TREX1 is expressed by microglia in normal human brain and increases in regions affected by ischemia

BACKGROUND: Mutations in the three-prime repair exonuclease 1 (TREX1) gene have been associated with neurological diseases, including Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL). However, the endogenous expression of TREX1 in human brain has not been studied. METHODS: We produced a rabbit polyclonal antibody (pAb) to TREX1 to characterize TREX1 by Western blotting (WB) of cell lysates from normal controls and subjects carrying an RVCL frame-shift mutation. Dual staining was performed to determine cell types expressing TREX1 in human brain tissue. TREX1 distribution in human brain was further evaluated by immunohistochemical analyses of formalin-fixed, paraffin-embedded samples from normal controls and patients with RVCL and ischemic stroke. RESULTS: After validating the specificity of our anti-TREX1 rabbit pAb, WB analysis was utilized to detect the endogenous wild-type and frame-shift mutant of TREX1 in cell lysates. Dual staining in human brain tissues from patients with RVCL and normal controls localized TREX1 to a subset of microglia and macrophages. Quantification of immunohistochemical staining of the cerebral cortex revealed that TREX1 CONCLUSIONS: TREX1 is expressed by a subset of microglia in normal human brain, often in close proximity to the microvasculature, and increases in the setting of ischemic lesions. These findings suggest a role for TREX

Standing genetic diversity and selection at functional gene loci are associated with differential invasion success in two non‐native fish species

Invasive species are expected to experience a unique combination of high genetic drift due to demographic factors while also experiencing strong selective pressures. The paradigm that reduced genetic diversity should limit the evolutionary potential of invasive species and thus their potential for range expansion has received little empirical support, possibly due to the choice of genetic markers. Our goal was to test for effects of genetic drift and selection at functional genetic markers as they relate to the invasion success of two paired invasive goby species, one widespread (successful) and one with limited range expansion (less successful). We genotyped fish using two marker types: single nucleotide polymorphisms (SNPs) in known-function, protein-coding genes and microsatellites to contrast the effects of neutral genetic processes. We identified reduced allelic variation in the invaded range for the less-successful tubenose goby. SNPs putatively under selection were responsible for the observed differences in population structure between marker types for round goby (successful) but not tubenose goby (less successful). A higher proportion of functional loci experienced divergent selection for round goby, suggesting increased evolutionary potential in invaded ranges may be associated with round goby’s greater invasion success. Genes involved in thermal tolerance were divergent for round goby populations but not tubenose goby, consistent with the hypothesis that invasion success for fish in temperate regions is influenced by capacity for thermal tolerance. Our results highlight the need to incorporate functional genetic markers in studies to better assess evolutionary potential for the improved conservation and management of species

Poorly controlled type 2 diabetes is accompanied by significant morphological and ultrastructural changes in both erythrocytes and in thrombin-generated fibrin: implications for diagnostics

We have noted in previous work, in a variety of inflammatory diseases, where iron dysregulation occurs, a strong tendency for erythrocytes to lose their normal discoid shape and to adopt a skewed morphology (as judged by their axial ratios in the light microscope and by their ultrastructure in the SEM). Similarly, the polymerization of fibrinogen, as induced in vitro by added thrombin, leads not to the common ‘spaghetti-like’ structures but to dense matted deposits. Type 2 diabetes is a known inflammatory disease. In the present work, we found that the axial ratio of the erythrocytes of poorly controlled (as suggested by increased HbA1c levels) type 2 diabetics was significantly increased, and that their fibrin morphologies were again highly aberrant. As judged by scanning electron microscopy and in the atomic force microscope, these could be reversed, to some degree, by the addition of the iron chelators deferoxamine (DFO) or deferasirox (DFX). As well as their demonstrated diagnostic significance, these morphological indicators may have prognostic value.Biotechnology and Biological Sciences Research Council (grant BB/L025752/1) as well as the National Research Foundation (NRF) of South Africa.http://www.cardiab.com/hb201

Predicting the ecological impacts of a new freshwater invader: functional responses and prey selectivity of the ‘killer shrimp’, Dikerogammarus villosus, compared to the native Gammarus pulex

