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The mTORC1 complex in pre-osteoblasts regulates whole-body energy metabolism independently of osteocalcin

Bone Research 2021年第1期9卷 109-125页

作者： Pawanrat Tangseefa Sally K.Martin Peck Yin Chin James Breen Chui Yan Mah Paul A.Baldock Gary A.Wittert Amanda J.Page Christopher G.Proud Stephen Fitter Andrew C.W.Zannettino Adelaide Medical School Faculty of Health and Medical ScienceUniversity of AdelaideAdelaide5005 SAAustralia Cancer Program Precision Medicine ThemeSouth Australian Health and Medical Research InstituteAdelaide5000 SAAustralia Research Centre for Reproductive Health School of Paediatrics and Reproductive HealthUniversity of AdelaideAdelaide5005 SAAustralia Computational&Systems Biology program Precision Medicine ThemeSouth Australian Health and Medical Research InstituteAdelaide5000 SAAustralia Robinson Research Institute University of AdelaideAdelaideSA 5005Australia Bioinformatics Hub University of AdelaideAdelaideSA 5005Australia Freemasons Foundation Centre for Men’s Health University of AdelaideAdelaide5005 SAAustralia Skeletal Metabolism Group Garvan Institute of Medical ResearchSydney2010 NSWAustralia Nutrition Diabetes&Metabolism ProgramLifelong Health ThemeSouth Australian Health and Medical Research InstituteAdelaide5000 SAAustralia School of Biological Sciences University of AdelaideAdelaide5005 SAAustralia Central Adelaide Local Health Network AdelaideSAAustralia

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin *** osteoblasts(OBs),insulin signaling plays a crucial role in the control of systemic glucose *** utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary *** to the controls,chow-fed Rptorob−/−mice had substantially less fat mass and exhibited adipocyte ***,upon feeding with high-fat diet,mice with pre-and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels,increased glucose tolerance and insulin *** leanness and resistance to weight gain was not attributable to changes in food intake,physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate ***-seq revealed an increase in glycolysis and skeletal insulin signaling pathways,which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptorknockout ***,these findings point to a critical role for the mTORC1 complex in the skeletal regulation of wholebody glucose metabolism and the skeletal development of insulin resistance.

关键词： metabolism mTORC1 homeostasis

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TGR5 potentiates GLP-1 secretion and cause pancreatic islet regeneration in response to Tithonia diversifolia saponin-rich extract in diabetic model mice

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Phytomedicine Plus 2022年第1期2卷 100203-100203页

作者： Ejelonu, Oluwamodupe Cecilia Elekofehinti, Olusola Olalekan Adanlawo, Isaac Gbadura Kundu, Rakesh Cell signaling laboratory Zoology Department Siksha Bhavana. Visva Bharati University WB Santiniketan India Phytomedicine/Molecular Biology &Bioinformatics Lab. Department of Chemical Sciences (Biochemistry Program) Olusegun Agagu University of Science and Technology Okitipupa Ondo State Nigeria Molecular Biology and Bioinformatics Unit Department of Biochemistry Federal University of Technology Akure Ondo State Nigeria Department of Biochemistry Ekiti State University Ado-Ekiti Ekiti State Nigeria

Background: Activation of Takeda G-protein bile acid receptor 5 (TGR5) secretes glucagon-like peptide-1 (GLP1) downstream insulin release. Saponin which has been indicated as the antidiabetic principle in plant shared similar steroidal scaffold with cholic acid (primary agonist of TGR5), hence antidiabetic mechanism of Tithonia diversifolia leaves saponin-rich extract (TDS) was investigated via TGR5/GLP-1 pathway. Methods: Insulin secretion and expression of GLP1 were measured in MIN6 β-cells incubated with TDS and cholic acid a known agonist of TGR5 at (25, 75, 125, 325) µg/ml and treatment were compared to incubation with insulin secretagogue metformin (50 mM). The action of TDS on TGR5 was studied in vivo using swiss albino mice. Results: β-cell assay showed dose dependent increase in insulin secretion/1 × 10⁶cells incubated with TDS (25, 75, 125, 325 µg/ml) when compared with positive control (50 mM metformin) and vehicle control (Cholic acid). TDS increased GLP-1 and insulin expression and decrease the percentage of%HbA1c in treated mice when compared with control (p < 0.05). TGR5 gene were highly expressed in cell incubated with 20–60 mg/kg body weight of TDS compared to STZ-induced diabetic mice and immunoblotting of TGR5 protein showed higher expression in all groups treated with TDS compared to STZ-induced diabetic mice. Conclusion: TDS exhibit its antidiabetic mechanism via TGR5 agonism leading to increase GLP-1 expression and subsequently insulin release. Hence TDS may represent a new therapeutic strategy for type-2 diabetes, a finding which could be further investigated in clinical trials. © 2021 The Author(s)

