medically used substances were tobacco (82%) for legal drugs, cocaine (53%) for illicit drugs, and prescription opioids (67%) for prescription drugs. Structural equation modeling suggested that psychiatric symptoms were positively associated with substance use behaviors (βs = .38 to .68,ps < .001), while psychosocial factors were negatively associated with substance use behaviors (βs = -.61 to -.43,ps < .001).ConclusionSubstance use is common in COVID-19 long haulers and psychiatric symptoms are the risk factors. Personal mastery and social support appear to offer protection offsetting the psychiatric influences. Substance use prevention and mental health services for COVID-19 long haulers should attend to personal mastery and social support.
Predicting Lung Cancer in Korean Never-Smokers with Polygenic Risk Scores
Authors: Kim Juyeon , Park Young Sik , Kim Jin Hee , Hong Yun-Chul , Kim Young-Chul , Oh In-Jae , Jee Sun Ha , Ahn Myung-Ju , Kim Jong-Won , Yim Jae-Joon , Won Sungho 
Published: November 2022

ABSTRACTIn the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer. Hence, recently, genetic data have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs). PRSs were calculated using a thresholding-pruning-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31−2.23), and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747−0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong’s test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.
Heterotopic reduction of forelimb progenitors underpins development of the vestigial emu wing; implications for vertebrate limb evolution
Authors: Newton Axel H , Williams Sarah M , Phipson Belinda , Pask Andrew J , Major Andrew T , Smith Craig A 
Published: November 2022

AbstractThe tetrapod limb has evolved a broad diversity of form and function, enabling vertebrates to adapt to a wide range of environments. One of the most striking examples of this is the evolution of powered flight in birds. However, during the avian radiation, flightless ratites (Paleognathae) secondarily evolved multiple instances of wing reductions, utilizing distinct molecular mechanisms, and displaying heterochrony with flighted birds (Neoaves). Among ratites, the emu displays the most marked reduction of wing anatomy, developing a small wing with a single clawed digit. This major divergence from the typical avian pattern provides a robust model to determine the mechanisms underpinning developmental plasticity in the tetrapod limb. To interrogate the ontogenetic origins of vestigial wing development, we applied comparative single cell transcriptomics of the embryonic emu forelimb field with the chicken, as it possess a typical wing. Stunted wing development in the emu occurs through a heterotopic reduction of lateral plate mesoderm (LPM)-derived limb progenitor cells, and accompanying downregulation of genes associated with LPM development and early limb initiation. Here, forelimb bud initiation and outgrowth is altered by changes to the specification and allocation of limb progenitor cells, acting as an underlying template for pre- and post-patterning mechanisms. These findings provide novel insights into the evolution of limb development in tetrapods, and emphasizes an important, yet underappreciated role for heterotopy as major driver of limb disparity.Significance statementAnimals exhibit a striking variety of morphologies, yet our understanding of how these forms evolve and arise during development are lagging. The emu is a large, flightless bird which has evolved a vestigial wing. This model allows detailed interrogations into the mechanisms which underlie evolution and development of a distinct morphological structure. Through application of comparative single cell transcriptomics between the emu and chicken, we identify an early embryological mechanism, heterotopy, underlying the evolution and vestigial development of the emu wing. This mechanism features reduced allocation of limb bud progenitor cells in the lateral plate mesoderm (LPM). This data provides new information on the mechanisms that underpin evolutionary diversity in morphological features.
Monitoring the intestinal magnetic field with optically pumped atomic magnetometers
Authors: Sun Chenxi , Zhao Biying , Wu Teng , Zhang Jianwei , Leng Yuxin , Guo Hong ,   CREAM Bioelectromagnetism Group
Published: November 2022

AbstractResearch has shown the potential of magnetoenterography (MENG) for detecting intestinal diseases noninvasively by superconducting quantum interference devices (SQUIDs). Nevertheless, these devices need to operate under a cytogenetic environment maintained by liquid helium. In this paper, we record the intestinal magnetic field of a rabbit with optically pumped magnetometers (OPMs) at room temperature. It demonstrates that the OPM-based system has sufficient sensitivity to measure the intestinal magnetic fields of the rabbit, and can be potentially developed into a cost-effective and flexible MENG system.
Accurate prediction of cohesin-mediated 3D genome organization from 2D chromatin features
Authors: Abbas Ahmed , Chandratre Khyati , Gao Yunpeng , Yuan Jiapei , Zhang Michael Q. , Mani Ram S. 
Published: November 2022

