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A murine model of tuberculosis/type 2 diabetes comorbidity for investigating the microbiome,metabolome and associated immune parameters

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Animal Models and Experimental Medicine 2021年第2期4卷 181-188页

作者： Harindra D.Sathkumara janet l.eaton Matt A.Field Brenda l.Govan Natkunam Ketheesan Andreas Kupz Centre for Molecular Therapeutics Australian Institute of Tropical Health and MedicineJames Cook UniversityCairns&TownsvilleQLDAustralia College of Public Health Medical and Veterinary SciencesJames Cook UniversityTownsvilleQLDAustralia Centre for Tropical Bioinformatics and Molecular Biology James Cook UniversityCairnsQLDAustralia John Curtin School of Medical Research Australian National UniversityCanberraACTAustralia Science and Technology University of New EnglandArmidaleNSWAustralia

Tuberculosis(TB)is one of the deadliest infectious diseases in the *** meta-bolic disease type 2 diabetes(T2D)significantly increases the risk of developing ac-tive *** new TB vaccine candidates and novel therapeutic interventions are required to meet the challenges of global TB *** evidence suggests that the microbiota plays a significant role in how the host responds to infection,in-jury and neoplastic *** models that closely reflect human physiology are crucial in assessing new treatments and to decipher the underlying immunological defects responsible for increased TB susceptibility in comorbid *** this study,using a diet-induced murine T2D model that reflects the etiopathogenesis of clinical T2D and increased TB susceptibility,we investigated how the intestinal microbiota may impact the development of T2D,and how the gut microbial composition changes following a very low-dose aerosol infection with Mycobacterium tuberculosis(Mtb).Our data revealed a substantial intestinal microbiota dysbiosis in T2D mice compared to non-diabetic *** observed differences were comparable to previous clini-cal reports in TB patients,in which it was shown that Mtb infection causes rapid loss of microbial ***,diversity index and principle component analyses demonstrated distinct clustering of Mtb-infected non-diabetic mice ***-infected T2D *** findings support a broad applicability of T2D mice as a tractable small animal model for studying distinct immune parameters,microbiota and the immune-metabolome of TB/T2D *** model may also enable answers to be found to critical outstanding questions about targeted interventions of the gut mi-crobiota and the gut-lung axis.

关键词： gut microbiota host microbe interaction infectious diseases tuberculosis type 2 diabetes

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Sexual selection and hermaphroditic organisms： Testing theory

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Current Zoology 2013年第4期59卷 579-588页

作者： janet l. lEONARD Joseph M. long Marine laboratory University of California-Santa Cruz Santa Cruz CA 94019 USA

Sexual selection is widespread if not ubiquitous in hermaphroditic organisms. Although many phenomena that have been described as sexual selection in gonochores, （e.g. harem polygamy, multiple mating, elaborate courtship, even secondary sexual characters） can be found in some hermaphrodites, what is more interesting is the ways in which sexual selection in her- maphrodites may differ from dioecious taxa. In hermaphrodites, an individual＇s mating success includes its success from both sexual roles. Secondly, in many simultaneously hermaphroditic taxa there is strong evidence of sexual selection and yet the ope- rational sex ratio is 1：1, by definition. Many simultaneous hermaphrodites have elaborate courtship and genital anatomy, suggest- ing sexual selection plays an important role in reproductive success. Sperm competition and cryptic female choice mean that the number of mates acquired is not necessarily a predictor of reproductive success. Even in simultaneous hermaphrodites with re- ciprocal mating, variance in reproductive success through the male role and through the female role may differ in a population. Moreover hermaphrodites may choose to emphasize one sexual role over the other. Data suggest that the preferred role varies in hermaphrodites, which creates an opportunity to test fundamental predictions and assumptions of sexual selection theory. Hermaphrodites may vary their emphasis on one sexual role over the other either developmentally or behaviorally in response to environmental or social parameters. How they use this capability in acquiring more or higher quality mates still requires study

关键词： Sexual selection Hermaphrodites Mate choice Reproductive success

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Practical problems in regulatory toxicology Ⅰ:Formulations

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中国药理学与毒理学杂志 2013年第3期 504-505页

作者： janet l KEllY CJS Scientific ltd HarrogateUKHG3 5BJ.

Although highly regulated,all non-clinical toxicology studies have the potential to experience practical *** of potential hurdles and planning for success are key actions for all investigators to ensure a study is robust and suitable for submission and regulatory *** presentation will examine an area of study conduct which can be problematic but which if approached correctly will ensure good study *** test materials under development today are *** a suitable formulation for administration to laboratory animalsis difficult and therefore having strategies for determining suitable vehicles and dosing regimen *** achieve the optimal bioavailability of the chemical you need to strike a balance between the dose concentration,dose volume and the dosing *** presentation will consider the interactions of factors such as the physical nature of the final formulation,physicalproperties of vehicles and potential side effects which should be considered together when optimising the final dosing *** will demonstrate how a methodical approach can assist the scientist in establishing a formulation that will achieve the best bioavailability possible with minimal effects to the test *** presentation will also illustrate how the Study Director can demonstrate strong involvement and active study management as required by the GlP authorities.