关键词： Antidiabetic GLP1 Insulin TGR5 Tithonia diversifolia

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General framework for the mechanical response of metallic glasses during strain-rate-dependent uniaxial compression

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Physical Review Materials 2023年第10期7卷 105604-105604页

作者： Weiwei Jin Amit Datye Udo D. Schwarz Mark D. Shattuck Corey S. O'Hern Department of Mechanical Engineering and Materials Science Yale University New Haven Connecticut 06520 USA Department of Chemical and Environmental Engineering Yale University New Haven Connecticut 06520 USA Benjamin Levich Institute and Physics Department The City College of New York New York New York 10031 USA Department of Physics Yale University New Haven Connecticut 06520 USA Department of Applied Physics Yale University New Haven Connecticut 06520 USA Graduate Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut 06520 USA

Experimental data on compressive strength σmax versus strain rate ɛ̇eng for metallic glasses undergoing uniaxial compression show varying strain rate sensitivity. For some metallic glasses, σmax decreases with increasing ɛ̇eng, while for others, σmax increases with increasing ɛ̇eng, and for certain alloys σmax versus ɛ̇eng is nonmonotonic. To understand their strain rate sensitivity, we conduct molecular dynamics simulations of metallic glasses undergoing uniaxial compression at finite strain rates and coupled to heat baths with a range of temperatures T0 and damping parameters b. In the T0→0 and b→0 limits, we find that the compressive strength σmax versus temperature T obeys a “chevron-shaped” scaling relation. In the low-strain-rate regime, σmax decreases linearly with increasing T, whereas σmax grows as a power law with decreasing T in the high-strain-rate regime. For T0>0, σmax(T) deviates from the scaling curve at low strain rates, but σmax(T) rejoins the scaling curve as the strain rate increases. Enhanced dissipation reduces compression-induced heating, which causes σmax(T) to deviate from the b→0 scaling behavior for intermediate strain rates, but σmax(T) converges to the high-strain-rate power-law scaling behavior at sufficiently high strain rates. Determining σmax(T) as a function of b and T0 provides a general framework for explaining the strain rate sensitivity of metallic glasses under compression.

关键词： Compressive strength Mechanical deformation Amorphous materials Metallic glasses Molecular dynamics

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piRNA-Independent Transposon Silencing by The Drosophila THO Complex

SSRN

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SSRN 2021年

作者： Zhang, Gen Yu, Tianxiong Parhad, Swapnil S. Ho, Samantha Weng, Zhiping Theurkauf, William E. Clinical Translational Research Center Program in Molecular Medicine Program in Bioinformatics and Integrative Biology University of Massachusetts Medical School 373 Plantation Street WorcesterMA01605 United States Department of Cell Biology Howard Hughes Medical Institute Harvard Medical School BostonMA02115 United States

piRNAs guide Piwi/Panoramix-dependent H3K9me3 chromatin modification and transposon silencing in the Drosophila germline. THO is a heteropenameric RNA export complex composed of Hpr1, Tho2, and Thoc5-7. Null thoc7 mutations displace Thoc5 and 6 from a Tho2-Hpr1 sub-complex, reduce expression of a subset ofgermline piRNAs, and increase steady state expression of a subset of transposon families, suggesting that THO silences transposons by promoting piRNA biogenesis. Here we show that thoc7 mutations increase transposon transcription, but do not reduce anti-sense piRNAs targeting half of the transcriptionally activated elements, disrupt piRNA-guided H3K9me3 chromatin modification, or block Panoramix-dependent silencing of a reporter transgene. In addition, unspliced transposon transcripts co-precipitate with THO through a Piwi- and Panoramix-independent mechanism, and piwi mutations dominantly enhance germline defects associated with thoc7 null alleles. We therefore propose that THO silences transposons through a piRNA-independent mechanism, which functions cooperatively with piRNAs to support germline development. © 2021, The Authors. All rights reserved.

