bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Novel Exogenous Ketone Supplements on Blood Beta-Hydroxybutyrate and Glucose
Authors: Falkenhain Kaja , Daraei Ali , Little Jonathan P 
Published: August 2022

ABSTRACTBackgroundRecently developed exogenous ketone monoester supplements can acutely raise blood β-OHB and lower blood glucose without the need for other nutritional modifications or invasive procedures. However, unpleasant taste and the potential for gastrointestinal discomfort may make adherence to a supplement regimen challenging. Two novel ketone supplements have been developed that promise an improved consumer experience but differ in their chemical properties; it is currently unknown how these affect blood β-OHB and blood glucose compared to the original ketone monoester supplement.MethodsIn a double-blind randomized cross-over pilot study, N = 12 healthy individuals (29 ± 5 years, BMI = 25 ± 4 kg/m2, 42% female) participated in three experimental trials with a different ketone supplement providing 10 grams of active ingredient in each trial; (i) the monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, (ii) D-β-hydroxybutyric acid with R-1,3-butanediol, and (iii) R-1,3-butanediol. Blood β-OHB and glucose were measured via finger prick capillary blood samples at baseline and across 240 minutes post-supplementation. Supplement acceptability, hunger, and gastrointestinal distress were assessed via questionnaires.Resultsβ-OHB was elevated compared to baseline in all conditions. Total and incremental area under the curve (bothp< 0.05) and peak β-OHB (p< 0.001) differed between conditions with the highest values seen in the ketone monoester condition. Blood glucose concentration was reduced after consumption of each supplement, with no differences in total and incremental area under the curve across supplements. Supplement acceptability was greatest for D-β-hydroxybutyric acid with R-1,3-butanediol, with no effect on hunger or evidence of gastrointestinal distress across all supplements.ConclusionsDespite differences in composition, all ketone supplements tested raised β-OHB with the highest values seen after ketone monoester ingestion. Blood glucose was lowered to a similar extent across the assessed time frame with all three supplements.
Clustering of adverse health and educational outcomes in adolescence following early childhood poverty: implications for UK’s ‘levelling up’ agenda
Authors: Villadsen Aase , Asaria Miqdad , Skarda Ieva , Ploubidis George B. , Williams Mark Mon , Brunner Eric John , Cookson Richard 
Published: August 2022

ABSTRACTBackgroundEarly childhood poverty is associated with poorer health and educational outcomes in adolescence. However, there is limited evidence about the clustering of these adverse outcomes by income group.MethodsWe analysed five outcomes at age 17 known to limit life chances – psychological distress, self-assessed ill health, smoking, obesity, and poor educational achievement – using data from the longitudinal UK Millennium Cohort Study (N=15,245). We compared how single and multiple outcomes were distributed across quintiles of household income in early childhood (0-5 years) and modelled the maximum potential benefit of tackling the income gradient in these outcomes.FindingsChildren from the poorest households were 12.7(95% CI 6.4-25.1) times more likely than those from the richest to experience four or five adverse adolescent outcomes, with poor educational achievement and smoking showing the largest single risk ratios–4.6(95% CI: 4.2-5.0) and 3.6(95% CI 3.0-4.2), respectively. We modelled hypothetical absolute and relative poverty elimination scenarios, as well as an income inequality elimination scenario, and found these would yield maximum reductions in multiple adolescent adversity of 5%, 30%, and 80% respectively.InterpretationEarly childhood poverty is more strongly correlated with multiple adolescent adversity than any single adverse outcome. Reducing absolute poverty alone is not sufficient to eliminate the life-long burden of multiple adversity, which disproportionately impacts children across the bottom three-fifths of the income distribution. An ambitious levelling up agenda needs co-ordinated multi-agency action to tackle the complex interacting factors generating the steep social gradient in multiple adolescent adversity.
Mislabeled learning for psychiatric disorder detection
Authors: Li Dongdong , Liu Wenbin , Han Henry 
Published: August 2022

