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Integrated Single-cell multiomic Analysis of HIV Latency reversal reveals Novel regulators of Viral reactivation

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Genomics, Proteomics & Bioinformatics 2024年第1期22卷 67-88页

作者： manickam Ashokkumar Wenwen mei jackson j.Peterson Yuriko Harigaya David m.murdoch David m.margolis Caleb Kornfein Alex Oesterling Zhicheng Guo Cynthia D.rudin Yuchao jiang Edward P.Browne Department of medicine University of North Carolina at Chapel HillChapel HillNC 27599USA HIV Cure Center University of North Carolina at Chapel HillChapel HillNC 27599USA Department of Biostatistics University of North Carolina at Chapel HillChapel HillNC 27599USA Department of microbiology and Immunology University of North Carolina at Chapel HillChapel HillNC 27599USA Department of Genetics University of North Carolina at Chapel HillChapel HillNC 27599USA Department of medicine Duke UniversityDurhamNC 27708USA Department of Computer Science Duke UniversityDurhamNC 27708USA Department of Statistics Texas A&M UniversityCollege StationTX 77843USA Department of Biology Texas A&M UniversityCollege StationTX 77843USA Department of Biomedical Engineering Texas A&M UniversityCollege StationTX 77843USA

Despite the success of antiretroviral therapy,human immunodeficiency virus(HIV)cannot be cured because of a reservoir of latently infected cells that evades *** understand the mechanisms of HIV latency,we employed an integrated single-cell rNA sequencing(scrNA-seq)and single-cell assay for transposase-accessible chromatin with sequencing(scATAC-seq)approach to simultaneously profile the transcriptomic and epigenomic characteristics of~125,000 latently infected primary CD4^(+)T cells after reactivation using three different latency reversing *** expressed genes and differentially accessible motifs were used to examine transcriptional pathways and transcription factor(TF)activities across the cell *** identified cellular transcripts and TFs whose expression/activity was correlated with viral reactivation and demonstrated that a machine learning model trained on these data was 75%-79%accurate at predicting viral ***,we validated the role of two candidate HIV-regulating factors,FOXP1 and GATA3,in viral *** data demonstrate the power of integrated multimodal single-cell analysis to uncover novel relationships between host cell factors and HIV latency.

关键词： HIV latency reversal Primary CD4þT cell Single-cell multiomics HIV-regulating factor machine learning

The NOrE1A/rASSF5 Tumor Suppressor Forms a Complex with GSK-3β to regulate β-Catenin

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journal of Biosciences and medicines 2024年第8期12卷 60-75页

作者： m. Lee Schmidt Howard Donninger Geoffrey j. Clark Department Pharmacology and Toxicology University of Louisville Louisville USA US Worldmeds LouisvilleUSA Department of medicine University of Louisville Louisville USA Experimental Therapeutics Program James Graham Brown Cancer Center University of Louisville Louisville USA

NOrE1A (rASSF5) is a tumor suppressor of the rASSF family that is often down-regulated in human tumors. NOrE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin by binding and modulating the ubiquitin ligase substrate recognition factor β-TrCP. β-catenin is a m.j.r.executor of the Wnt pathway. The ubiquitin SCF-β-TrCP ligase complex acts on a phospho-degron site in β-catenin that can be phosphorylated by GSK-3β. We now show that in addition to binding β-TrCP, NOrE1A also promotes the phosphorylation of the β-catenin phospho-degron by complexing with the kinase GSK-3β. Indeed, NOrE1A enhances the formation of a GSK-3β/β-TrCP complex. A structural mutant of NOrE1A that retains β-TrCP binding but will no longer interact with GSK-3β inhibits the β-catenin degrading action of NOrE1A. The GSK-3β interaction with NOrE1A plays an important role in the biology of NOrE1A as a GSK-3β inhibitor blocks NOrE1A induced senescence. Thus, we identify a new role for the tumor suppressor NOrE1A: The regulation of GSK-3β. GSK-3β has many other substrates including multiple transcription factors and co-activators such as p53 and the Hippo component TAZ. The work implies that NOrE1A may be able to influence all of them via this new kinase scaffolding interaction.

