Gene Expression Profiling of Vasoregression in the Retina—Involvement of Microglial Cells

Vasoregression is a hallmark of vascular eye diseases but the mechanisms involved are still largely unknown. We have recently characterized a rat ciliopathy model which develops primary photoreceptor degeneration and secondary vasoregression. To improve the understanding of secondary vasoregression in retinal neurodegeneration, we used microarray techniques to compare gene expression profiles in this new model before and after retinal vasoregression. Differential gene expression was validated by quantitative RT-PCR, Western blot and immunofluorescence. Of the 157 genes regulated more than twofold, the MHC class II invariant chain CD74 yielded the strongest upregulation, and was allocated to activated microglial cells close to the vessels undergoing vasoregression. Pathway clustering identified genes of the immune system including inflammatory signaling, and components of the complement cascade upregulated during vasoregression. Together, our data suggest that microglial cells involved in retinal immune response participate in the initiation of vasoregression in the retina

Higgs Boson Masses in the Complex NMSSM at One-Loop Level

The Next-to-Minimal Supersymmetric Extension of the Standard Model (NMSSM) with a Higgs sector containing five neutral and two charged Higgs bosons allows for a rich phenomenology. In addition, the plethora of parameters provides many sources of CP violation. In contrast to the Minimal Supersymmetric Extension, CP violation in the Higgs sector is already possible at tree-level. For a reliable understanding and interpretation of the experimental results of the Higgs boson search, and for a proper distinction of Higgs sectors provided by the Standard Model or possible extensions, the Higgs boson masses have to be known as precisely as possible including higher-order corrections. In this paper we calculate the one-loop corrections to the neutral Higgs boson masses in the complex NMSSM in a Feynman diagrammatic approach adopting a mixed renormalization scheme based on on-shell and $\bar{DR}$ conditions. We study various scenarios where we allow for tree-level CP-violating phases in the Higgs sector and where we also study radiatively induced CP violation due to a non-vanishing phase of the trilinear coupling $A_t$ in the stop sector. The effects on the Higgs boson phenomenology are found to be significant. We furthermore estimate the theoretical error due to unknown higher-order corrections by both varying the renormalization scheme of the top and bottom quark masses and by adopting different renormalization scales. The residual theoretical error can be estimated to about 10%

Soccer Attenuates the Asymmetry of Rectus Abdominis Muscle Observed in Non-Athletes

Purpose: To determine the volume and degree of asymmetry of the rectus abdominis muscle (RA) in professional soccer players. Methods: The volume of the RA was determined using magnetic resonance imaging (MRI) in 15 professional male soccer players and 6 non-active male control subjects. Results: Soccer players had 26% greater RA volume than controls (P<0.05), due to hypertrophy of both the dominant (28% greater volume, P<0.05) and non-dominant (25% greater volume, P<0.01) sides, after adjusting for age, length of the RA muscle and body mass index (BMI) as covariates. Total volume of the dominant side was similar to the contralateral in soccer players (P = 0.42) and in controls (P = 0.75) (Dominant/non-dominant = 0.99, in both groups). Segmental analysis showed a progressive increase in the degree of side-to-side asymmetry from the first lumbar disc to the pubic symphysis in soccer players (r = 0.80, P<0.05) and in controls (r = 0.75, P<0.05). The slope of the relationship was lower in soccer players, although this trend was not statistically significant (P = 0.14). Conclusions: Professional soccer is associated with marked hypertrophy of the rectus abdominis muscle, which achieves a volume that is 26% greater than in non-active controls. Soccer induces the hypertrophy of the non-dominant side in proximal regions and the dominant side in regions closer to pubic symphysis, which attenuates the pattern of asymmetry of rectus abdominis observed in non-active population. It remains to be determined whether the hypertrophy of rectus abdominis in soccer players modifies the risk of injury

Somatostatin receptor in human hepatocellular carcinomas: Biological, patient and tumor characteristics

Background/Aim: The evidence on the efficacy of somatostatin analogues in the treatment of hepatocellular carcinoma (HCC) in humans is conflicting. A variety of human tumors demonstrate somatostatin receptors. All subtypes bind human somatostatin with high affinity, while somatostatin analogues bind with high affinity to somatostatin receptor subtype 2 (sst2). We investigated the sst2 expression in HCC and examined whether HCCs expressing sst2 are a distinct subgroup. Patients and Methods: Forty-five human HCCs were tested for sst2 expression and biological alterations. The proliferative capacity was determined with Ki67 immunostaining and the DNA ploidy status was measured by fluorescent in situ hybridization with a chromosome 1-specific repetitive DNA probe. Expression of tumor suppressor genes (p16, p53 and Rb1) was measured by immunohistochemistry. Results: sst2 expression was detected in 30 tumors (67%). No correlation existed between sst2 expression and the immunoprofiles of the tumor suppressor genes, aneuploidy, proliferation, age, gender, α-fetoprotein levels, tumor size, tumor grade and underlying liver disease. Conclusion: In 67% of the patients with HCC, sst2 could be detected in the tumor. No clinical, pathological or biological characteristics were specific for sst2-positive tumors. Copyrigh

