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Revealing the identity of regulatory T-cell-suppressed self-reactive CD4^(+)T cells

Cellular & Molecular Immunology 2023年第10期20卷 1093-1094页

作者： judith N.Mandl heather j.melichar Department of Physiology and McGill Research Centre on Complex Traits McGill UniversityMontrealQCCanada Immunology-Oncology Unit Maisonneuve-Rosemont Hospital Research CenterMontrealQCCanada Department of Medicine Universitéde MontréalMontrealQCCanada

A recent study published in Nature Immunology by Peter Savage and colleagues sought to characterize regulatory T-cell(Treg)-suppressed self-reactive CD4^(+)T cells using an elegant system combining the depletion of Tregs with T-cell receptor(TCR)sequencing of expanded conventional CD4^(+)T-cell *** tracking the fate of T cells engineered to express the identified TCRs,Lee et *** a‘new’subpopulation of CD4^(+)T cells bearing antigen receptors with high levels of self-reactivity that take on a T follicular helper(TFH)-like phenotype in the periphery in the absence of immune challenge[1].Antigen-specificαβTCRs are generated through the somatic recombination of V(D)j gene segments during thymic development,giving rise to T cells that can recognize an enormously diverse set of peptides presented by major histocompatibility complex(pMHC)molecules.A risk of this process is that it can also lead to the generation of potentially highly self-reactive TCRs.T cells with TCRs with high affinity for self-pMHC molecules are purged in the thymus by clonal deletion,a key tolerance mechanism that prevents ***,this process is incomplete,and highly self-reactive T cells can escape negative selection and join the peripheral naive T-cell ***,while the naive CD4^(+)T-cell pool is heterogeneous with regard to an individual T cell’s reactivity for self-pMHC molecules,the distribution of T cells with differing strengths of self-reactivity leaving the thymus is skewed toward those with relatively higher self-pMHC binding strengths[2].A subset of these highly self-reactive CD4^(+)T cells in the periphery are deleted,some become functionally anergic,and others differentiate into Tregs,which go on to play an important role in peripheral tolerance,holding other CD4^(+)T cells with potentially dangerous levels of self-reactivity in check[3].What is the fate of these Treg-suppressed self-reactive cells?

关键词： reactivity incomplete expanded

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Quantifying Electronic Effects in QM and QM/MM Biomolecular Modeling with the Fukui Function

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物理化学学报 2018年第1期34卷 81-91页

作者： QI Helena W. KARELINA Maria KULIK heather j. Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA. Department of Chemistry Massachusetts Institute of Technology Cambridge MA 02139 USA.

Multi-scale quantum-mechanical/molecular-mechanical(QM/MM) and large-scale QM simulation provide valuable insight into enzyme mechanism and structure-property relationships. Analysis of the electron density afforded through these methods can enhance our understanding of how the enzyme environment modulates reactivity at the enzyme active site. From this perspective, tools from conceptual density functional theory to interrogate electron densities can provide added insight into enzyme function. We recently introduced the highly parallelizable Fukui shift analysis(FSA) method, which identifies how frontier states of an active site are altered by the presence of an additional QM residue to identify when QM treatment of a residue is essential as a result of quantum-mechanically affecting the behavior of the active site. We now demonstrate and analyze distance and residue dependence of Fukui function shifts in pairs of residues representing different non-covalent interactions. We also show how the interpretation of the Fukui function as a measure of relative nucleophilicity provides insight into enzymes that carry out S_N2 methyl transfer. The FSA method represents a promising approach for the systematic, unbiased determination of quantum mechanical effects in enzymes and for other complex systems that necessitate multi-scale modeling.

关键词：《物理化学学报》期刊编辑工作发行工作

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Immunophilin-like FKBP42/TWISTED DWARF1 Interacts with the Receptor Kinase BRI1 to Regulate Brassinosteroid Signaling in Arabidopsis

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Molecular Plant 2016年第4期9卷 593-600页

作者： juthamas Chaiwanon Veder j. Garcia heather Cartwright Ying Sun Zhi-Yong Wang Department of Plant Biology Carnegie Institution for Science Stanford CA 94305 USA Department of Botany Center of Excellence in Environment and Plant Physiology Faculty of Science Chulalongkorn University Bangkok 10330 Thailand present address: Institute of Molecular Cell Biology Hebei Key Laboratory of Molecular and Cellular Biology Hebei Normal University Shijiazhuang 050024 China