AbstractMislabeled learning for high-dimensional data is essentially important in AI health and relevant fields but rarely investigated in machine learning. In this study, we address the challenge by proposing a novel mislabeled learning algorithm for high-dimensional data: psychiatric map diagnosis and applying it to solve a long-time bipolar disorder and schizophrenia misdiagnosis in psychiatry. The proposed algorithm converts each input high-dimensional SNP sample into a corresponding 2D characteristic image called a psychiatric map through feature self-organizing learning. It can automatically detect mislabeled observations and relabel them with the most likely ground truth before reproducible machine learning besides providing informative visualization for mislabeling detection. Our method attains more accurate and reproducible psychiatry diagnoses, besides discovering latent psychiatry subtypes not reported before. It works well for those datasets with a limited number of samples and achieves leading advantages over the deep learning peers. This study also presents new insight into the pathology of psychiatric disorders by constructing the devolution path of psychiatric states via relative entropy analysis that discloses latent internal transfer and devolution road maps between different psychiatric states. To the best of our knowledge, it is the first study to solve mislabeled learning for high-dimensional data and will inspire more future work in this field.
Common Genetic Variation Important in Early Subcortical Brain Development
Authors: Cullen Harriet , Dimitrakopoulou Konstantina , Patel Hamel , Curtis Charles , Batalle Dafnis , Gale-Grant Oliver , Cordero-Grande Lucilio , Price Anthony , Hajnal Joseph , Edwards A David 
Published: August 2022

1.AbstractRecent genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with subcortical brain volumes. These studies have been undertaken in largely adult cohorts. To better understand the role of genetic variability in foetal and perinatal brain development, we investigate how common genetic variation affects subcortical brain development in a cohort of 208 term-born infants from the Developing Human Connectome Project.We examine six SNPs, that have shown robust associations with subcortical brain volumes in adult studies and ask if these associations exist at birth. We then investigate whether genome-wide polygenic scores (GPSs) for adult subcortical brain volumes are predictive of the corresponding neonatal brain volume. Finally, we explore the relationship between GPSs for psychiatric disorders and subcortical brain volume at birth.We find the association between SNP rs945270 and putamen volume, seen in adults, is present at birth (p=3.67×10-3, β=0.13, SE=0.04). The associations between SNP rs61921502 and hippocampal volume and SNP rs11111090 and brainstem volume are also nominally present in our neonatal cohort. We show that neonatal hippocampal, brainstem, putamen and thalamic volume are all significantly associated with the GPSs for their corresponding volume in adults. Finally, we find that GPSs for five psychiatric disorders and a cross-disorder score are not significantly predictive of subcortical brain volumes or total brain volume at birth. Our results indicate that SNPs important in shaping adult subcortical brain volume are also significant in foetal and perinatal brain development.Key PointsWe show that the association between the single nucleotide polymorphism, rs945270 and putamen volume, seen in adults, is present in neonates.We show that neonatal hippocampal, putamen, brainstem and thalamic volumes are all significantly predicted by the genome-wide polygenic scores for corresponding adult brain volumes.We do not find any robust association between genome-wide polygenic scores for psychiatric disorders and neonatal brain volume although we observe several nominal associations.
Screening Avian Pathogens in Eggs from Commercial Hatcheries in Nepal- an Effective Poultry Disease Surveillance Tool
Authors: Sharma Shreeya , Dhital Kavya , Puri Dhiraj , Pradhan Saman , Rajbhandari Udaya , Basnet Amit , Ghaju Sajani , Manandhar Prajwol , Ghimire Nabin U , Shahi Manoj K , Poudel Ajit , Napit Rajindra , Karmacharya Dibesh 
Published: August 2022

