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The RNA helicase DHX15 is a critical regulator of natural killer-cell homeostasis and functions

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Cellular & molecular Immunology 2022年第6期19卷 687-701页

作者： Guangchuan Wang Xiang Xiao Yixuan Wang Xiufeng Chu Yaling Dou Laurie J.minze rafik.m.ghobrial Zhiqiang Zhang Xian C.Li Immunobiology and Transplant Science Center and Department of Surgery Houston Methodist HospitalTexas Medical CenterHoustonTXUSA Department of Surgery Weill Cornell Medical College of Cornell UniversityNew YorkNYUSA

The RNA helicase DHX15 is widely expressed in immune cells and traditionally thought to be an RNA splicing factor or a viral RNA ***,the role of DHX15 in NK-cell activities has not been studied thus ***,we generated Dhx15-floxed mice and found that conditional deletion of Dhx15 in NK cells(Ncr1CreDhx15fl/fl mice)resulted in a marked reduction in NK cells in the periphery and that the remaining Dhx15-deleted NK cells failed to acquire a mature *** a result,Dhx15-deleted NK cells exhibited profound defects in their cytolytic *** also found that deletion of Dhx15 in NK cells abrogated their responsiveness to IL-15,which was associated with inhibition of IL-2/IL-15Rβ(CD122)expression and IL-15R *** defects in Dhx15-deleted NK cells were rescued by ectopic expression of a constitutively active form of ***,DHX15 did not affect CD122 mRNA splicing and stability in NK cells but instead facilitated the surface expression of CD122,likely through interaction with its 3′UTR,which was dependent on the ATPase domain of DHX15 rather than its splicing ***,our data identify a key role for DHX15 in regulating NK-cell activities and provide novel mechanistic insights into how DHX15 regulates the IL-15 signaling pathway in NK cells.

关键词： DEAH-box helicase 15(DHX15) Innate immunity Natural killer(NK)cells Homeostasis IL-15 signaling pathway

molecular and cellular pathways involved in the therapeutic functions of mHC molecules;a novel approach for mitigation of chronic rejection

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Open Journal of Immunology 2011年第2期1卷 15-26页

作者： Thomas S. Skelton malgorzata Kloc rafik.m. ghobrial 不详

The mutated major histocompatibility complex (mHC) class I that contains donor-type epitopes displayed on recipient-type molecule was show- n to inhibit acute and chronic rejection and in-duce indefinite survival of heterotopic cardiac allografts when administered in combination with a sub-therapeutic dose of cyclosporine (CsA) in a rat transplantation model. To eluci-date the molecular pathways involved in the immunosuppressive effects of the mutated mHC molecule, we analyzedgene and protein expres-sion profile during early and late phase follow-ing post-transplantation. Cytoskeletal structure analysis and expression status of Rho GTPase proteins, vacuolar transport and cytoskeleton regulatory pathways involved in immune re-sponse in T and dendritic cells demonstrated the novel mechanism for the abrogation of chronic rejection. Our studies confirm a new role of Rho GTPase pathway in the modification of T cell motility and infiltration of the graft. We discuss these results within the framework of the most recent literature on mHC and molecu-lar machinery controlling T cell functions and dendritic cell antigen presentation.

关键词： mHC Transplantation Allograft Chronic Rejection Rat

Research in spinal surgery: Evaluation and practice of evidence-based medicine

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World Journal of Orthopedics 2014年第2期5卷 89-93页

作者： mark E Oppenlander Christopher m maulucci George m ghobrial James S Harrop Department of Neurological Surgery Thomas Jefferson University Hospital Philadelphia PA19107 United States Division of Neurological Surgery Barrow Neurological Institute St. Joseph Hospital and Medical CenterPhoenix AZ 85003 United States