Mutation of the immunophilin-like FK506-binding protein TWlSTED DWARF1 （FKBP42/TWD1） causes dwarf and twisted-organ phenotypes in Arabidopsis. However, the function of FKBP42 is not fully understood at the molecular level. Using genetic, physiological, and immunological experiments, we show here that FKBP42/TWD1 is necessary for brassinosteroid （BR） signal transduction. The twdl mutant showed reduced BR sensitivity in growth responses and activation of the BZR1 transcription factor. However, twdl showed normal responses to an inhibitor of BIN2/GSK3, suggesting that twdl has a defect upstream of BIN2 in the BR signaling pathway. In vitro and in vivo assays showed that TWD1 interacts physically with the kinase domains of the BR receptor kinases BRI1 and BAK1. TWD1 is not required for normal localization of BRI1-GFP to the plasma membrane or for activation of the flagellin receptor kinase FLS2. Our results suggest that FKBP42/TWD1 plays a specific role in the activation of BRI1 receptor kinase.

关键词： brassinosteroid signaling BRI1 FKBP42

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A rare case of failed healing in previously burned skin after a secondary burns

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Burns & Trauma 2017年第4期5卷 268-271页

作者： Stephen j. Goldie Shaun Parsons Hana Menezes Andrew Ives heather Cleland Victorian Adult Burns Service Alfred Hospital Melbourne Australia Department of Surgery Monash University Melbourne Australia Victorian Adult Burns Service Alfred Hospital Melbourne Australia

Background:Patients presenting with large surface area burns are common in our practice;however, patients with a secondary large burn on pre-existing burn scars and grafts are rare and not reported. Case presentation:We report on an unusual case of a patient sustaining a secondary large burn to areas previously injured by a burn from a different mechanism. We discuss the potential implications when managing a case like this and suggest potential biological reasons why the skin may behave differently. Our patient was a 33-year-old man who presented with a 5%TBSA burn on skin scarred by a previous 40%total body surface area (TBSA) burn and skin grafts. Initially assessed as superficial partial thickness in depth, the wounds were treated conservatively with dressings;however, they failed to heal and became infected requiring surgical management. Conclusions:Burns sustained in areas of previous burn scars and grafts may behave differently to normal patterns of healing, requiring more aggressive management and surgical intervention at an early stage.

关键词： Previous burns Burn scar Non-healing

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A functional type I interferon pathway drives resistance to cornea herpes simplex virus type 1 infection by recruitment of leukocytes

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The journal of Biomedical Research 2011年第2期25卷 111-119页

作者： Christopher D. Conrady heather jones Min Zheng Daniel j.j. Carr Departments of Microbiology Immunology The University of Oklahoma Health Science Center Oklahoma City OK 73104 USA Departments of Ophthalmology The University of Oklahoma Health Science Center Oklahoma City OK 73104 USA

Type I interferons are critical antiviral cytokines produced following herpes simplex virus type-1 （HSV-1） infection that act to inhibit viral spread. In the present study, we identify HSV-infected and adjacent uninfected corneal epithelial cells as the source of interferon-a. We also report mice deficient in the A1 chain of the type I IFN receptor （CDl18-/） are extremely sensitive to ocular infection with low doses （100 PFU） of HSV-1 as seen by significantly elevated viral titers in the cornea Compared to wild type （WT） controls. The enhanced susceptibil- ity correlated with a loss of CD4＋ and CD8＋ T cell recruitment and aberrant chemokine production in the cornea despite mounting an adaptive immune response in the draining mandibular lymph node of CDll8/ mice. Taken together, these results highlight the importance of IFN production in both the innate immune response as well as eliciting chemokine production required to facilitate adaptive immune cell trafficking.

关键词： herpes simplex virus type 1 type I interferon comea viral infection leukocytes ocular immunology

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Sperm fine-needle aspiration (FNA)mapping after failed microdissection testicular sperm extraction (TESE):location and patterns of found sperm

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Asian journal of Andrology 2019年第1期21卷 50-55页

作者： Sheba jarvis heather K Yee Natalia Thomas Imok Cha Kedar Che Prasad jonathan W A Ramsay Paul j Turek Imperial College London Hammersmlth HospitalLondon W12 ONNUK The Turek Clinic San FranciscoCA 94133USA Marin Medical Laboratories Greenbrae CA 94904USA.