关键词： Genes

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An efficient linear mixed model framework for meta-analytic Association studies across multiple contexts 21

An efficient linear mixed model framework for meta-analytic ...

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21st International Workshop on Algorithms in bioinformatics, WABI 2021

作者： Jew, Brandon Li, Jiajin Sankararaman, Sriram Sul, Jae Hoon Bioinformatics Interdepartmental Program University of California Los AngelesCA United States Department of Human Genetics University of California Los AngelesCA United States Department of Computer Science University of California Los AngelesCA United States Department of Computational Medicine University of California Los AngelesCA United States Department of Psychiatry and Biobehavioral Sciences University of California Los AngelesCA United States

ISBN: (纸本)9783959772006

Linear mixed models (LMMs) can be applied in the meta-analyses of responses from individuals across multiple contexts, increasing power to detect associations while accounting for confounding effects arising from within-individual variation. However, traditional approaches to fitting these models can be computationally intractable. Here, we describe an efficient and exact method for fitting a multiple-context linear mixed model. Whereas existing exact methods may be cubic in their time complexity with respect to the number of individuals, our approach for multiple-context LMMs (mcLMM) is linear. These improvements allow for large-scale analyses requiring computing time and memory magnitudes of order less than existing methods. As examples, we apply our approach to identify expression quantitative trait loci from large-scale gene expression data measured across multiple tissues as well as joint analyses of multiple phenotypes in genome-wide association studies at biobank scale. © Brandon Jew, Jiajin Li, Sriram Sankararaman, and Jae Hoon Sul;licensed under Creative Commons License CC-BY 4.0 21st International Workshop on Algorithms in bioinformatics (WABI 2021).

关键词： bioinformatics

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Local and global measures of the shear moduli of jammed disk packings

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Physical Review E 2023年第5期107卷 054903-054903页

作者： Shiyun Zhang Weiwei Jin Dong Wang Ding Xu Jerry Zhang Mark D. Shattuck Corey S. O'Hern Department of Physics University of Science and Technology of China Hefei Anhui 230026 China Department of Mechanical Engineering and Materials Science Yale University New Haven Connecticut 06520 USA Benjamin Levich Institute and Physics Department The City College of New York New York New York 10031 USA Department of Physics Yale University New Haven Connecticut 06520 USA Department of Applied Physics Yale University New Haven Connecticut 06520 USA Graduate Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut 06520 USA

Strain-controlled isotropic compression gives rise to jammed packings of repulsive, frictionless disks with either positive or negative global shear moduli. We carry out computational studies to understand the contributions of the negative shear moduli to the mechanical response of jammed disk packings. We first decompose the ensemble-averaged, global shear modulus as 〈G〉=(1−F−)〈G+〉+F−〈G−〉, where F− is the fraction of jammed packings with negative shear moduli and 〈G+〉 and 〈G−〉 are the average values from packings with positive and negative moduli, respectively. We show that 〈G+〉 and 〈|G−|〉 obey different power-law scaling relations above and below pN2∼1. For pN2>1, both 〈G+〉N and 〈|G−|〉N∼(pN2)β, where β∼0.5 for repulsive linear spring interactions. Despite this, 〈G〉N∼(pN2)β′ with β′≳0.5 due to the contributions from packings with negative shear moduli. We show further that the probability distribution of global shear moduli P(G) collapses at fixed pN2 and different values of p and N. We calculate analytically that P(G) is a Γ distribution in the pN2≪1 limit. As pN2 increases, the skewness of P(G) decreases and P(G) becomes a skew-normal distribution with negative skewness in the pN2≫1 limit. We also partition jammed disk packings into subsystems using Delaunay triangulation of the disk centers to calculate local shear moduli. We show that the local shear moduli defined from groups of adjacent triangles can be negative even when G>0. The spatial correlation function of local shear moduli C(r⃗) displays weak correlations for pnsub2<10−2, where nsub is the number of particles within each subsystem. However, C(r⃗) begins to develop long-ranged spatial correlations with fourfold angular symmetry for pnsub2≳10−2.

