Resident macrophages of pancreatic islets have a seminal role in the initiation of autoimmune diabetes of NOD mice

Significance Our studies indicate that the resident macrophages of the pancreatic islets of Langerhans have a seminal role in the initiation and progression of autoimmune diabetes in NOD mice. In this study, islet macrophages were depleted by administration of a monoclonal antibody to the CSF-1 receptor. Macrophage depletion, either at the start of the autoimmune process or when diabetogenesis is active, leads to a significant reduction in diabetes incidence. Depletion of the islet macrophages reduces the entrance of T cells into islets and results in the absence of antigen presentation. Concordantly, a regulatory pathway develops that controls diabetes progression. We conclude that treatments that target the islet macrophages may have important clinical relevance for the control of autoimmune type 1 diabetes.</jats:p

Analysis of the Brinkman-Forchheimer equations with slip boundary conditions

In this work, we study the Brinkman-Forchheimer equations driven under slip boundary conditions of friction type. We prove the existence and uniqueness of weak solutions by means of regularization combined with the Faedo-Galerkin approach. Next we discuss the continuity of the solution with respect to Brinkman's and Forchheimer's coefficients. Finally, we show that the weak solution of the corresponding stationary problem is stable

Toward Personalized Gene Therapy: Characterizing the Host Genetic Control of Lentiviral-Vector-Mediated Hepatic Gene Delivery

The success of lentiviral vectors in curing fatal genetic and acquired diseases has opened a new era in human gene therapy. However, variability in the efficacy and safety of this therapeutic approach has been reported in human patients. Consequently, lentiviral-vector-based gene therapy is limited to incurable human diseases, with little understanding of the underlying causes of adverse effects and poor efficacy. To assess the role that host genetic variation has on efficacy of gene therapy, we characterized lentiviral-vector gene therapy within a set of 12 collaborative cross mouse strains. Lentiviral vectors carrying the firefly luciferase cDNA under the control of a liver-specific promoter were administered to female mice, with total-body and hepatic luciferase expression periodically monitored through 41 weeks post-vector administration. Vector copy number per diploid genome in mouse liver and spleen was determined at the end of this study. We identified major strain-specific contributions to overall success of transduction, vector biodistribution, maximum luciferase expression, and the kinetics of luciferase expression throughout the study. Our results highlight the importance of genetic variation on gene-therapeutic efficacy; provide new models with which to more rigorously assess gene therapy approaches; and suggest that redesigning preclinical studies of gene-therapy methodologies might be appropriate

Early stage morphology of quench condensed Ag, Pb and Pb/Ag hybrid films

Scanning Tunneling Microscopy (STM) has been used to study the morphology of Ag, Pb and Pb/Ag bilayer films fabricated by quench condensation of the elements onto cold (T=77K), inert and atomically flat Highly Oriented Pyrolytic Graphite (HOPG) substrates. All films are thinner than 10 nm and show a granular structure that is consistent with earlier studies of QC films. The average lateral diameter, $\bar {2r}$, of the Ag grains, however, depends on whether the Ag is deposited directly on HOPG ($\bar {2r}$ = 13 nm) or on a Pb film consisting of a single layer of Pb grains ($\bar {2r}$ = 26.8 nm). In addition, the critical thickness for electrical conduction ($d_{G}$) of Pb/Ag films on inert glass substrates is substantially larger than for pure Ag films. These results are evidence that the structure of the underlying substrate exerts an influence on the size of the grains in QC films. We propose a qualitative explanation for this previously unencountered phenomenon.Comment: 11 pages, 3 figures and one tabl

Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites

Autoantibodies to insulin are a harbinger of autoimmunity in type 1 diabetes in humans and in non-obese diabetic mice. To understand the genesis of these autoantibodies, we investigated the interactions of insulin-specific T and B lymphocytes using T cell and B cell receptor transgenic mice. We found spontaneous anti-insulin germinal center (GC) formation throughout lymphoid tissues with GC B cells binding insulin. Moreover, because of the nature of the insulin epitope recognized by the T cells, it was evident that GC B cells presented a broader repertoire of insulin epitopes. Such broader recognition was reproduced by activating naive B cells ex vivo with a combination of CD40 ligand and interleukin 4. Thus, insulin immunoreactivity extends beyond the pancreatic lymph node–islets of Langerhans axis and indicates that circulating insulin, despite its very low levels, can have an influence on diabetogenesis

Uni-directional ciliary membrane protein trafficking by a cytoplasmic retrograde IFT motor and ciliary ectosome shedding

The role of the primary cilium in key signaling pathways depends on dynamic regulation of ciliary membrane protein composition, yet we know little about the motors or membrane events that regulate ciliary membrane protein trafficking in existing organelles. Recently, we showed that cilium-generated signaling in Chlamydomonas induced rapid, anterograde IFT-independent, cytoplasmic microtubule-dependent redistribution of the membrane polypeptide, SAG1-C65, from the plasma membrane to the periciliary region and the ciliary membrane. Here, we report that the retrograde IFT motor, cytoplasmic dynein 1b, is required in the cytoplasm for this rapid redistribution. Furthermore, signaling-induced trafficking of SAG1-C65 into cilia is unidirectional and the entire complement of cellular SAG1-C65 is shed during signaling and can be recovered in the form of ciliary ectosomes that retain signal-inducing activity. Thus, during signaling, cells regulate ciliary membrane protein composition through cytoplasmic action of the retrograde IFT motor and shedding of ciliary ectosomes