ABSTRACTThe three-dimensional (3D) genome organization influences diverse nuclear processes. Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) and Hi-C are powerful methods to study the 3D genome organization. However, ChIA-PET and Hi-C experiments are expensive, time-consuming, require tens to hundreds of millions of cells, and are challenging to optimize and analyze. Predicting ChIA-PET/Hi-C data using cheaper ChIP-Seq data and other easily obtainable features could be a useful alternative. It is well-established that the cohesin protein complex is a key determinant of 3D genome organization. Here we present Chromatin Interaction Predictor (ChIPr), a suite of regression models based on deep neural networks (DNN), random forest, and gradient boosting, respectively, to predict cohesin-mediated chromatin interaction strength between any two loci in the genome. Comprehensive tests on four cell lines show that the predictions of ChIPr correlate well with the original ChIA-PET data at the peak-level resolution and bin sizes of 25 and 5 Kbp. In addition, ChIPr can accurately capture most of the cell-type-dependent loops identified by ChIA-PET and Hi-C data. Rigorous feature testing indicated that genomic distance and RAD21 (a cohesin component) ChIP-Seq signals are the most important inputs for ChIPr in determining chromatin interaction strength. The standard ChIPr model requires three experimental inputs: ChIP-Seq signals for RAD21, H3K27ac (enhancer/active chromatin mark) and H3K27me3 (inactive chromatin mark). The minimal ChIPr model performs comparably and requires a single experimental input: ChIP-Seq signals for RAD21. Integrative analysis revealed novel insights into the role of CTCF motif, its orientation, and CTCF binding on the prevalence and strength of cohesin-mediated chromatin interactions. These studies outline the general features of genome folding and open new avenues to analyze spatial genome organization in specimens with limited cell numbers.
Accelerating cryptic pocket discovery using AlphaFold
Authors: Meller Artur , Bhakat Soumendranath , Solieva Shahlo , Bowman Gregory R. 
Published: November 2022

AbstractCryptic pockets, or pockets absent in ligand-free, experimentally determined structures, hold great potential as drug targets. However, cryptic pocket opening is often beyond the reach of conventional biomolecular simulations because certain cryptic pocket openings involve slow motions. Here, we investigate whether AlphaFold can be used to accelerate cryptic pocket discovery either by generating structures with open pockets directly or generating structures with partially open pockets that can be used as starting points for simulations. We use AlphaFold to generate ensembles for 10 known cryptic pocket examples, including 5 that were deposited after AlphaFold’s training data was extracted from the PDB. We find that in 6 out of 10 cases AlphaFold samples the open state. For plasmepsin II, an aspartic protease from the causative agent of malaria, AlphaFold only captures partial pocket opening. As a result, we ran simulations from an ensemble of AlphaFold-generated structures and show that this strategy samples cryptic pocket opening, even though an equivalent amount of simulations launched from a ligand-free experimental structure fails to do so. Markov state models (MSMs) constructed from the AlphaFold-seeded simulations quickly yield a free energy landscape of cryptic pocket opening that is in good agreement with the same landscape generated with well-tempered metadynamics. Taken together, our results demonstrate that AlphaFold has a useful role to play in cryptic pocket discovery but that many cryptic pockets may remain difficult to sample using AlphaFold alone.
Does the Ice Age legacy end in Central Europe? The shrinking distributions of glacial relict crustaceans
Authors: Arbačiauskas Kęstutis , Smith Carl , Audzijonyte Asta 
Published: November 2022

AbstractGlacial relict mysid and amphipod crustaceans are characterised by their affinity for cold and well-oxygenated waters and inability to disperse upstream or by external agents. These crustaceans occur in large and deep lakes of Northern and Central Europe and North America, their distributions shaped by glaciation events. In Europe, along the southern edge of their distribution (Germany, Poland, Lithuania, Belarus), glacial relict crustaceans are threatened by eutrophication and global warming.This study assesses the status of three glacial relict malacostracan species in Lithuania; the amphipodsMonoporeia affinisandPallaseopsis quadrispinosa, and mysidMysis relicta, and models their abundance as a function of environmental variables and the presence of invasive Ponto-Caspian mysids and amphipods.Our results revealed thatM. affinisis likely extinct in the country, whereasM. relictawas found in only 9 out of 16 locations from which it was previously recorded. The distribution ofP. quadrispinosaappears to be shrinking.Lake depth and water flowthrough intensity were significantly and positively associated with the relative abundance of relict mysids and amphipods, but no association was found with lake size or the presence of invasive Ponto-Caspian crustaceans.We conclude that urgent action to mitigate the effects of nutrient run-off is needed to improve the status of glacial relict and other species that require good water quality. We also propose the re-introduction of glacial relict species in Lake Drūkšiai, where they went extinct during the operation of the Ignalina nuclear power plant that heated the lake, but where deep-water environmental conditions have improved following the powerplant closure in 2010.
The intracellular amastigote ofTrypanosoma cruzimaintains an actively beating flagellum
Authors: Won Madalyn M. , Krüger Timothy , Engstler Markus , Burleigh Barbara A. 
Published: November 2022