关键词： Jamming Packing & jamming problems Granular materials

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Retrieval-Augmented Generation for Generative Artificial Intelligence in Medicine

arXiv

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arXiv 2024年

作者： Yang, Rui Ning, Yilin Keppo, Emilia Liu, Mingxuan Hong, Chuan Bitterman, Danielle S. Ong, Jasmine Chiat Ling Ting, Daniel Shu Wei Liu, Nan Center for Quantitative Medicine Duke-NUS Medical School Singapore Singapore Faculty of Arts and Science University of Toronto TorontoON Canada Department of Biostatistics and Bioinformatics Duke University DurhamNC United States Artificial Intelligence in Medicine Program Mass General Brigham Harvard Medical School BostonMA United States Division of Pharmacy Singapore General Hospital Singapore Singapore Singapore Eye Research Institute Singapore National Eye Center Singapore Singapore Byers Eye Institute Stanford University StanfordCA United States Program in Health Services and Systems Research Duke-NUS Medical School Singapore Singapore Institute of Data Science National University of Singapore Singapore Singapore

Generative artificial intelligence (AI) has brought revolutionary innovations in various fields, including medicine. However, it also exhibits limitations. In response, retrieval-augmented generation (RAG) provides a potential solution, enabling models to generate more accurate contents by leveraging the retrieval of external knowledge. With the rapid advancement of generative AI, RAG can pave the way for connecting this transformative technology with medical applications and is expected to bring innovations in equity, reliability, and personalization to health care. © 2024, CC BY.

关键词： Medical applications

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A Path Analysis Model for Explaining Factors That Influence the Use of Masker among Commuting Workers Using KRL Commuter Line Bogor Jakarta

Research Square

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Research Square 2021年

作者： Kusmawan, David Andari, Shofi Indri Hapsari, S. Faculty Medicine and Health Science Universitas Jambi Indonesia Bioinformatics and Computational Biology Graduate Program Iowa State University United States Occupational Health and Safety Department Faculty of Public Health Universitas Indonesia Indonesia

Jakarta is one of the most air polluted cities in the world, it can increase the risk of healthy of commuting worker. As one of the most air polluted cities in the world, Jakarta is at high risk of its commuting worker’s health. They are at risk of being exposed to pollutant. This study aims to determine the factors influencing directly and indirectly to healthy behavior (using masker) for commuting workers who use the KRL Commuterline Bogor - Jakarta. A total of 155 respondents participated in the study and the collected data were then analyzed using descriptive and path analysis. Commuters are aware of the hazard potential related to air pollution during commuting were 137 people (88.4%). Commuters with good perception of pollution were 104 people (67.1%). Commuters used masker during commuting was 125 people (80.6%). Healthy behavior (using masker) in commuting worker using KRL Commuter Line were affected by some factors both directly and indirectly. Knowledge and commuting experience toward healthy behavior using masker were two variables with a significant direct influence on healthy behavior using masker, and knowledge was also the only mediated variable with a significant indirect effect of education to healthy behavior (using masker). © 2021, CC BY.

关键词： Pollution

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How Does ChatGPT Perform on the United States Medical Licensing Examination? The Implications of Large Language Models for Medical Education and Knowledge Assessment

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JMIR Medical Education 2023年 9卷 e45312页

作者： Gilson, Aidan Safranek, Conrad W. Huang, Thomas Socrates, Vimig Chi, Ling Taylor, Richard Andrew Chartash, David Section for Biomedical Informatics and Data Science Yale University School of Medicine New Haven CT United States Department of Emergency Medicine Yale University School of Medicine New Haven CT United States Program of Computational Biology and Bioinformatics Yale University New Haven CT United States School of Medicine University College Dublin National University of Ireland Dublin Ireland