AbstractBackgroundCommercial hatcheries play an important role in the overall poultry value chain-providing small to large poultry farmers with day old chicks. Any outbreak in such hatcheries can spread diseases to other farms. Regular screening of major avian pathogens, along with strict bio-security measures, can prevent spread of diseases in hatcheries. Newcastle Disease Virus (NDV), Infectious Bronchitis Virus (IBV), Mycoplasma gallisepticum (MG), Mycoplasma synoviae (MS), Infectious Bursal Disease Virus (IBDV) and Influenza A Virus (IAV) are among the most prevalent poultry diseases which can be detected in egg albumin.MethodWe retrospectively (August 2020-August 2021, except October 2020) analyzed diagnostic results for six selected avian pathogens (NDV, IBV, MS, MG, IBDV and IAV) on eggs (n=4343) received from eleven major commercial poultry hatcheries located in the five adjoining districts of Kathmandu, Nepal. Albumin from 10% randomly selected eggs from each hatchery were tested for the six avian pathogens using multiplex PCR.ResultMajority (7/11, 64%) of the poultry hatcheries had at least one of the six pathogens present. We detected at least one avian pathogen in nine out of eleven months (82%) of screening. Except for IBDV, we found one or more of the other major avian pathogens-Influenza A (IAV) (n=4 times) and Mycoplasma gallisepticum (MG) (n=4 times) were detected the most, followed by Newcastle Virus (NDV) (n=3 times). Infectious bronchitis virus (IBV) were detected twice, and Mycoplasma synoviae (MS) was detected once.ConclusionIn a resource strapped country like Nepal, poultry disease outbreak investigation in particular and surveillance in general are challenging. Meanwhile, poultry production is highly impacted by disease outbreaks often triggered by poor bio-security and lack of pathogen screening practices. Our molecular screening tests have picked up major poultry pathogens present throughout the year in eggs collected from hatcheries. Influenza A was detected at 4 different incidences throughout the year, which is of concern to both human and animal health. Quick systematic screening of eggs at key distribution points (hatcheries) for major avian pathogens is an effective surveillance tool for early disease detection and containment of outbreaks.
Phenotypic Plasticity of Symbiotic Organ Highlight Deep-sea Mussel as Model Species in Monitoring Exploitation of Deep-sea Methane Hydrate
Authors: Li Mengna , Chen Hao , Wang Minxiao , Zhong Zhaoshan , Lian Chao , Zhou Li , Zhang Huan , Wang Hao , Cao Lei , Li Chaolun 
Published: August 2022

AbstractThe rapid progress of deep-sea methane hydrate exploration and exploitation calls for a thorough evaluation of its potential impact on local chemosynthetic ecosystems, particularly on endemic species. As one dominant megafauna in cold seeps, the deep-sea mussels mainly rely on methanotrophic endosymbionts for nutrition and therefore could serve as a promising model in monitoring the exploitation of methane hydrate. However, knowledge on the long-term responses of deep-sea mussels to environmental stresses induced by methane hydrate exploitation, especially to methane reduction and deprivation, is still lacking. Here, we set up a laboratory system and cultivated methanotrophic deep-sea musselGigantidas platifronswithout methane supply to survey the phenotypic changes after methane deprivation. While the mussels managed to survive for more than 10 months after the methane deprivation, drastic changes in the metabolism, function, and development of gill tissue, and in the association with methanotrophic symbionts were observed. In detail, the mussel digested all methanotrophic endosymbionts shortly after methane deprivation for nutrition and remodeled the global metabolism of gill to conserve energy. As the methane deprivation continued, the mussel replaced its bacteriocytes with ciliated cells to support filter-feeding, which is an atavistic trait in non-symbiotic mussels. During the long-term methane deprivation assay, the mussel also retained the generation of new cells to support the phenotypic changes of gill and even promoted the activity after being transplanted back to deep-sea, showing the potential resilience after long-term methane deprivation. Evidences further highlighted the participation of symbiont sterol metabolism in regulating these processes, which might be one direct cue for the mussels to respond to methane deprivation. These results collectively show the phenotypic plasticity of deep-sea mussels and their dynamic responses to methane deprivation, providing essential information in assessing the long-term influence of methane hydrate exploitation.
Is cold-induced nuclear import of CBF4 regulating freezing tolerance?
Authors: Shi Wenjing , Riemann Michael , Rieger Sophie-Marie , Nick Peter 
Published: August 2022

AbstractC-repeat binding factors (CBFs) are crucial transcriptional activators in plant responses to low temperature. CBF4 differs by a slower, but more persistent regulation and its role in cold acclimation. Cold acclimation is of accentuated relevance for the tolerance to late spring frosts as they become progressively common as consequence of blurred seasonality in the context of global climate change. In the current study, we explore the functions of CBF4 from grapevine, VvCBF4. Overexpression of VvCBF4 fused to GFP in tobacco BY-2 cells confers cold tolerance. Furthermore, this protein shuttles from the cytoplasm to the nucleus in response to cold stress, associated with accumulation of transcripts for other CBFs and the cold responsive gene ERD10d. This response differs for chilling as compared to freezing and is regulated differently by upstream signalling involving oxidative burst, proteasome activity and jasmonate synthesis. This difference between chilling and freezing is also seen in the regulation of CBF4 transcripts in leaves from different grapevines differing in their cold tolerance. We propose the quality of cold stress is transduced by different upstream signals inducing nuclear import to regulate other CBF factor and activate COR genes.
Post-phagocytosis activation of NLRP3 inflammasome by two novel T6SS effectors
Authors: Cohen Hadar , Baram Noam , Fridman Chaya M. , Edry-Botzer Liat , Salomon Dor , Gerlic Motti 
Published: August 2022