We sought to evaluate the ability of fine-needle aspiration (FNA)mapping to find sperm and to guide sperm retrieval after failed microdissection testicular sperm extraction (micro-TESE)in nonobstructive azoospermic *** this study of consecutive male infertility cases,interventions included testicular FNA mapping and subsequent sperm *** included the frequency and location of found sperm on FNA maps after failed micro-TESE and the salvage sperm retrieval *** 548 patients undergoing FNA mapping from 2010 to 2016,82 men with previous micro-TESE procedures were *** mean time between micro-TESE and FNA mapping was 2.2 years.A total of 2825 (1424 on right and 1401 on left)sites were *** least one site revealed mature sperm in 24 (29.3%)of 82 men with prior failed micro-TESE *** was an equal likelihood of detecting sperm in either testis (6.1%right;5.7%left;P=0.58).Digital "heat maps"revealed differences in sperm findings within the testis with mature sperm more likely found in the testis periphery rather than *** (62.5%)patients subsequently underwent sperm retrieval procedures guided by FNA *** sperm were retrieved in all cases,and in 10 (66.7%)of 15 cases,extra sperm were frozen for future *** a significant proportion of failed micro-TESE procedures representing the largest study to date,sperm were detected by FNA mapping and could be reliably retrieved through FNA map-guided surgical sperm *** present,sperm were more likely to be found in the testis periphery rather than centrally with FNA mapping.

关键词： azoospermia hypogonadism IVF-ICSI microdissection TESE sperm FNA mapping sperm retrieval

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Androgen abuse in sports

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Asian journal of Andrology 2008年第3期10卷 403-415页

作者： David j. Handelsman Alison heather ANZAC Research Institute and Department of Andrology Concord Hospital Sydney NSW 2139 Australia Heart Research Institute University of Sydney Sydney NSW 2050 Australia

Androgens remain the most effective and widely abused ergogenic drugs in sport. Although androgen doping has been prohibited for over 3 decades with a ban enforced by mass spectrometric （MS）-based urine testing for synthetic and exogenous natural androgens, attempts continue to develop increasingly complex schemes to circumvent the ban. A prominent recent approach has been the development of designer androgens. Such never-marketed androgens evade detection because mass spectrometry relies on identifying characteristic chemical signatures requiring prior knowledge of chemical structure. Although once known, designer androgens are readily detected and added to the Prohibited List. However, until their structures are elucidated, designer androgens can circumvent the ban on androgen doping. To combat this, in vitro androgen bioassays offer powerful new possibilities for the generic detection of unidentified bioactive androgens, regardless of their chemical structure. Another approach to circumvent the ban on androgen doping has been the development of indirect androgen doping, the use of exogenous drugs to produce a sustained increase in endogenous testosterone （T） production. Apart from estrogen blockers, however, such neuroendocrine active drugs mostly provide only transient increases in blood T. Finally the ban on androgen doping must allow provision for rare athletes with incidental, proven androgen deficiency who require T replacement therapy. The Therapeutic Use Exemption mechanism makes provision for such necessary medical treatment, subject to rigorous criteria for demonstrating a genuine ongoing need for T and monitoring of T dosage. Effective deterrence of sports doping requires novel, increasingly sophisticated detection options calibrated to defeat these challenges, without which fairness in sport is tarnished and the social and health idealization of sporting champions devalued.

关键词： androgen doping sport testosterone bioassay

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Experimental repetitive mild traumatic brain injury induces deficits in trabecular bone microarchitecture and strength in mice

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Bone Research 2017年第4期5卷 357-366页

作者： Chandrasekhar Kesavan Nikita M Bajwa heather Watt Subburaman Mohan Musculoskeletal Disease Center VA Loma Linda Healthcare SystemLama LindaCAUSA Department of Medicine Loma DndaCAUSA Department of Orthopedic Surgery Loma Linda UniversityLoma LindaCAUSA

To evaluate the long-term consequence of repetitive mild traumatic brain injury （mTBI） on bone, mTBI was induced in 10-week-old female C57BL/6j mice using a weight drop model, once per day for 4 consecutive days at different drop heights （0.5, 1 and 1.5 m） and the skeletal phenotype was evaluated at different time points after the impact. In vivo micro-CT （μ-CT） analysis of the tibial metaphysis at 2, 8 and 12 weeks after the impact revealed a 5%-32% reduction in trabecular bone mass. Histomorphometric analyses showed a reduced bone formation rate in the secondary spongiosa ofl.5 m impacted mice at 12 weeks post impact. Apparent modulus （bone strength）, was reduced by 30% （P 〈 0.05） at the proximal tibial metaphysis in the 1.5 m drop height group at 2 and 8 weeks post impact. Ex vivo μ-CT analysis of the fifth lumbar vertebra revealed a significant reduction in trabecular bone mass at 12 weeks of age in all three drop height groups. Serum levels of osteocalcin were decreased by 22%, 15%, and 19% in the 0.5, 1.0 and 1.5 m drop height groups, respectively, at 2 weeks post impact. Serum IGF-I levels were reduced by 18%-32% in mTBI mice compared to control mice at 2 weeks post impact. Serum osteocalcin and IGF-I levels correlated with trabecular BV/TV （r2 = 0.14 and 0.16, P 〈 0.05）. In conclusion, repetitive mTBI exerts significant negative effects on the trabecular bone microarchitecture and bone mechanical properties by influencing osteoblast function via reduced endocrine IGF-I actions.