Nuclear Receptor Rev-erb Alpha (Nr1d1) Functions in Concert with Nr2e3 to Regulate Transcriptional Networks in the Retina

The majority of diseases in the retina are caused by genetic mutations affecting the development and function of photoreceptor cells. The transcriptional networks directing these processes are regulated by genes such as nuclear hormone receptors. The nuclear hormone receptor gene Rev-erb alpha/Nr1d1 has been widely studied for its role in the circadian cycle and cell metabolism, however its role in the retina is unknown. In order to understand the role of Rev-erb alpha/Nr1d1 in the retina, we evaluated the effects of loss of Nr1d1 to the developing retina and its co-regulation with the photoreceptor-specific nuclear receptor gene Nr2e3 in the developing and mature retina. Knock-down of Nr1d1 expression in the developing retina results in pan-retinal spotting and reduced retinal function by electroretinogram. Our studies show that NR1D1 protein is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina. In the adult retina, NR1D1 is expressed in the ganglion cell layer and is co-expressed with NR2E3 in the outer nuclear layer, within rods and cones. Several genes co-targeted by NR2E3 and NR1D1 were identified that include: Nr2c1, Recoverin, Rgr, Rarres2, Pde8a, and Nupr1. We examined the cyclic expression of Nr1d1 and Nr2e3 over a twenty-four hour period and observed that both nuclear receptors cycle in a similar manner. Taken together, these studies reveal a novel role for Nr1d1, in conjunction with its cofactor Nr2e3, in regulating transcriptional networks critical for photoreceptor development and function

Femoroacetabular impingement: normal values of the quantitative morphometric parameters in asymptomatic hips.

OBJECTIVE: To determine the means and the reference intervals of the quantitative morphometric parameters of femoroacetabular impingement (FAI) in normal hips with high-resolution computed tomography (CT). METHODS: We prospectively included 94 adult individuals who underwent CT for thoracic, abdominal or urologic pathologies. Patients with a clinical history of hip pathology and/or with osteoarthritis on CT were excluded. We calculated means and 95 % reference intervals for imaging signs of cam-type (alpha angle at 90° and 45° and femoral head-neck offset) and pincer-type impingement (acetabular version angle, lateral centre-edge angle and acetabular index). RESULTS: The 95 % reference interval limits were all far beyond the abnormal thresholds found in the literature for cam-type and to a lesser extent for pincer-type FAI. The upper limits of the reference intervals for the alpha angles (at 90°/45°) were 68°/83° (men) and 69°/84° (women), compared to thresholds from the literature (50°, 55° or 60°). Reference intervals were similar between genders for cam-type parameters, and slightly differed for pincer-type. CONCLUSION: The 95 % reference intervals of morphometric measurements of FAI in asymptomatic hips were beyond the abnormal thresholds, which was especially true for cam-type FAI. Our results suggest the need for redefining the current morphometric parameters used in the diagnosis of FAI. KEY POINTS: ? 95 % reference intervals limits of FAI morphotype were beyond currently defined thresholds. ? Reference intervals of pincer-type morphotype measurements were close to current definitions. ? Reference intervals of cam-type morphotype measurements were far beyond the current definitions. ? Current morphometric definitions of cam-type morphotype should be used with care

A review on herbal antiasthmatics

In traditional systems of medicine, many plants have been documented to be useful for the treatment of various respiratory disorders including asthma. In the last two decades the use of medicinal plants and natural products has been increased dramatically all over the world. Current synthetic drugs used in pharmacotherapy of asthma are unable to act at all the stages and targets of asthma. However some herbal alternatives employed in asthma are proven to provide symptomatic relief and assist in the inhibition of disease progression also. The herbs have shown interesting results in various target specific biological activities such as bronchodilation, mast cell stabilization, anti-anaphylactic, anti-inflammatory, anti-spasmodic, anti-allergic, immunomodulatory and inhibition of mediators such as leukotrienes, lipoxygenase, cyclooxygenase, platelet activating, phosphodiesterase and cytokine, in the treatment of asthma. This paper is an attempt to classify these pharmacological and clinical findings based on their possible mechanism of action reported. It also signifies the need for development of polyherbal formulations containing various herbs acting at particular sites of the pathophysiological cascade of asthma for prophylaxis as well as for the treatment of asthma

Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice

Background: There is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation. Methods and Findings: Expression of genes involved in ER stress were examined in beta cell enriched tissue obtained with laser capture microdissection (LCM) from frozen sections of pancreases obtained from non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 wk. Because mice have higher glucose levels than humans, the transplanted beta cells were exposed to mild hyperglycemia and the abnormal environment of the transplant site. RNA was extracted from the LCM specimens, amplified and then subjected to microarray analysis. The transplanted beta cells showed an unfolded protein response (UPR). There was activation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress, increased expression of ER chaperones and ERAD (ER-associated protein degradation) proteins. The other two arms of ER stress, PERK and ATF-6, had many down regulated genes. Downregulation of EIF2A could protect by inhibiting protein synthesis. Two genes known to contribute to apoptosis, CHOP and JNK, were downregulated. Conclusions: Human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins

Using a limited mapping strategy to identify major QTLs for resistance to grapevine powdery mildew (Erysiphe necator) and their use in marker-assisted breeding

A limited genetic mapping strategy based on simple sequence repeat (SSR) marker data was used with five grape populations segregating for powdery mildew (Erysiphe necator) resistance in an effort to develop genetic markers from multiple sources and enable the pyramiding of resistance loci. Three populations derived their resistance from Muscadinia rotundifolia ‘Magnolia’. The first population (06708) had 97 progeny and was screened with 137 SSR markers from seven chromosomes (4, 7, 9, 12, 13, 15, and 18) that have been reported to be associated with powdery or downy mildew resistance. A genetic map was constructed using the pseudo-testcross strategy and QTL analysis was carried out. Only markers from chromosome 13 and 18 were mapped in the second (04327) and third (06712) populations, which had 47 and 80 progeny, respectively. Significant QTLs for powdery mildew resistance with overlapping genomic regions were identified for different tissue types (leaf, stem, rachis, and berry) on chromosome 18, which distinguishes the resistance in ‘Magnolia’ from that present in other accessions of M. rotundifolia and controlled by the Run1 gene on chromosome 12. The ‘Magnolia’ resistance locus was termed as Run2.1. Powdery mildew resistance was also mapped in a fourth population (08391), which had 255 progeny and resistance from M. rotundifolia ‘Trayshed’. A locus accounting for 50% of the phenotypic variation mapped to chromosome 18 and was named Run2.2. This locus overlapped the region found in the ‘Magnolia’-based populations, but the allele sizes of the flanking markers were different. ‘Trayshed’ and ‘Magnolia’ shared at least one allele for 68% of the tested markers, but alleles of the other 32% of the markers were not shared indicating that the two M. rotundifolia selections were very different. The last population, 08306 with 42 progeny, derived its resistance from a selection Vitis romanetii C166-043. Genetic mapping discovered a major powdery mildew resistance locus termed Ren4 on chromosome 18, which explained 70% of the phenotypic variation in the same region of chromosome 18 found in the two M. rotundifolia resistant accessions. The mapping results indicate that powdery mildew resistance genes from different backgrounds reside on chromosome 18, and that genetic markers can be used as a powerful tool to pyramid these loci and other powdery mildew resistance loci into a single line

Dehydrocostuslactone Suppresses Angiogenesis In Vitro and In Vivo through Inhibition of Akt/GSK-3β and mTOR Signaling Pathways

The traditional Chinese medicine component dehydrocostuslactone (DHC) isolated from Saussurea costus (Falc.) Lipschitz, has been shown to have anti-cancer activity. Angiogenesis is an essential process in the growth and progression of cancer. In this study, we demonstrated, for the first time, the anti-angiogenic mechanism of action of DHC to be via the induction of cell cycle progression at the G0/G1 phase due to abrogation of the Akt/glycogen synthase kinase-3β (GSK-3β)/cyclin D1 and mTOR signaling pathway. First, we demonstrated that DHC has an anti-angiogenic effect in the matrigel-plug nude mice model and an inhibitory effect on human umbilical vein endothelial cell (HUVEC) proliferation and capillary-like tube formation in vitro. DHC caused G0/G1 cell cycle arrest, which was associated with the down-regulation of cyclin D1 expression, leading to the suppression of retinoblastoma protein phosphorylation and subsequent inhibition of cyclin A and cdk2 expression. With respect to the molecular mechanisms underlying the DHC-induced cyclin D1 down-regulation, this study demonstrated that DHC significantly inhibits Akt expression, resulting in the suppression of GSK-3β phosphorylation and mTOR expression. These effects are capable of regulating cyclin D1 degradation, but they were significantly reversed by constitutively active myristoylated (myr)-Akt. Furthermore, the abrogation of tube formation induced by DHC was also reversed by overexpression of Akt. And the co-treatment with LiCl and DHC significantly reversed the growth inhibition induced by DHC. Taken together, our study has identified Akt/GSK-3β and mTOR as important targets of DHC and has thus highlighted its potential application in angiogenesis-related diseases, such as cancer