Background: Chat Generative Pre-trained Transformer (ChatGPT) is a 175-billion-parameter natural language processing model that can generate conversation-style responses to user input. Objective: This study aimed to evaluate the performance of ChatGPT on questions within the scope of the United States Medical Licensing Examination Step 1 and Step 2 exams, as well as to analyze responses for user interpretability. Methods: We used 2 sets of multiple-choice questions to evaluate ChatGPT’s performance, each with questions pertaining to Step 1 and Step 2. The first set was derived from AMBOSS, a commonly used question bank for medical students, which also provides statistics on question difficulty and the performance on an exam relative to the user base. The second set was the National Board of Medical Examiners (NBME) free 120 questions. ChatGPT’s performance was compared to 2 other large language models, GPT-3 and InstructGPT. The text output of each ChatGPT response was evaluated across 3 qualitative metrics: logical justification of the answer selected, presence of information internal to the question, and presence of information external to the question. Results: Of the 4 data sets, AMBOSS-Step1, AMBOSS-Step2, NBME-Free-Step1, and NBME-Free-Step2, ChatGPT achieved accuracies of 44% (44/100), 42% (42/100), 64.4% (56/87), and 57.8% (59/102), respectively. ChatGPT outperformed InstructGPT by 8.15% on average across all data sets, and GPT-3 performed similarly to random chance. The model demonstrated a significant decrease in performance as question difficulty increased (P=.01) within the AMBOSS-Step1 data set. We found that logical justification for ChatGPT’s answer selection was present in 100% of outputs of the NBME data sets. Internal information to the question was present in 96.8% (183/189) of all questions. The presence of information external to the question was 44.5% and 27% lower for incorrect answers relative to correct answers on the NBME-Free-Step1 (P<.001

关键词： artificial intelligence chatbot ChatGPT conversational agent education technology generative pre-trained transformer GPT machine learning medical education MedQA natural language processing NLP

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A Human-Centered Design Approach to SOVTE Straw Phonation Instruction

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Journal of Voice 2023年

作者： Bhatt, Sandeep Scearce, Leda Frank-Ito, Dennis Nixon, Tara Umstead, Kelly A. Department of Industrial Design North Carolina State University Raleigh NC United States Department of Head and Neck Surgery & Communication Sciences Duke University School of Medicine Durham NC United States Computational Biology and Bioinformatics Program Duke University Durham NC United States Department of Mechanical Engineering and Materials Science Duke University Durham NC United States

Objectives: Extensive research has demonstrated that straw/tube phonation exercises produce positive effects on the voice quality of the user. The purpose of this study was to explore pedagogical practices employed by a range of voice professionals when using SOVTEs by applying human-centered design approaches to examine workflow and communication between teachers and students. Method/Design: The researchers conducted a series of five participatory role-playing workshop activities at a multi-disciplinary vocology conference that included speech-language pathologists, voice scientists, physicians, singing teachers, acting voice teachers, choral directors, and singers. Volunteers were asked to assume the role of teaching or learning straw phonation exercises. The other participants from each workshop were asked to provide written and verbal feedback regarding the teacher/student dynamics and what they found most important and relevant in terms of best practices for SOVTEs. Expert evaluators subsequently provided similar feedback based on video recordings of the workshops. Results: While there was variability noted in teaching techniques and results, common themes emerged in the analysis. Successful and unsuccessful student and teacher techniques were identified by the workshop participants. Through the video analysis, the research team identified themes in instructional teaching, experiential learning, and straw articulation and mechanics. Conclusions: The benefits of straw/tube phonation exercises on voice quality have been well-established and are clear. As we continue to refine best practices in SOVTEs and, in particular, straw phonation, involvement of experts in HCD as part of multidisciplinary teams may lead to the eventual design of SOVTE tools that provide greater precision, consistency, and effectiveness both in clinical and pedagogical settings, and aid in the differentiation of SOVTE approaches within the taxonomy of vocal habilitation and rehabilitation te

关键词： Voice disorder Voice habilitation Voice pedagogy Voice rehabilitation Voice therapy Voice training

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