Identification of Tetranectin as a Potential Biomarker for Metastatic Oral Cancer

Lymph node involvement is the most important predictor of survival rates in patients with oral squamous cell carcinoma (OSCC). A biomarker that can indicate lymph node metastasis would be valuable to classify patients with OSCC for optimal treatment. In this study, we have performed a serum proteomic analysis of OSCC using 2-D gel electrophoresis and liquid chromatography/tandem mass spectrometry. One of the down-regulated proteins in OSCC was identified as tetranectin, which is a protein encoded by the CLEC3B gene (C-type lectin domain family 3, member B). We further tested the protein level in serum and saliva from patients with lymph-node metastatic and primary OSCC. Tetranectin was found significantly under-expressed in both serum and saliva of metastatic OSCC compared to primary OSCC. Our results suggest that serum or saliva tetranectin may serve as a potential biomarker for metastatic OSCC. Other candidate serum biomarkers for OSCC included superoxide dismutase, ficolin 2, CD-5 antigen-like protein, RalA binding protein 1, plasma retinol-binding protein and transthyretin. Their clinical utility for OSCC detection remains to be further tested in cancer patients

Why Does Disaster Recovery Work Influence Mental Health?: Pathways through Physical Health and Household Income

Disaster recovery work increases risk for mental health problems, yet the mechanisms underlying this association are unclear. We explored links from recovery work to posttraumatic stress (PTS), major depression (MD) and generalized anxiety disorder (GAD) symptoms through physical health symptoms and household income in the aftermath of the Deepwater Horizon oil spill. As part of the NIEHS GuLF STUDY, participants (N = 10,141) reported on cleanup work activities, spill-related physical health symptoms, and household income at baseline, and mental health symptoms an average of 14.69 weeks (SD = 16.79) thereafter. Cleanup work participation was associated with higher physical health symptoms, which in turn were associated with higher PTS, MD, and GAD symptoms. Similar pattern of results were found in models including workers only and investigating the influence of longer work duration and higher work-related oil exposure on mental health symptoms. In addition, longer worker duration and higher work-related oil exposure were associated with higher household income, which in turn was associated with lower MD and GAD symptoms. These findings suggest that physical health symptoms contribute to workers’ risk for mental health symptoms, while higher household income, potentially from more extensive work, might mitigate risk

Lead Levels and Ischemic Heart Disease in a Prospective Study of Middle-Aged and Elderly Men: the VA Normative Aging Study

Background: Lead exposure has been associated with higher blood pressure, hypertension, electrocardiogram abnormalities, and increased mortality from circulatory causes.Objective We assessed the association between bone lead—a more accurate biomarker of chronic lead exposure than blood lead—and risk for future ischemic heart disease (IHD). Methods: In a prospective cohort study (VA Normative Aging Study), 837 men who underwent blood or bone lead measurements at baseline were followed-up for an ischemic heart disease event between 1 September 1991 and 31 December 2001. IHD was defined as either a diagnosis of myocardial infarction or angina pectoris that was confirmed by a cardiologist. Events of fatal myocardial infarction were assessed from death certificates. Results: An IHD event occurred in 83 cases (70 nonfatal and 13 fatal). The mean blood, tibia, and patella lead levels were higher in IHD cases than in noncases. In multivariate Cox-proportional hazards models, one standard deviation increase in blood lead level was associated with a 1.27 (95% confidence interval, 1.01–1.59) fold greater risk for ischemic heart disease. Similarly, a one standard deviation increase in patella and tibia lead levels was associated with greater risk for IHD (hazard ratio for patella lead = 1.29; 95% confidence interval, 1.02–1.62). Conclusions: Men with increased blood and bone lead levels were at increased risk for future IHD. Although the pathogenesis of IHD is multifactorial, lead exposure may be one of the risk factors

Revisiting the pH-gated conformational switch on the activities of HisKA-family histidine kinases

Histidine is a versatile residue playing key roles in enzyme catalysis thanks to the chemistry of its imidazole group that can serve as nucleophile, general acid or base depending on its protonation state. In bacteria, signal transduction relies on two-component systems (TCS) which comprise a sensor histidine kinase (HK) containing a phosphorylatable catalytic His with phosphotransfer and phosphatase activities over an effector response regulator. Recently, a pH-gated model has been postulated to regulate the phosphatase activity of HisKA HKs based on the pH-dependent rotamer switch of the phosphorylatable His. Here, we have revisited this model from a structural and functional perspective on HK853-RR468 and EnvZ-OmpR TCS, the prototypical HisKA HKs. We have found that the rotamer of His is not influenced by the environmental pH, ruling out a pH-gated model and confirming that the chemistry of the His is responsible for the decrease in the phosphatase activity at acidic pH