DNA Polymerase Theta Plays a Critical Role in Pancreatic Cancer Development and Metastasis.

Pancreatic ductal adenocarcinoma (PDAC), due to its genomic heterogeneity and lack of effective treatment, despite decades of intensive research, will become the second leading cause of cancer-related deaths by 2030. Step-wise acquisition of mutations, due to genomic instability, is considered to drive the development of PDAC; the KRAS mutation occurs in 95 to 100% of human PDAC, and is already detectable in early premalignant lesions designated as pancreatic intraepithelial neoplasia (PanIN). This mutation is possibly the key event leading to genomic instability and PDAC development.

The podocyte-specific knockout of palladin in mice with a 129 genetic background affects podocyte morphology and the expression of palladin interacting proteins.

Proper and size selective blood filtration in the kidney depends on an intact morphology of podocyte foot processes. Effacement of interdigitating podocyte foot processes in the glomeruli causes a leaky filtration barrier resulting in proteinuria followed by the development of chronic kidney diseases. Since the function of the filtration barrier is depending on a proper actin cytoskeleton, we studied the role of the important actin-binding protein palladin for podocyte morphology.

Molecular Epidemiology of Methicillin-Susceptible and Methicillin-Resistant in Wild, Captive and Laboratory Rats: Effect of Habitat on the Nasal Population.

Rats are a reservoir of human- and livestock-associated methicillin-resistant (MRSA). However, the composition of the natural population in wild and laboratory rats is largely unknown. Here, 144 nasal isolates from free-living wild rats, captive wild rats and laboratory rats were genotyped and profiled for antibiotic resistances and human-specific virulence genes.

Obesity Impairs Mobility and Adult Hippocampal Neurogenesis.

Currently, it is controversially discussed whether a relationship between obesity and cognition exists. We here analyzed a mouse model of obesity (leptin-deficient mice) to study the effects of obesity on the morphology of the hippocampus (a brain structure involved in mechanisms related to learning and memory) and on behavior. Mice aged 4 to 6 months were analyzed.

The Role of Palladin in Podocytes.

Podocyte loss and effacement of interdigitating podocyte foot processes are the major cause of a leaky filtration barrier and ESRD. Because the complex three-dimensional morphology of podocytes depends on the actin cytoskeleton, we studied the role in podocytes of the actin bundling protein palladin, which is highly expressed therein. We knocked down palladin in cultured podocytes by siRNA transfection or in zebrafish embryos by morpholino injection and studied the effects by immunofluorescence and live imaging.

Global spread of mouse-adapted Staphylococcus aureus lineages CC1, CC15, and CC88 among mouse breeding facilities.

We previously reported that laboratory mice from all global vendors are frequently colonized with Staphylococcus aureus (S. aureus). Genotyping of a snap sample of murine S.

Laboratory Mice Are Frequently Colonized with and Mount a Systemic Immune Response-Note of Caution for Infection Experiments.

Whether mice are an appropriate model for infection and vaccination studies is a matter of debate, because they are not considered as natural hosts of . We previously identified a mouse-adapted strain, which caused infections in laboratory mice. This raised the question whether laboratory mice are commonly colonized with and whether this might impact on infection experiments.

The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity.

T cell activation is an energy-demanding process fueled by increased glucose consumption and accompanied by upregulation of the insulin receptor (INSR). In this article, we report that silencing the INSR in inducible knockdown rats impairs selective T cell functions but not thymocyte development. Glucose transport and glycolysis in activated CD4 T cells were compromised in the absence of the INSR, which was associated with alterations in intracellular signaling pathways.

A novel assay to assess the effect of pharmaceutical compounds on the differentiation of podocytes.

Background And Purpose: Therapeutic options for treating glomerulopathies, the main cause of chronic kidney disease, are limited. Podocyte dedifferentiation is a major event in the pathogenesis of glomerulopathies. The goal of the present study was, therefore, to develop an assay to monitor podocyte differentiation suitable for compound screening.

The Angiotensin-(1-7)/Mas Axis Improves Pancreatic β-Cell Function in Vitro and in Vivo.

The angiotensin-converting enzyme 2/angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system often opposes the detrimental effects of the angiotensin-converting enzyme/Ang II/Ang II type 1 receptor axis and has been associated with beneficial effects on glucose homeostasis, whereas underlying mechanisms are mostly unknown. Here we investigate the effects of Ang-(1-7) and its receptor Mas on β-cell function. Isolated islets from Mas-deficient and wild-type mice were stimulated with Ang-(1-7) or its antagonists and effects on insulin secretion determined.

Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity.

T-cell lymphopenia is a major risk factor for autoimmunity. Here we describe congenic Lewis (LEW) rats with a loss-of-function mutation in the Gimap5 gene, leading to a 92% reduction in peripheral T-cell numbers. Gimap5-deficient LEW rats developed eosinophilic autoimmune gastroenteritis accompanied by a 40-fold increase in IgE serum levels.

Modulation of CNS autoimmune responses by CD8(+) T cells coincides with their oligoclonal expansion.

MS is a highly prevalent neuroinflammatory disease of presumed autoimmune origin. Clinical observations and animal studies suggest that CD8(+) T cells play an important role in MS but their exact mechanisms are ill defined. When we actively induced EAE in CD8 knock-out DA rats, or adoptively transferred encephalitogenic CD4(+) T cells into CD8 knock-out DA rats, the disease course was indistinguishable from controls.

