Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension.

Experimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimics events occurring in human glaucoma. Senescence-related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence-associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix-degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies

A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population

Background: The human ATP-binding cassette, subfamily B, member 11 (ABCB11) gene encodes the bile salt export pump, which is exclusively expressed at the canalicular membrane of hepatocytes. A frequent variant in the coding region, c.1331 T > C, leading to the amino acid exchange p.V444A, has been associated with altered serum bile salt levels in healthy individuals and predisposes homozygous carriers of the [C] allele for obstetric cholestasis. Recently, elevated bile salt levels were shown to be significantly associated with rates and risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon-alpha2 and ribavirin, suggesting a potential role for bile salt levels in HCV treatment outcomes and in the fibrogenic evolution of HCV-related liver disease. The aim of this study was to investigate a possible association of ABCB11 c.1331 T > C with hepatitis C virus (HCV) infection and fibrosis stages as assessed by non-invasive transient elastography in a German cohort of patients. Methods: ABCB11 c.1331 T > C genotype was determined by allelic discrimination assay in 649 HCV infected cases and 413 controls. Overall, 444 cases were staged for fibrotic progression by measurement of liver stiffness. Results: Homo- or heterozygous presence of the frequent [C] allele was associated with HCV positivity (OR = 1.41, CI = 1.02 - 1.95, p = 0.037). No association was detectable between the ABCB11 c.1331 T > C genotype and increased liver stiffness. Conclusions: Our data confirm that homozygous presence of the major [C] allele of ABCB11 c.1331 T > C is a genetic susceptibility factor for HCV infection, but not for liver fibrosis

Symmetries of Two Higgs Doublet Model and CP violation

We use the invariance of physical picture under a change of Lagrangian, the reparametrization invariance in the space of Lagrangians and its particular case -- the rephrasing invariance, for analysis of the two-Higgs-doublet extension of the SM. We found that some parameters of theory like tan beta are reparametrization dependent and therefore cannot be fundamental. We use the Z2-symmetry of the Lagrangian, which prevents a phi_1 phi_2 transitions, and the different levels of its violation, soft and hard, to describe a physical content of the model. In general, the broken Z2-symmetry allows for a CP violation in the physical Higgs sector. We argue that the 2HDM with a soft breaking of Z2-symmetry is a natural model in the description of EWSB. To simplify an analysis we choose among different forms of Lagrangian describing the same physical reality a specific one, in which the vacuum expectation values of both Higgs fields are real. A possible CP violation in the Higgs sector is described by using a two-step procedure with the first step identical to a diagonalization of mass matrix for CP-even fields in the CP conserved case. We find very simple necessary and sufficient condition for a CP violation in the Higgs sector. We determine the range of parameters for which CP violation and Flavor Changing Neutral Current effects are naturally small,what corresponds to a small dimensionless mass parameter nu= Re m_{12}^2/(2v1v2). We discuss how for small nu some Higgs bosons can be heavy, with mass up to about 0.6 TeV, without violating of the unitarity constraints. We discuss main features of the large nu case, which corresponds for nu -> infty to a decoupling of heavy Higgs bosons.Comment: 27 pages, extended discussion, references added, one figure, Revtex

Altered Expression of Antimicrobial Peptides in the Upper Gastrointestinal Tract of Patients with Diabetes Mellitus

Antimicrobial peptides (AMP) are essential components of innate immunity with a broad range of antimicrobial activities against bacteria, viruses, and fungi. The aim of this study was to investigate AMP expression in the upper gastrointestinal tract in normal and pathological metabolic states in humans. Furthermore, we examined the correlation between vitamin D levels and AMP expression in the same cohort. Serum concentrations of 25-hydroxyvitamin D3 were measured, and mRNA expression of β-defensins HBD-1, -2, -3, -4, α-defensins HD-5 and -6 and cathelicidin in the upper gastrointestinal tract epithelia were determined by quantitative RT-PCR in 31 individuals (10 with type 2 diabetes, 10 with insulin resistance, and 11 healthy controls). The majority of the cohort showed low vitamin D concentrations, which were negatively correlated with mRNA expression levels of HBD-3 in corpus mucosa. HBD-1 and HBD-3 mRNA were expressed in corpus mucosa, with the former significantly decreased in patients with diabetes. Hence, we conclude that type 2 diabetes is associated with reduced AMP expression in the upper gastrointestinal tract, which might contribute towards epithelial barrier dysfunction and increased bacterial translocation in these patients