关键词： Formulations Practical problems in regulatory toxicology

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Practical problems in regulatory toxicology Ⅱ:Control of contamination

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中国药理学与毒理学杂志 2013年第3期 513-514页

作者： janet l KEllY CJS Scientific ltd HarrogateUKHG3 5BJ.

Although highly regulated,all non-clinical toxicology studies have the potential to experience practical *** of potential hurdles and planning for success are key actions for all investigators to ensure a study is robust and suitable for submission and regulatory *** presentation will examine the whole study conduct process and illustrate steps you can take to the potential contamination of control samples and,in the event of an unexpected result being obtained,the procedures that must be carried out to investigate the *** authorities across the globe have focused on the contamination of control biological samples as a serious risk to compound development.A number of studies have been rejected by regulatory authorities in recent years due to the occurrence of test material in control samples and various legislationhas been introduced on the *** it was common place to only demonstrate the presence of test material at one or two time points in treated animals during a study and either not take or not analyse control *** today almost every study has a complete time profile of blood levels in all animals and analytical techniques have become ever more ***,the potential to identify test material in control samples is *** is a very costly problem for all involved in regulatory toxicology as it leads to additional time investigating the source of the problem,possible extra costs in repeating studies and the consequent use of more animals and potentially delays in registration and even loss of market *** which can be taken to limit its occurrence and a process of investigation of any positive results will be *** presentation will illustrate the need for scientists from all departments involved in a regulatory study to contribute to the successful *** regards to GlP compliance,the involvement and leadership of the Study Director in determ

关键词： Control of contamination Practical problems in regulatory toxicology

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Tertiary lymphoid structures in cancer – considerations for patient prognosis

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Cellular & Molecular Immunology 2020年第6期17卷 570-575页

作者： luis Munoz-Erazo janet l.Rhodes Valentine C.Marion Roslyn A.Kemp Department of Microbiology and Immunology University of OtagoDunedinNew Zealand Ecole Normale Superieure de lyon LyonFrance and Universite Claude Bernard Lyon 1LyonFrance

Tertiary lymphoid structures(TlS)are ectopic lymphoid formations that form within nonlymphoid *** share structural and functional characteristics with secondary lymphoid structures such as lymph nodes and can contain B-cell follicles and germinal centers surrounded by a T-cell *** have been described in several types of cancers and are usually associated with positive patient ***,TlS differ vastly in cellular composition and location within tissue *** this review,we discuss factors confounding the interpretation of the evidence for a prognostic role for TlS in cancer and frame these factors in the context of translation to regular clinical use.

关键词： tertiary lymphoid structure prognosis cancer tissue

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Multiparametric analysis of colorectal cancer immune responses

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World Journal of Gastroenterology 2018年第27期24卷 2995-3005页

作者： Julia KH leman Sarah K Sandford janet l Rhodes Roslyn A Kemp Department of Microbiology and Immunology University of Otago

Colorectal cancer(CRC) is a heterogeneous disease, with a diverse and plastic immune cell infiltrate. These immune cells play an important role in regulating tumour growth-progression or elimination. Some populations of cells have a strong correlation with disease-free survival, making them useful prognostic markers. In particular, the infiltrate of CD3^+ and CD8^+ T cells into CRC tumours has been validated worldwide as a valuable indicator of patient prognosis. However, the heterogeneity of the immune response, both between patients with tumours of different molecular subtypes, and within the tumour itself, necessitates the use of multiparametric analysis in the investigation of tumour-specific immune responses. This review will outline the multiparametric analysis techniques that have been developed and applied to studying the role of immune cells in the tumour, with a focus on colorectal cancer. Because much of the data in this disease relates to T cell subsets and heterogeneity, we have used T cell populations as examples throughout. Flow and mass cytometry give a detailed representation of the cells within the tumour in a single-cell suspension on a per-cell basis. Imaging technologies, such as imaging mass cytometry, are used to investigate increasing numbers of markers whilst retaining the spatial and structural information of the tumour section and the infiltrating immune cells. Together, the analyses of multiple immune parameters can provide valuable information to guide clinical decision-making in CRC.

关键词： Colorectal cancer Flow cytometry Immune cells Multiparametric analysis Immunohistochemistry Mass cytometry Microscopy

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IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition

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Bone Research 2018年第1期6卷 60-71页

作者： Tao Qiu janet l.Crane liang Xie lingling Xian Hui Xie Xu Cao Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Department of Pediatrics Johns Hopkins University School of Medicine State Key laboratory of Oral Diseases West China Hospital of Stomatology Sichuan University