The ability to predict the likely ecological impacts of invasive species in fresh waters is a pressing research requirement. Whilst comparisons of species traits and considerations of invasion history have some efficacy in this respect, we require robust methods that can compare the effects of native and invasive species. Here, we utilise comparative functional responses and prey selectivity experiments to understand and predict the ecological impact of an invader as compared to a native.We compared the predatory functional responses of an emerging invasive species in Europe, the ‘killer shrimp’, Dikerogammarus villosus, and an analogous native species, Gammarus pulex, towards three representative prey species: Asellus aquaticus, Daphnia magna and Chironomus sp. Furthermore, as ecological impact may be greater for invasive species with more indiscriminate feeding habits, we compared the selectivity for the three prey types between the invasive and native species.In both the presence and absence of experimental habitats, large D. villosus, and those matched for body size with G. pulex, generally showed higher (Type II) functional responses than G. pulex, with the invasive species exhibiting higher maximum feeding rates. Further, D. villosus exhibited significantly more indiscriminate prey selection compared with G. pulex, a trait that became more evident as the invader increased in size. Differences in functional responses and prey selectivity were prey species specific, with higher to lower predicted impacts in the order A. aquaticus, D. magna and Chironomus sp. This is in accord with the impact of this invasive species on macroinvertebrates in the field.We thus provide understanding of the known ecological impact of D. villosus and discuss the utility of the phenomenological use of comparative functional responses and resource use as a tool through which the potential ecological impacts of invasive species may be identified

Ig V region restrictions in human chronic lymphocytic leukemia suggest some cases have a common origin

The factors that contribute to the development of B cell chronic lymphocytic leukemia (B-CLL) are unknown, and the groups of individuals at the greatest risk for developing this common leukemia are not well defined. Molecular features are important for classifying cases of B-CLL, and it is now apparent that similarities among Ig rearrangements between patients may give important clues to the origin of this disease

Cerebroretinal Vasculopathies

Cerebroretinal vasculopathy (CRV) and the related diseases hereditary endotheliopathy with retinopathy, neuropathy, and stroke (HERNS), hereditary vascular retinopathy (HVR) and hereditary systemic angiopathy (HSA) [subsequently combined as retinovasculopathy and cerebral leukodystrophy (RVCL)] are devastating autosomal-dominant disorders of early to middle-age onset presenting with a core constellation of neurologic and ophthalmologic findings. This family of diseases is linked by specific mutations targeting a core region of a gene. Frameshift mutations in the carboxyl-terminus of three prime exonuclease-1 (TREX1), the major mammalian 3' to 5' DNA exonuclease on chromosome 3p21.1-p21.3, result in a systemic vasculopathy that follows an approximately 5-year course leading to death secondary to progressive neurologic decline, with sometimes a more protracted course in HERNS. Neuropathological features include a fibrinoid vascular necrosis or thickened hyalinized vessels associated with white matter ischemia, necrosis and often striking dystrophic calcifications. Ultrastructural studies of the vessel walls often demonstrate unusual multilaminated basement membranes

The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis

Objective: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation and fibrosis. There are currently no targeted therapies for NASH. We developed a liver-specific LXR inverse agonist, SR9238, which effectively reduces hepatic lipogenesis in models of obesity and hepatic steatosis. We hypothesized that suppression of lipogenesis, which is pathologically elevated in NASH may suppress progression of hepatic steatosis to NASH. Methods: NASH was induced in B6 V-lep ob/J (ob/ob) mice using a custom complete rodent diet (HTF) containing high amounts of trans-fat, fructose, and cholesterol. Once NASH was induced, mice were treated with SR9238 for one month by i.p. injection. Plasma lipid levels and liver health were analyzed by clinical chemistry. QPCR, western blot, and immunohistochemistry were used to assess disease severity. Results: Ob/ob mice are obese and diabetic thus they are commonly used as models for the study of metabolic diseases. These mice quickly developed the NASH phenotype when provided the HTF diet. The mice develop hepatic steatosis, severe hepatic inflammation and fibrosis on the HTF diet. Treatment with SR9238 significantly reduced the severity of hepatic steatosis and most importantly reduced hepatic inflammation and ameliorated hepatic fibrosis. Conclusions: Here, we demonstrate that an LXR inverse agonist, SR9238, is effective in reduction of hepatic steatosis, inflammation and fibrosis in an animal model of NASH. These results have important implications for the development of therapeutics for treatment NASH in humans