In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response.

A20 is an ubiquitin-editing enzyme that ensures the transient nature of inflammatory signaling pathways induced by cytokines like TNF-α and IL-1 or pathogens via Toll-like receptor (TLR) pathways. It has been identified as a negative regulator of dendritic cell (DC) maturation and attenuator of their immunostimulatory properties. Ex vivo A20-depleted dendritic cells showed enhanced expression of pro-inflammatory cytokines and costimulatory molecules, which resulted in hyperactivation of tumor-infiltrating T lymphocytes and inhibition of regulatory T cells.

Thymocyte-derived BDNF influences T-cell maturation at the DN3/DN4 transition stage.

Brain-derived neurotrophic factor (BDNF) promotes neuronal survival, regeneration, and plasticity. Emerging evidence also indicates an essential role for BDNF outside the nervous system, for instance in immune cells. We therefore investigated the impact of BDNF on T cells using BDNF knockout (KO) mice and conditional KO mice lacking BDNF specifically in this lymphoid subset.

Glucocorticoids induce gastroparesis in mice through depletion of l-arginine.

Glucocorticoids (GCs) constitute a highly pleiotropic class of drugs predominantly employed in the treatment of inflammatory diseases. In our search for new mechanisms of action, we identified a hitherto unknown effect of GCs in the gastrointestinal tract. We found that oral administration of dexamethasone (Dex) to mice caused an enlargement of the stomach due to the induction of gastroparesis and that this effect was abolished in GR(dim) mice carrying the A458T mutation in the GC receptor (GR).

Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses.

Glucocorticoids (GCs) are the standard therapy for treating multiple sclerosis (MS) patients suffering from an acute relapse. One of the main mechanisms of GC action is held to be the induction of T cell apoptosis leading to reduced lymphocyte infiltration into the CNS, yet our analysis of experimental autoimmune encephalomyelitis (EAE) in three different strains of genetically manipulated mice has revealed that the induction of T cell apoptosis is not essential for the therapeutic efficacy of GCs. Instead, we identified the redirection of T cell migration in response to chemokines as a new therapeutic principle of GC action.

CD8⁺ T cell help is required for efficient induction of EAE in Lewis rats.

The role of CD8⁺ T cells in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is still unclear. We describe here significantly reduced disease activity of EAE both in Lewis rats depleted of CD8⁺ T cells by monoclonal antibodies and CD8 knockout rats, which was accompanied by reduced leukocyte infiltration into the spinal cord. We detected myelin basic protein (MBP)-specific CD8⁺ T cells in peripheral lymphoid organs of CD8-depleted animals which, however, failed to differentiate into interferon-γ-producing effector cells.

A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity.

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that is initiated when self-reactive T cells enter the brain and become locally activated after encountering their specific nervous antigens. When and where the disease-relevant antigen encounters occur is unclear. Here we combined fluorescently labeled nuclear factor of activated T cells (NFAT) with histone protein H2B to create a broadly applicable molecular sensor for intravital imaging of T cell activation.

The hedgehog receptor patched1 in T cells is dispensable for adaptive immunity in mice.

Hedgehog (Hh) signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue we made use of conditional knock-out mice in which the Hh receptor Patched1 (Ptch) is inactivated in the T cell lineage. Thymocyte development was moderately compromised by the deletion of Ptch as characterized by reduced numbers of CD4 and CD8 single-positive cells.

Glucocorticoids induce effector T cell depolarization via ERM proteins, thereby impeding migration and APC conjugation.

Glucocorticoids (GCs) repress lymphocyte function by controlling gene expression. In this study, we investigated Ag-specific effector T cells and provide evidence that GCs also modulate these cells' cytoskeletal architecture by nongenomic mechanisms. Following GC treatment, effector T cells rapidly lose their polarized morphology, which impedes both their migratory capacity and their interaction with APCs.

Preventive treatment with methylprednisolone paradoxically exacerbates experimental autoimmune encephalomyelitis.

Glucocorticoids (GCs) represent the standard treatment for acute disease bouts in multiple sclerosis (MS) patients, for which methylprednisolone (MP) pulse therapy is the most frequently used protocol. Here, we compared the efficacy of therapeutic and preventive MP application in MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) in C57Bl/6 mice. When administered briefly after the onset of the disease, MP efficiently ameliorated EAE in a dose-dependent manner.

Healthy bone marrow cells reduce progression of kidney failure better than CKD bone marrow cells in rats with established chronic kidney disease.

Chronic kidney disease (CKD) is a major health care problem. New interventions to slow or prevent disease progression are urgently needed. We studied functional and structural effects of infusion of healthy and CKD bone marrow cells (BMCs) in a rat model of established CKD.

Acid sphingomyelinase is required for protection of effector memory T cells against glucocorticoid-induced cell death.

The activity of acid sphingomyelinase (aSMase) was previously reported to be involved in glucocorticoid-induced cell death (GICD) of T lymphocytes. This mechanism in turn is believed to contribute to the therapeutic efficacy of glucocorticoids (GCs) in the treatment of inflammatory diseases. In this study, we reassessed the role of aSMase in GICD by using aSMase knockout mice.