Evidence-based medicine(EBm) is a common concept among medical practitioners, yet unique challenges arise when EBm is applied to spinal surgery. Due to the relative rarity of certain spinal disorders, and a lack of management equipoise, randomized controlled trials may be difficult to execute. Despite this, responsibility rests with spinal surgeons to design high quality studies in order to justify certain treatment modalities. The authors therefore review the tenets of implementing evidencebased research, through the lens of spinal disorders. The process of EBm begins with asking the correct *** appropriate study is then designed based on the research question. Understanding study designs allows the spinal surgeon to assess the level of evidence *** outcome measurements allow clinicians to communicate the success of treatment strategies, and will increase the quality of a given study design. Importantly,one must recognize that the randomized controlled trial is not always the optimal study design for a given research question. Rather, prospective observational cohort studies may be more appropriate in certain circumstances, and would provide superior generalizability. Despite the challenges involved with EBm, it is the future of medicine. These issues surrounding EBm are important for spinal surgeons, as well as health policy makers and editorial boards, to have familiarity.

关键词： Evidence-based medicine Spinal surgery Trial design Research methodology

Rock1 Inhibitor Abrogates Chronic Rejection in Rat Cardiac model System

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Open Journal of Organ Transplant Surgery 2012年第4期2卷 46-51页

作者： Li Zhang malgorzata Kloc Neelam Tejpal Junping You Andrea m. Cordero-Reyes Keith A. Youker rafik.m. ghobrial Department of Surgery The Methodist Hospital The methodist DeBakey Heart & Vascular Center Houston TX USA

Background: We have shown previously that the abrogation of acute and chronic rejection of rat cardiac allografts occurs through the down-regulation of RhoA pathway and involves the changes in RhoA kinase (ROCK)-dependent actin cytoskeleton and T cell motility. Here we studied the ability of the Y-27632, a highly selective inhibitor of Rho-associated protein kinase p160ROCK (ROCK1), to abrogate chronic rejection of the allograft and influence T cell infiltration. methods: Heterotopic cardiac transplants were performed between donor Wistar Furth (WF) and ACI recipient rats. Controls received sub-therapeutic dose of cyclosporine (CsA, 10 mg/kg) for 3 days or 7 days therapeutic dose of cyclosporine. The experimental groups of ACI recipient received one preoperative dose of the Y-27632 inhibitor (2 mg/kg, gavage feed) in conjunction with the sub-therapeutic dose of CsA for 3 days or inhibitor alone for 7 days. The cardiac grafts were harvested at 100 days of post-transplantation for histological and immunohistochemical assessment of chronic rejection, vascular sclerosis, and infiltration by different T cell subtypes. Results: Cardiac allografts from recipients exposed to Y-27632 inhibitor in conjunction with sub-therapeutic dose of CsA showed drastically reduced vascular sclerosis, minimal myocardial total cellular infiltration, and were selectively infiltrated with Foxp3+ T regulatory (Treg) cells. Conclusions: Our novel finding that a single dose of the ROCK1 inhibitor Y-27632 attenuates chronic rejection in rat cardiac model system by promoting development of Treg cells warrants its potential as a novel therapeutic agent specific for the inhibition of chronic rejection.

关键词： Chronic Rejection Transplantation ROCK1 RhoA T Cell

Correlation between rpoB gene mutation in mycobacterium avium subspecies paratuberculosis and clinical rifabutin and rifampicin resistance for treatment of Crohn’s disease

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World Journal of Gastroenterology 2008年第17期14卷 2723-2730页

作者： Daniel R Beckler Sammer Elwasila George ghobrial John F Valentine Saleh A Naser Department of molecular Biology and microbiology Burnett School of Biomedical Sciences Center for Biomolecular Sciences College of Medicine University of Central Florida Department of medicine University of Florida Gainesville