Parathyroid hormone(PTH) regulates bone remodeling by activating PTH type 1 receptor(PTH1R) in osteoblasts/osteocytes. Insulinlike growth factor type 1(IGF-1) stimulates mesenchymal stem cell differentiation to osteoblasts. However, little is known about the signaling mechanisms that regulates the osteoblast-to-osteocyte transition. Here we report that PTH and IGF-I synergistically enhance osteoblast-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytoplasmic domain of PTH1R can be phosphorylated by insulin-like growth factor type I receptor(IGF1R) in vitro. Phosphorylated PTH1R localized to the barbed ends of actin filaments and increased actin polymerization during morphological change of osteoblasts into *** of the phosphorylation site reduced actin polymerization and dendrite length. Mouse models with conditional ablation of PTH1R in osteoblasts demonstrated a reduction in the number of osteoctyes and dendrites per osteocyte, with complete overlap of PTH1R with phosphorylated-PTH1R positioning in osteocyte dendrites in wild-type mice. Thus, our findings reveal a novel signaling mechanism that enhances osteoblast-to-osteocyte transition by direct phosphorylation of PTH1R by IGF1R.

关键词： Parathyroid hormone Phosphorylated PTH1R phosphorylated-PTH1R

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Transforming growth factor-β in stem cells and tissue homeostasis

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Bone Research 2018年第1期6卷 1-31页

作者： Xin Xu liwei Zheng Quan Yuan Gehua Zhen janet l.Crane Xuedong Zhou Xu Cao State Key laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics West China Hospital of StomatologySichuan University State Key laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Pediatric Dentistry West China Hospital of Stomatology Sichuan University State Key laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Implantology West China Hospital of Stomatology Sichuan University Department of Orthopedic Surgery Johns Hopkins University School of Medicine Department of Pediatrics Johns Hopkins University

TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix(ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.

关键词： cells metastasis TGF-β1 ligand human lead can not

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IGF-1 Signaling is Essential for Differentiation of Mesenchymal Stem Cells for Peak Bone Mass

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Bone Research 2013年第2期1卷 186-194页

作者： janet l. Crane luo Zhao Joseph S. Frye lingling Xian Tao Qiu Xu Cao Department of Pediatrics Johns Hopkins University School of Medicine Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Department of Orthopedics Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical Sciences University of Missouri School of Medicine

Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass （PBM）. Insulin-like growth factor type Ⅰ （IGF-1） levels correlate with the pattern of bone mass accrual and many chronic illnesses are associated with low IGF-1 levels. Reduced serum levels of IGF-1 minimally affect the integrity of the skeleton, whereas recent studies suggest that skeletal IGF-I regulates PBM. To determine the role of IGF-1 in postnatal bone mass accrual regardless of source, we established an inducible type 1 Igf receptor Cre/lox knockout mouse model, in which the type 1 Igf receptor was deleted inducibely in the mesenchymal stem cells （MSCs） from 3-7 weeks of age. The size of the mouse was not affected as knockout and wild type mice had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type controls, indicating that IGF-1 is critical for bone mass. IGF-1 signaling in MSCs in vitro has been implicated to be involved in both migration to the bone surface and differentiation into bone forming osteoblasts. To clarify the exact role of IGF-1 in bone, we found by immunohistochemical analysis that a similar number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantly, 56% fewer osteocalcin-positive mature osteoblasts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wild type littermates. These in vivo data demonstrate that the primary role of skeletal IGF-1 is for the terminal differentiation of osteoprogenitors, but refute the role of IGF-1 in MSC migration in vivo. Additionally, these findings confirm that impaired IGF-1 signaling in bone MSCs is sufficient to impair bone mass acquisition.

关键词： osteoblasts knockout mice cell migration IGF receptor nestin

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驱动蛋白Kinesin-14在双极纺锤体装配中跳跃至极点位置

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癌症 2008年第9期27卷 989-992页

作者： janet l. Paluh Department of Biology Center for Biotechnology and Interdisciplinary Studies Rensselaer Polytechnic Institute

在细胞周期中极易形成有丝分裂纺锤体,其对染色体的分离必不可少。在细胞周期初期,中心体复制或纺锤体极体紧密连接,并在G1/S期离开母极和子极。直到有丝分裂开始时,二者才互相分离,从而形成双极排列。驱动蛋白样蛋白(kinesin-like prot... 详细信息

在细胞周期中极易形成有丝分裂纺锤体,其对染色体的分离必不可少。在细胞周期初期,中心体复制或纺锤体极体紧密连接,并在G1/S期离开母极和子极。直到有丝分裂开始时,二者才互相分离,从而形成双极排列。驱动蛋白样蛋白(kinesin-like proteins,Klps)能产生各种作用力,该作用力有利于纺锤体双极性的形成时间、组装和维护。驱动蛋白-5与驱动蛋白-14是2个主要的作用因子,二者具有平行和反向平行于微管互相交联的能力,从而使纺锤体组装机制中纺锤体微管的相互作用倍受重视。最近,驱动蛋白-14在γ-微管蛋白的结合位点得到了确认,该位点为微管组织中心(microtubule organizing centers,MTOCs)中位于极点的常见构件,具有转化为微管组织中心复合物的能力,进而调节双极性。该位点的发现也引起了关于极点机制和MTOCs复杂性的广泛好奇和关注。

关键词：驱动蛋白样蛋白微管蛋白结合位点微管组织中心微管

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