SummaryThe type VI secretion system (T6SS) is used by bacteria to deliver toxic effectors directly into target cells. Most T6SSs mediate antibacterial activities, whereas the potential anti-eukaryotic role of T6SS remains understudied. Here, we found a Vibrio T6SS that delivers two novel effectors into mammalian host immune cells. We showed that these effectors induce a pyroptotic cell death in a phagocytosis-dependent manner; we identified the NLRP3 inflammasome as being the underlying mechanism leading to the T6SS-induced pyroptosis. Moreover, we identified a compensatory T6SS-induced pathway that is activated upon inhibition of the canonical pyroptosis pathway. Genetic analyses revealed possible horizontal spread of this T6SS and its anti-eukaryotic effectors into emerging pathogens in the marine environment. Our findings reveal novel T6SS effectors that activate the host inflammasome and possibly contribute to virulence and to the emergence of bacterial pathogens.
Intratumoral heterogeneity and clonal evolution induced by HPV integration
Authors: Akagi Keiko , Symer David E. , Mahmoud Medhat , Jiang Bo , Goodwin Sarah , Wangsa Darawalee , Li Zhengke , Xiao Weihong , Dunn Joe Dan , Ried Thomas , Coombes Kevin R. , Sedlazeck Fritz J. , Gillison Maura L. 
Published: August 2022

ABSTRACTThe human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines revealed a unique form of structural variation, i.e., heterocateny, characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoint sequences shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus-host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. The data indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.
Structure and thermodynamics of a UGG motif interacting with Ba2+ and other metal ions: accommodating changes in the RNA structure and the presence of a G(syn)–G(syn) pair
Authors: Kiliszek Agnieszka , Pluta Martyna , Bejger Magdalena , Rypniewski Wojciech 
Published: August 2022

ABSTRACTThe self-complementary triplet 5’UGG3’/5’UGG3’ is a particular structural motif containing noncanonical G-G pair and two U·G wobble pairs. It constitutes a specific structural and electrostatic environment attracting metal ions, particularly Ba2+ ions. Crystallographic research has shown that two Ba2+ cations are located in the major groove of the helix and interact directly with the UGG triplet. A comparison with the unliganded structure has revealed global changes in the RNA structure in the presence of metal ions, whereas thermodynamic measurements have shown increased stability. Moreover, in the structure with Ba2+, an unusual noncanonical G(syn)-G(syn) pair is observed instead of the common G(anti)-G(syn). We further elucidate the metal binding properties of the UGG/UGG triplet by performing crystallographic and thermodynamic studies using DSC and UV melting with other metal ions. The results explain the preferences of the UGG sequence for Ba2+ cations and point to possible applications of this metal-binding propensity.
Generation of Recombinant Rotaviruses Expressing Human Norovirus Capsid Proteins
Authors: Philip Asha A. , Patton John T. 
Published: August 2022