关键词： IGF TBI Experimental repetitive mild traumatic brain injury induces deficits in trabecular bone microarchitecture and strength in mice

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Correlation of endoscopic disease severity with pediatric ulcerative colitis activity index score in children and young adults with ulcerative colitis

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World journal of Gastroenterology 2017年第18期23卷 3322-3329页

作者： Basavaraj Kerur heather j Litman julia Bender Stern Sarah Weber jenifer R Lightdale Paul A Rufo Athos Bousvaros Pediatric Gastroenterology Hasbro Children's Hospital Corrona LLC Southborough Inflammatory Bowel Disease Center Children's Hospital Boston Division of Pediatric Gastroenterology UMass Memorial Medical CenterUniversity Campus Worcester

To investigate of pediatric ulcerative colitis activity index (PUCAI) in ulcerative colitis correlate with mucosal inflammation and endoscopic assessment of disease activity (Mayo endoscopic score).METHODSWe reviewed charts from ulcerative colitis patients who had undergone both colonoscopy over 3 years. Clinical assessment of disease severity within 35 d (either before or after) the colonoscopy were included. Patients were excluded if they had significant therapeutic interventions (such as the start of corticosteroids or immunosuppressive agents) between the colonoscopy and the clinical assessment. Mayo endoscopic score of the rectum and sigmoid were done by two gastroenterologists. Inter-observer variability in Mayo score was *** identified 99 patients (53% female, 74% pancolitis) that met inclusion criteria. The indications for colonoscopy included ongoing disease activity (62%), consideration of medication change (10%), assessment of medication efficacy (14%), and cancer screening (14%). Based on PUCAI scores, 33% of patients were in remission, 39% had mild disease, 23% had moderate disease, and 4% had severe disease. There was “moderate-substantial” agreement between the two reviewers in assessing rectal Mayo scores (kappa = 0.54, 95%CI: 0.41-0.68).CONCLUSIONEndoscopic disease severity (Mayo score) assessed by reviewing photographs of pediatric colonoscopy has moderate inter-rater reliability, and agreement was less robust in assessing patients with mild disease activity. Endoscopic disease severity generally correlates with clinical disease severity as measured by PUCAI score. However, children with inflamed colons can have significant variation in their reported clinical symptoms. Thus, assessment of both clinical symptoms and endoscopic disease severity may be required in future clinical studies.

关键词： Ulcerative colitis Pediatric ulcerative colitis activity index Mayo score

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Influences and drivers of woody debris movement in urban watercourses

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Science China(Technological Sciences) 2014年第8期57卷 1512-1521页

作者： ALLEN Deonie ARTHUR Scott HAYNES heather WALLIS Stephen G WALLERSTEIN Nicholas Institute for Infrastructure and Environment Heriot-Watt University

It is recognised that the blockage of culverts by woody debris can result in an increased risk of infrastructure damage and *** date,debris transport analysis has focused on regional fluvial systems and large woody debris,both in flume and field *** the social and economic risk associated with urban flooding,and as urban drainage design shifts away from subsurface piped network reliance,there is an increasing need to understand debris movement in urban *** prediction of urban watercourse small woody debris(SWD)movement,both quantity and risk,has undergone only limited analysis predominantly due to lack of field *** paper describes the development of a methodology to enable the collection of accurate and meaningful SWD residency and transportation data from *** presented research examines the limitations and effective function of PIT tag technology to collect SWD transport data in the field appropriate for risk and prediction *** integrated transponder(PIT)technology provides a method to collect debris transport data within the urban *** this study,the tags are installed within small woody debris and released at known locations into a small urban natural watercourse enabling monitoring of movement and travel *** velocity and detention are collated with solute time of travel,watercourse and point flow characteristics to identify the relationships between these key *** work presented tests three hypotheses:firstly,that the potential for unobstructed or un-detained SWD movement increases with flow velocity and water ***,that SWD travel distance,and the resistance forces along this travel path,influence SWD transport ***,the relationship between SWD and channel dimensions is examined with the aim of advancing representative debris transport prediction modelling.

关键词： woody debris transport prediction urban flood risk blockage solute dye tracing

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