关键词： rAS NOrE1A rASSF5 GSK-3β Beta Catenin HIPPO

Advances in magnesium-containing bioceramics for bone repair

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Biomaterials Translational 2024年第1期5卷 3-20页

作者： Qi L. Zhao T. Yan j. Ge W. jiang W. Wang j. Gholipourmalekabadi m. Lin K. Wang X. Zhang L. Department of Oral and Cranio-maxillofacial Surgery Shanghai Ninth People’s Hospital College of Stomatology Shanghai Jiao Tong University School of Medicine National Clinical Research Center for Oral Diseases Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology Shanghai China Department’s Education Deputy Department of Medical Biotechnology Iran University of Medical Sciences Tehran Iran Institute of Translational medicine Shanghai University Organoid Research Center Shanghai University Shanghai China

reconstruction of bone defects or fractures caused by ageing, trauma and tumour resection is still a great challenge in clinical treatment. Although autologous bone graft is considered as gold standard, the source of natural bone is limited. In recent years, regenerative therapy based on bioactive materials has been proposed for bone reconstruction. Specially, numerous studies have indicated that bioactive ceramics including silicate and phosphate bioceramics exhibit excellent osteoinductivity and osteoconductivity, further promote bone regeneration. In addition, magnesium (mg) element, as an indispensable mineral element, plays a vital role in promoting bone mineralisation and formation. In this review, different types of mg-containing bioceramics including mg-containing calcium phosphate-based bioceramics (such as mg-hydroxyapatite, mg-biphasic calcium phosphate), mg-containing calcium silicate-based bioceramics (such as mg2SiO4, Ca2mgSi2O7and mg-doped bioglass), mg-based biocements, mg-containing metal/polymer-bioceramic composites were systematacially summarised. Additionally, the fabrication technologies and their materiobiological effects were deeply discussed, Clinical applications and perspectives of magnesium-containing bioceramics for bone repair are highlighted. Overall, mg-containing bioceramics are regarded as regenerative therapy with their optimised performance. Furthermore, more in-depth two-way researches on their performance and structure are essential to satisfy their clinical needs. © 2024, Chinese medical multimedia Press Co Ltd. All rights reserved.

关键词： bioactive ions bioceramics bone repair magnesium osteoconductivity

Association of initial assessment variables and mortality in severe pediatric traumatic brain injury

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World journal of Pediatric Surgery 2024年第2期7卷 125-133页

作者： Katherine C Bergus Kelli N Patterson Lindsey Asti josh Bricker Tariku j Beyene Lauren N Schulz Dana m Schwartz rajan K Thakkar Eric A Sribnick Pediatric Surgery Nationwide Children's HospitalColumbusOhioUSA CenterforSurgical Outcomes research Nationwide Children's HospitalColumbusOhioUSA Neurologic Surgery The Ohio State UniversityColumbusOhioUSA Neurologic Surgery Nationwide Children's HospitalColumbusOhioUSA

Background Predictive scales have been used to prognosticate long-term outcomes of traumatic brain injury(TBI),but gaps remain in predicting mortality using initial trauma resuscitation *** sought to evaluate the association of clinical variables collected during the initial resuscitation of intubated pediatric severe patients with TBI with in-hospital *** Intubated pediatric trauma patientsrs with severe TBI(Glasgow coma scale(GCS)score≤8)from january 2011 to December 2020 were *** between initial trauma resuscitation variables(temperature,pulse,mean arterial blood pressure,GCS score,hemoglobin,international normalized ratio(INr),platelet count,oxygen saturation,end tidal carbon dioxide,blood glucose and pupillary response)and mortality were evaluated with multivariable logistic *** Among 314 patients,median age was 5.5 years(interquartile range(IQr):2.2-12.8),GCS score was 3(IQr:3-6),Head Abbreviated Injury Score(hAIS)was 4(IQr:3-5),and most had a severe(25-49)Injury Severity Score(ISS)(48.7%,153/314).Overall mortality was 26.8%.GCS score,hAIS,ISS,INr,platelet count,and blood glucose were associated with in-hospital mortality(all pre increased,the odds of mortality *** 1-point increase in GCS score was associated with a 35%decrease in odds of *** hAIS,INr,and blood glucose increased,the odds of mortality *** each 1.0 unit increase in INr,the odds of mortality increased by 1427%.Conclusions Pediatric patients with severe TBI are at substantial risk for in-hospital *** are needed to examine whether earlier interventions targeting specific parameters of INr and blood glucose impact mortality.