AIm： To investigate overlapping regions of the rpoB gene previously involved with rifamycin resistance in m. tuberculosis and seek correlation between rpoB mutations in dinical mAP strains with susceptibility to RIF and RFB. mETHODS： We designed a molecular-based PCR method for the evaluation of rifabutin （RFB） and rifampicin （RIF） resistance based on probable determinant regions within the rpoB gene of mAP, including the 81 bp variable site located between nucleotides 1363 and 1443. The minimum inhibitory concentration （mIC） for RIF was also determined against 11 mAP isolates in attempt to seek correlation with rpoB sequences. RESULTS： We determined that mAP strain 18 had an mIC of 〉 30 mg/L and ≤ 5 mg/L for RIF and RFB respectively, and a significant and novel rpoB mutation C1367T, compared to an mIC of ≤ 1.0 mg/L for both drugs in the wild type mAP. The 30-fold increase in the mIC was a direct result of the rpoB mutation C1367T, which caused an amino acid change Thr456 to Ile456 in the drug＇s binding site. In addition, mAP strain 185 contained five silent rpoB mutations and exhibited an mIC comparable to the wild-type. moreover, our in vitro selected mutation in mAP strain UCF5 resulted in the generation of a new resistant strain （UCF5-RIF16r） that possessed T1442C rpoB mutation and an mIC 〉 30 mg/L and 〉 10 mg/L for RIF and RFB respectively. Sequencing of the entire rpoB gene in mAP strains UCF4, 18, and UCF5-RIF16r revealed an rpoB mutation A2284C further downstream of the 81 bp variable region in UCF4, accounting for observed slight increase in mIC. In addition, no other significant mutations were found in strains 18 and UCF-RIF16r. CONCLUSION： The data clearly illustrates that clinical and in vitro-selected mAP mutants with rpoB mutations result in resistance to RIF and RFB, and that a single amino acid change in the beta subunit may have a significant impact on RIF resistance. Unconventional drug susceptibility testing such as our molecular approach wi

关键词： mycobacterium paratuberculosis Crohn's disease Rifabutin Rifampicin rpoB minimum inhibitoryconcentration

Noncanonical intercellular communication in immune response

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World Journal of Immunology 2016年第1期6卷 67-74页

作者： malgorzata Kloc Jacek Z Kubiak Xian C Li rafik.m.ghobrial Department of Surgery Methodist Hospital Houston methodist Research Institute Centre National de la Recherche Scientifique Unités mixtes de Recherche 6290 Institute of Genetics and Development of RennesCell Cycle GroupFaculty of Medic-ineUniversity of Rennes Faculty of medicine University of Rennes 1 Sherrie and Alan Conover Center for Liver Disease and Transplantation

The classical view of signaling between cells of immune system includes two major routes of intercellular communication:Through the release of extracellular molecules or a direct interaction between membrane bound receptor and its membrane bound ligand,which initiate a cascade of signaling in target ***,recent studies indicate that besides these canonical modes of signaling there are also noncanonical routs of intercellular communications through membrane stripping/membrane exchange/trogocytosis,extracellular traps,exosomes and ectososmes/*** this review we discuss what are the components of noncanonical pathways of signaling and what role they play in immune cells interactions.

关键词： Trogocytosis membrane stripping Extracellular traps Exosomes Ectososmes microparticles

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用上限元法进行锻件和预成形件设计

兵器材料科学与工程 1986年第6期 67-71页

作者： F.H.Osman ,A.N.Bramley ,m.I.ghobrial ,胡亚民 ,王红亚

用上限元法可模拟轴对称闭式模锻锻造过程中体积的流动特征。这种方法是应用增量法完成的。用使能耗率减至最小的速度场来预测型腔中的内部变形。这种方法包括对使用各种尺寸比的毛坯在上、下深型腔内的飞边形成和填充程度的估算。介绍... 详细信息

用上限元法可模拟轴对称闭式模锻锻造过程中体积的流动特征。这种方法是应用增量法完成的。用使能耗率减至最小的速度场来预测型腔中的内部变形。这种方法包括对使用各种尺寸比的毛坯在上、下深型腔内的飞边形成和填充程度的估算。介绍了一种用上限元法进行预成形件设计的新方法,该方法是一种从需要获得的锻件形状入手,反过来再分析过程的方法。

关键词：锻件型腔金属压制材料上限元法飞边预成形