AbstractThroughout its complex life cycle, the uniflagellate parasitic protist,Trypanosoma cruzi, adapts to different host environments by transitioning between elongated motile extracellular forms and non-motile intracellular amastigote forms that replicate in the cytoplasm of mammalian host cells. Despite their name, intracellularT. cruziamastigotes retain a short flagellum that extends beyond the opening of the flagellar pocket with access to the extracellular milieu. Contrary to the long-held view that theT. cruziamastigote flagellum is inert, we now report that this organelle is motile and displays quasiperiodic beating inside mammalian host cells. Kymograph analysis determined an average flagellar beat frequency of ~0.7 Hz for intracellular amastigotes. Similar beat frequencies were measured in extracellular amastigotes following their isolation from host cells. Inhibitor studies reveal roles for parasite mitochondrial respiration and intracellular calcium availability in modulating flagellar beat inT. cruziamastigotes. Together, these findings demonstrate that flagellar motility is an intrinsic property ofT. cruziamastigotes and suggest that this organelle may play an active role in the parasite infection process. To our knowledge, this is the first record of an intracellular eukaryotic flagellum beating within another eukaryotic cell.
An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission
Authors: Li Weizhong , Wang Tao , Rajendrakumar Arunraj M. , Acharya Gyanada , Miao Zizhen , Varghese Berin P. , Yu Hailiang , Dhakal Bibek , LeRoith Tanya , Tuo Wenbin , Zhu Xiaoping 
Published: November 2022

AbstractSARS-CoV-2 and its variants cause COVID-19, which is primarily transmitted through droplets and airborne aerosols. To prevent viral infection and reduce viral spread, vaccine strategies must elicit protective immunity in the airways. FcRn transfers IgG across epithelial barriers; we explore FcRn-mediated respiratory delivery of SARS-CoV-2 spike (S). A monomeric IgG Fc was fused to a stabilized S protein; the resulting S-Fc bound to S-specific antibodies (Ab) and FcRn. A significant increase in Ab responses was observed following the intranasal immunization of mice with S-Fc formulated in CpG as compared to the immunization with S alone or PBS. Furthermore, we intranasally immunize adult or aged mice and hamsters with S-Fc. A significant reduction of virus replication in nasal turbinate, lung, and brain was observed following nasal challenges with SARS-CoV-2, including Delta and Omicron variants. Intranasal immunization also significantly reduced viral transmission between immunized and naive hamsters. Protection was mediated by nasal IgA, serum-neutralizing Abs, tissue-resident memory T cells, and bone marrow S-specific plasma cells. Hence FcRn delivers an S-Fc antigen effectively into the airway and induces protection against SARS-CoV-2 infection and transmission. Based on these findings, FcRn-targeted non-invasive respiratory immunizations are superior strategies for preventing highly contagious respiratory viruses from spreading.
CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake
Authors: Nikolaou Savvas , Juin Amelie , Whitelaw Jamie A. , Paul Nikki R. , Fort Loic , Nixon Colin , Spence Heather J. , Bryson Sheila , Machesky Laura M. 
Published: November 2022

AbstractPancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signaling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53- driven pancreatic cancer. Deletion of CYRI-B accelerates tumourigenesis, leading to enhanced ERK and JNK-induced proliferation in precancerous lesions, indicating a role as a buffer of RAC1 hyperactivation in early stages. However, as disease progresses, loss of CYRI-B inhibits metastasis. CYRI-B depleted tumour cells show reduced chemotactic responses to lysophosphatidic acid, a major driver of tumour spread, due to impaired macropinocytic uptake of LPAR1 receptor. Overall, we implicate CYRI-B as a mediator of growth and signaling in pancreatic cancer, providing new insights into pathways controlling metastasis.
Semisynthesis reveals Apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse
Authors: Wyatt Jasmine , Tavassoli Mahvash , Müller Manuel M. 
Published: November 2022

ABSTRACTApoptin is a small viral protein capable of inducing cell death selectively in cancer cells. Despite its potential as an anticancer agent, relatively little is known about its mechanism of toxicity and cancer-selectivity. Previous experiments suggest that cancer-selective phosphorylation modulates Apoptin toxicity, although a lack of chemical tools has hampered the dissection of underlying mechanisms. Here, we describe structure-function studies with site-specifically phosphorylated Apoptin (Apoptin-T108ph) in living cells which revealed that Thr108 phosphorylation is the selectivity switch for Apoptin toxicity. Mechanistic investigations link T108ph to actin binding, cytoskeletal disruption and downstream inhibition of anoikis-resistance as well as cancer cell invasion. These results establish Apoptin as a protein pro-drug, selectively activated in cancer cells by phosphorylation, which disrupts the cytoskeleton and promotes cell death. We anticipate that this mechanism provides a framework for the design of next generation anticancer proteins with enhanced selectivity and potency.