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Machine learning-guided accelerated discovery of structure-property correlations in lean magnesium alloys for biomedical applications

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Journal of Magnesium and Alloys 2024年第6期12卷 2267-2283页

作者： Sreenivas Raguraman Maitreyee Sharma Priyadarshini Tram Nguyen Ryan McGovern Andrew Kim Adam J.Griebel Paulette Clancy Timothy P.Weihs Department of Materials Science and Engineering Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A hopkins Extreme Materials institute Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A Department of Chemical and Biomolecular Engineering Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A Translational Tissue Engineering Center Johns Hopkins School of Medicine400 N BroadwayBaltimore21231MDU.S.A Department of Biomedical Engineering Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A Research and Development Fort Wayne Metals Research ProductsLLC9609 Ardmore AveFort Wayne46809INU.S.A Department of Mechanical Engineering Johns Hopkins University3400 N Charles StBaltimore21218MDU.S.A

Magnesium alloys are emerging as promising alternatives to traditional orthopedic implant materials thanks to their biodegradability,biocompatibility,and impressive mechanical ***,their rapid in-vivo degradation presents challenges,notably in upholding mechanical integrity over *** study investigates the impact of high-temperature thermal processing on the mechanical and degradation attributes of a lean Mg-Zn-Ca-Mn alloy,*** rapid,cost-efficient characterization methods like X-ray diffraction and optical microscopy,we swiftly examine microstructural changes post-thermal *** Pearson correlation coefficient analysis,we unveil the relationship between microstructural properties and critical targets(properties):hardness and corrosion ***,leveraging the least absolute shrinkage and selection operator(LASSO),we pinpoint the dominant microstructural factors among closely correlated *** findings underscore the significant role of grain size refinement in strengthening and the predominance of the ternary Ca_(2)Mg_(6)Zn_(3)phase in corrosion *** suggests that achieving an optimal blend of strength and corrosion resistance is attainable through fine grains and reduced concentration of ternary *** thorough investigation furnishes valuable insights into the intricate interplay of processing,structure,and properties in magnesium alloys,thereby advancing the development of superior biodegradable implant materials.

关键词： Magnesium alloys Machine learning Corrosion Mechanical properties Rapid characterization

Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain

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Bone Research 2024年第1期12卷 107-121页

作者： Feng Gao Qimiao Hu Wenwei Chen Jilong Li Cheng Qi Yiwen Yan Cheng Qian Mei Wan James Ficke Junying Zheng Xu Cao Department of Orthopedic Surgery Johns Hopkins University School of MedicineBaltimoreMaryland 21205USA Department of Biomedical Engineering Johns Hopkins University School of MedicineBaltimoreMaryland 21205USA

Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading ***,it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the *** this study,we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2(PGE2)concentration in response to mechanical *** PGE2 levels are in proportion to their weight *** weight bearing changes in the tail-suspension mice,the PGE2 concentrations in bones change in line with their weight bearing *** of cyclooxygenase-2(COX2)in the osteoblast lineage cells or knockout of receptor 4(EP4)in sensory nerve blunts bone formation in response to mechanical ***,knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone ***,mechanical loading induces cAMP-response element binding protein(CREB)phosphorylation in the hypothalamic arcuate nucleus(ARC)to inhibit sympathetic tyrosine hydroxylase(TH)expression in the paraventricular nucleus(PVN)for ***,we show that elevated PGE2 is associated with ankle osteoarthritis(AOA)and ***,our data demonstrate that in response to mechanical loading,skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis,while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.

关键词： pain elevated PGE2

Mechanism of Cu entry into the brain:many unanswered questions

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Neural Regeneration Research 2024年第11期19卷 2421-2429页

作者： Shubhrajit Roy Svetlana Lutsenko Department of Physiology Johns Hopkins University School of MedicineBaltimoreMDUSA

Brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical *** requirements for Cu in the brain vary depending on specific brain regions,cell types,organism age,and nutritional *** imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease,Wilson disease,Alzheimer’s disease,Parkinson’s disease,and *** the well-established role of Cu homeostasis in brain development and function,the mechanisms that govern Cu delivery to the brain are not well *** review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.

关键词： ATOX1 ATP7A ATP7B blood-brain barrier brain choroid plexus copper SLC31A1

Promising use of metformin in treating neurological disorders:biomarker-guided therapies

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Neural Regeneration Research 2024年第5期19卷 1045-1055页

作者： Allison Loan Charvi Syal Margarita Lui Ling He Jing Wang Regenerative Medicine Program Ottawa Hospital Research InstituteOttawaONCanada Department of Biology Faculty of ScienceUniversity of OttawaOttawaONCanada Department of Pediatrics and Medicine Johns Hopkins Medical SchoolBaltimoreMDUSA Department of Cellular and Molecular Medicine Faculty of MedicineUniversity of OttawaOttawaONCanada University of Ottawa Brain and Mind Research institute OttawaONCanada

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available *** most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy ***,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological *** that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological *** molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted *** this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

关键词： Alzheimer’s disease Huntington’s disease metformin mitochondrial perturbation multiple sclerosis neural degenerative diseases Parkinson’s disease stroke targeted therapy

Compartmentalized regulation of organelle integrity in neurodegenerative diseases:lessons from the Drosophila motor neuron

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Neural Regeneration Research 2025年第1期20卷 195-196页

作者： Hyun Sung Department of Neurology Johns Hopkins University School of MedicineBaltimoreMDUSA medical Research institute and Department of PharmacologyPusan National University School of MedicineYangsanRepublic of Korea

Neurons are highly polarized,morphologically asymmetric,and functionally compartmentalized cells that contain long axons extending from the cell *** this reason,their maintenance relies on spatiotemporal regulation of organelle distribution between the somatodendritic and axonal *** some organelles,such as mitochondria and smooth endoplasmic reticulum,are widely distributed throughout the neuron,others are segregated to either the somatodendritic or axonal *** example,Golgi outposts and acidified lysosomes are predominantly present in the somatodendritic domain and rarely distributed along the axon,whereas newly formed autophagosomes and synaptic vesicles are mainly distributed in the distal axon(Britt et al.,2016).