关键词： mortality pediatric traumatic

A multi-shot target wheel assembly for high-repetition-rate, laser-driven proton acceleration

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High Power Laser Science and Engineering 2024年第02期 91-98页

作者： j.Pe?as A.Bembibre D.Cortina-Gil L.martín A.reija C.ruiz m.Seimetz A.Alejo j.Benlliure Instituto Galego de Física de Altas Enerxías Universidade de Santiago de Compostela Laboratorio Láser de Aceleración y Aplicaciones RIAIDT Universidade de Santiago de Compostela Instituto Universitario de Física Fundamental y matemáticas y Dpto.de Didáctica de la matemática y de las Ciencias Experimentales Universidad de Salamanca Instituto de Instrumentación para Imagen molecular (I3m) CSIC-Universitat Politècnica de València

A multi-shot target assembly and automatic alignment procedure for laser–plasma proton acceleration at high repetition rate are introduced. The assembly is based on a multi-target rotating wheel capable of hosting more than 5000 targets,mounted on a 3D motorized stage to allow rapid replenishment and alignment of the target material between laser irradiations. The automatic alignment procedure consists of a detailed mapping of the impact positions at the target surface prior to the irradiation that ensures stable operation of the target, which alongside the purpose-built design of the target wheel, enables operation at rates up to 10 Hz. Stable and continuous laser-driven proton acceleration at 10 Hz is demonstrated, with observed cut-off energy stability about 15%.

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Physiological phenotypes differ among color morphs in introduced common wall lizards(Podarcis muralis)

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Integrative Zoology 2024年第3期19卷 505-523页

作者： Ali AmEr Sierra SPEArS Princeton L.VAUGHN Cece COLWELL Ethan H.LIVINGSTON Wyatt mCQUEEN Anna SCHILL Dustin G.rEICHArD Eric j.GANGLOFF Kinsey m.BrOCK Department of Biological Sciences Ohio Wesleyan UniversityDelawareOhioUSA Department of Ecology and Evolutionary Biology Princeton UniversityPrincetonNew JerseyUSA Department of Biology Idaho State UniversityPocatelloIdahoUSA Department of Environmental Science Policyand ManagementCollege of Natural ResourcesUniversity of CaliforniaBerkeleyUSA museum of Vertebrate Zoology University of CaliforniaBerkeleyUSA

many species exhibit color polymorphisms which have distinct physiological and behavioral ***,the consistency of morph trait covariation patterns across species,time,and ecological contexts remains *** trait covariation is especially relevant in the context of invasion biology and urban ***,physiological traits pertaining to energy maintenance are crucial to fitness,given their immediate ties to individual reproduction,growth,and population *** investigated the physiological traits of Podarcis muralis,a versatile color polymorphic species that thrives in urban environments(including invasive populations in Ohio,USA).We measured five physiological traits(plasma corticosterone and triglycerides,hematocrit,body condition,and field body temperature),which compose an integrated multivariate *** then tested variation among co-occurring color morphs in the context of establishment in an urban *** found that the traits describing physiological status and strategy shifted across the active season in a morph-dependent manner—the white and yellow morphs exhibited clearly different multivariate physiological phenotypes,characterized primarily by differences in plasma *** suggests that morphs have different strategies in physiological regulation,the flexibility of which is crucial to urban *** white-yellow morph exhibited an intermediate phenotype,suggesting an intermediary energy maintenance *** morphs also exhibited distinct phenotypes,but the low prevalence of this morph in our study populations precludes clear *** work provides insight into how differences among stable polymorphisms exist across axes of the phenotype and how this variation may aid in establishment within novel environments.

关键词： color polymorphism physiological status seasonal variation thermoregulation urban habitat

A multi-shot target wheel assembly for high-repetition-rate, laser-driven proton acceleration

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High Power Laser Science and Engineering 2024年第2期12卷 87-94页

作者： j.Penas A.Bembibre D.Cortina-Gil L.martin A.reija C.ruiz m.Seimetz A.Alejo j.Benlliure Instituto Galego de Fisica de Altas Enerxias Universidade de Santiago de CompostelaSantiago de CompostelaSpain Laboratorio Laser de Aceleracion y Aplicaciones RIAIDTUniversidade de Santiago de CompostelaSantiago de CompostelaSpain Instituto Universitario de Física Fundamental y matematicas y Dpto.de Didactica de la matematica y de las Ciencias Experimentales Universidad de SalamancaSalamancaSpain Instituto de Instrumentación para Imagen molecular(I3m) CSIC-Universitat Politecnica de ValenciaValenciaSpain

A multi-shot target assembly and automatic alignment procedure for laser–plasma proton acceleration at high repetition rate are *** assembly is based on a multi-target rotating wheel capable of hosting more than 5000 targets,mounted on a 3D motorized stage to allow rapid replenishment and alignment of the target material between laser *** automatic alignment procedure consists of a detailed mapping of the impact positions at the target surface prior to the irradiation that ensures stable operation of the target,which alongside the purpose-built design of the target wheel,enables operation at rates up to 10 *** and continuous laser-driven proton acceleration at 10 Hz is demonstrated,with observed cut-off energy stability about 15%.

关键词： high repetition rate laser-plasma acceleration multi-shot operation proton source target assembly

Inflammatory myofibroblastic tumor from molecular diagnostics to current treatment

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Oncology research 2024年第7期32卷 1141-1162页

作者： PAULINA CHmIEL ALEKSANDrA SŁOWIKOWSKA ŁUKASZ BANASZEK ANNA SZUmErA-CIEĆKIEWICZ BArTŁOmIEj SZOSTAKOWSKI mATEUSZ j.SPAŁEK TOmASZŚWITAj PIOTr rUTKOWSKI ANNA m.CZArNECKA Department of Soft Tissue/Bone Sarcoma and melanoma Maria Sklodowska-Curie National Research Institute of OncologyWarsaw02-781Poland Faculty of medicine Medical University of WarsawWarsaw02-091Poland Department of Pathology Maria Sklodowska Curie National Research Institute of OncologyWarsaw02-781Poland Department of radiotherapy Maria Sklodowska-Curie National Research Institute of OncologyWarsaw02-781Poland

Inﬂammatory myoﬁbroblastic tumor(ImT)is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic *** challenges arise from the diverse pathological presentation,variable symptomatology,and lack of different imaging ***,ImT is identiﬁed by the fusion of the anaplastic lymphoma kinase(ALK)gene,which is present in approximately 70%of cases,with various fusion partners,including ran-binding protein 2(rANBP2),which allows conﬁrmation of the *** surgery is the preferred approach for localized tumors,the optimal long-term treatment for advanced or metastatic disease is difﬁcult to deﬁ*** therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in ***,an ALK tyrosine kinase inhibitor(TKI),was ofﬁcially approved by the US Food and Drug Administration(FDA)in 2020 to treat ImT with ALK ***,most patients face resistance and disease progression,requiring consideration of sequential *** radiotherapy with targeted therapy appears to be beneﬁcial in this *** promising results have also been achieved with immunotherapy,indicating potential for combined therapy ***,deﬁned recommendations are still *** review analyzes the available research on ImT,including genetic disorders and their impact on the course of the disease,data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication,as well as summarizing general knowledge about prognostic and predictive factors,also in terms of resistance to systemic therapy.

关键词： Inﬂammatory myoﬁbroblastic tumor(ImT) Epithelioid inﬂammatory myoﬁbroblastic sarcoma Tyrosine kinase inhibitors(TKI) Anaplastic lymphoma kinase(ALK)

辣椒素治疗神经病理性疼痛:4周后轴突反射血管舒张与疼痛减轻相关

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中国疼痛医学杂志 2024年第4期30卷 251-254页

作者： Sendel m Dunst A Forsten pointer j 贺婷(译) 郑拥军(校) 不详复旦大学附属华东医院

辣椒素是瞬时受体电位香草酸亚型1(transient receptor potential vanilloid 1,TrPV1)的激动剂,用于外周神经病理性疼痛的局部治疗。其作用机制是皮肤痛觉感受器可逆的去功能化和变性及随后的再生。该研究假设伤害性传入的一个亚类,肽... 详细信息

辣椒素是瞬时受体电位香草酸亚型1(transient receptor potential vanilloid 1,TrPV1)的激动剂,用于外周神经病理性疼痛的局部治疗。其作用机制是皮肤痛觉感受器可逆的去功能化和变性及随后的再生。该研究假设伤害性传入的一个亚类,肽能血管活性伤害感受器的功能加速恢复是辣椒素镇痛的潜在原因。在非干预性探索性试验中,23名患有外周神经病理性疼痛的病人接受了1次局部高浓度辣椒素治疗。评估基线疼痛等级、共病和生活质量。在受影响的皮肤中进行功能性激光散斑对比分析(热诱发神经源性血管舒张以评估肽能伤害感受器的功能特性)和定量感觉测试。治疗4周后,再次进行功能性激光散斑对比分析和问卷调查。在第2、10和12周进行电话随访。局部辣椒素治疗诱导疼痛强度显著降低,最大值出现在第4周。同时,热诱发的神经源性血管舒张平均值与治疗前相似。一半的病人不仅显示出功能恢复,而且显示出血管舒张的改善,表明神经纤维的再生。在第4周,热诱发的神经源性血管扩张改善病人比恶化的病人疼痛减轻更多。血管舒张程度与疼痛减轻显著相关。表明肽能感受器的再生可能是辣椒素诱导镇痛的机制,辣椒素对这些纤维的疾病缓解作用在应用4周后已经发生。

关键词：伤害感受器痛觉感受器疼痛减轻血管舒张辣椒素神经病理性疼痛激光散斑血管扩张