AbstractRotaviruses, segmented dsRNA viruses of the Reoviridae family, are a primary cause of acute gastroenteritis in young children. In countries where rotavirus vaccines are widely used, norovirus (NoV) has emerged as the major cause of acute gastroenteritis. Towards the goal of creating a combined rotavirus-NoV vaccine, we explored the possibility of generating recombinant rotaviruses (rRVs) expressing all or portions of NoV GII.4 VP1 capsid proteins. This was accomplished by replacing the segment 7 NSP3 ORF with a cassette encoding sequentially NSP3, a 2A stop-restart translation element, and all or portions (P, P2) of NoV VP1. In addition to successfully recovering SA11 rRVs with modified SA11 segment 7 RNAs encoding NoV capsid proteins, analogous rRVs were recovered through modification of the RIX4414 segment 7 RNA. Immunoblot assay confirmed that rRVs expressed NoV capsid proteins as independent products. Moreover, VP1 expressed by rRVs underwent dimerization and was recognized by conformational-dependent anti-VP1 antibodies. Serially passaged rRVs that expressed the NoV P and P2 were genetically stable, retaining sequences up to 1.1 kbp without change. However, serially passaged rRVs containing the longer 1.5 kb VP1 sequence were less stable and gave rise to virus populations with segment 7 RNAs lacking VP1 coding sequences. Together, these studies suggest that it may be possible to develop combined rotavirus-NoV vaccines using modified segment 7 RNA to express NoV P or P2. In contrast, development of potential rotavirus-NoV vaccines expressing NoV VP1 will need additional efforts to improve genetic stability.ImportanceRotavirus (RV) and norovirus (NoV) are the two most important causes of viral acute gastroenteritis (AGE) in young children. While the incidence of RV AGE has been brought under control in many countries through the introduction of live attenuated RV vaccines, similar highly effective NoV vaccines are not available. To pursue the development of a combined RV-NoV vaccine, we examined the potential usefulness of RV as an expression vector of all or portions of the NoV capsid protein VP1. Our results showed that by replacing the NSP3 open reading frame in RV genome segment 7 RNA with a coding cassette for NSP3, a 2A stop-restart translation element, and VP1, recombinant RVs can be generated that express NoV capsid proteins as separate products. These findings raise the possibility of developing a new generation of RV-based combination vaccines that can provide protection against a second enteric pathogen, such as the NoV.
Machine learning with validation to detect diabetic microvascular complications using clinical and metabolomics data
Authors: He Feng , Ling Clarissa Ng Yin , Nusinovici Simon , Cheng Ching-Yu , Wong Tien Y. , Li Jialiang , Sabanayagam Charumathi 
Published: August 2022

ABSTRACTAIMSUsing machine learning integrated with clinical and metabolomic data to identify biomarkers associated with diabetic kidney disease (DKD) and diabetic retinopathy (DR), and to improve the performance of DKD/DR detection models beyond traditional risk factors.METHODSWe examined a population-based cross-sectional sample of 2,772 adults with type 1 or type 2 diabetes from Singapore Epidemiology of Eye Diseases study (SEED, 2004-2011). LASSO logistic regression (LASSO) and gradient boosting decision tree (GBDT) were used to select markers of prevalent DKD (defined as an eGFR < 60ml/min/1.73m2) and prevalent DR (defined as an ETDRS severity level ≥ 20) from an expanded set of 19 established risk factors and 220 NMR-quantified circulating metabolites. Risk assessment models were developed based on the variable selection results and externally validated in UK Biobank (n=5,843, 2007-2010). Model performance (AUC with 95% CI, sensitivity, and specificity) of machine learning was compared to that of traditional logistic regression adjusted for age, gender, diabetes duration, HbA1c%, systolic BP, and BMI.RESULTSSEED participants had a median age of 61.7 years, with 49.1% female, 20.2% having DKD, and 25.4% having DR. UK Biobank participants had a median age of 61.0 years, with 39.2% female, 6.4% having DKD, and 5.7% having DR. Both algorithms identified diabetes duration, insulin usage, age, and tyrosine as the most important factors of both DKD and DR. DKD was additionally associated with CVD, hypertension medication, and three metabolites (lactate, citrate, and cholesterol esters to total lipids ratio in intermediate-density-lipoprotein); While DR was additionally associated with HbA1c, blood glucose, pulse pressure, and alanine. Machine-learned models for DKD and DR detection outperformed traditional logistic regression in both internal (AUC: 0.832-0.838 vs. 0.743 for DKD, and 0.779-0.790 vs. 0.764 for DR) and external validation (AUC: 0.737-0.790 vs. 0.692 for DKD, and 0.778 vs. 0.760 for DR).CONCLUSIONSMachine-learned biomarkers suggested insulin resistance to be a primary factor associated with diabetic microvascular complications. Integrating machine learning with biomedical big data enabled biomarker discovery from a wide range of correlated variables, which may facilitate our understanding of the disease mechanisms and improve disease screening.