关键词： organelle regulation distribution

How Does ESG Performance Impact Corporate Financing Costs?An Empirical Study in China

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Journal of Systems Science and Information 2024年第2期12卷 229-244页

作者： Wei LI Mei MEI Xiaoyan YU Jiahao WANG Tiangeng (Becky) GENG School of Economics and Management University of Chinese Academy of SciencesBeijing 100190China institute of medical Information&Library Chinese Academy of Medical SciencesBeijing 100005China Business and Management Royal HollowayUniversity of LondonSurrey TW200EXUK Krieger School of Arts and Sciences Johns Hopkins UniversityBaltimore MD 21218USA

In the background of the green transformation of the economy and society,the ESG performance of enterprises has been paid more and more attention in the investment ***,previous studies have inadequately explored how the ESG performance affects corporate financing *** on the information asymmetry theory,this paper analyzes the impact mechanism of ESG performance on corporate financing ***,taking 1044 A-share listed companies in2016–2020 as a sample,through the sorting and analysis of ESG report disclosure and rating data,the company’s ESG performance indicators are obtained,and an empirical model is built to test the relationship between ESG performance and corporate financing *** paper constructs a panel regression model using ESG rating data and corporate financial data and finds that in the overall sample,the higher the ESG performance,the lower the equity financing cost;The higher the ESG performance,the lower the debt financing *** addition,it also discussed the moderating effect of enterprise scale and media attention on the impact of ESG performance on enterprise financing *** empirical results show that the influence of company size on ESG performance on financing costs has a moderating effect and a positive moderating effect.

关键词： ESG performance financing cost corporate heterogeneity media attention

An Asynchronous Variational Integrator for Contact Problems Involving Elastoplastic Solids

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Acta Mechanica Solida Sinica 2024年第2期37卷 305-315页

作者： Zongwu Niu Zixiao Wang Yongxing Shen University of Michigan-Shanghai Jiao Tong University Joint institute Shanghai Jiao Tong UniversityShanghai200240China School of Agriculture and Biology Shanghai Jiao Tong UniversityShanghai200240China Department of Biostatistics Johns Hopkins Bloomberg School of Public HealthBaltimoreMaryland21205USA

Simulations of contact problems involving at least one plastic solid may be costly due to their strong nonlinearity and requirements of *** this work,we develop an explicit asynchronous variational integrator(AVI)for inelastic non-frictional contact problems involving a plastic *** AVI assigns each element in the mesh an independent time step and updates the solution at the elements and nodes *** asynchrony makes the AVI highly efficient in solving such bi-material *** advantage of the AVI,the constitutive update is locally performed in one element at a time,and contact constraints are also enforced on only one *** time step of the contact element is subdivided into multiple segments,and the fields are updated *** a contact event,only one element involving a few degrees of freedom is considered,leading to high *** proposed formulation is first verified with a pure elastodynamics benchmark and further applied to a contact problem involving an elastoplastic solid with non-associative volumetric *** numerical results indicate that the AVI exhibits excellent energy behaviors and has high computational efficiency.

关键词： Asynchronous variational integrator Plasticity Contact Computational efficiency Finite element method

Drug repurposing for cancer therapy

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1981-2013页

作者： Ying Xia Ming Sun Hai Huang Wei-Lin Jin Center for Clinical Laboratories The Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004PR China The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine Guiyang 550001PR China School of Clinical Laboratory Science Guizhou Medical UniversityGuiyang 550004PR China Division of Gastroenterology and Hepatology Department of Medicine andDepartment of OncologySidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21287USA institute of Cancer Neuroscience Medical Frontier Innovation Research CenterThe First Hospital of Lanzhou UniversityThe First Clinical Medical College of Lanzhou UniversityLanzhou 730000PR China

Cancer,a complex and multifactorial disease,presents a significant challenge to global *** significant advances in surgical,radiotherapeutic and immunological approaches,which have improved cancer treatment outcomes,drug therapy continues to serve as a key therapeutic ***,the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects,and thus there remains a critical need to develop novel cancer *** promising strategy that has received widespread attention in recent years is drug repurposing:the identification of new applications for existing,clinically approved *** repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective,proven to be safe,and can significantly expedite the drug development process due to their already established safety *** light of this,the present review offers a comprehensive overview of the various methods employed in drug repurposing,specifically focusing on the repurposing of drugs to treat *** describe the antitumor properties of candidate drugs,and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor *** addition,we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug *** also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy *** conclude,we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

关键词： drugs integrating spite

RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone Research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit Kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal Disorders and Mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on Membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA Metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established *** evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment *** this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical *** analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL *** sequencing of human and mouse tissue supported these *** interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on *** results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within *** findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding