Rtg signaling sustains mitochondrial respiratory capacity in hog1-dependent osmoadaptation

Mitochondrial RTG-dependent retrograde signaling, whose regulators have been characterized in Saccharomyces cerevisiae, plays a recognized role under various environmental stresses. Of special significance, the activity of the transcriptional complex Rtg1/3 has been shown to be modu-lated by Hog1, the master regulator of the high osmolarity glycerol pathway, in response to osmotic stress. The present work focuses on the role of RTG signaling in salt-induced osmotic stress and its interaction with HOG1. Wild-type and mutant cells, lacking HOG1 and/or RTG genes, are compared with respect to cell growth features, retrograde signaling activation and mitochondrial function in the presence and in the absence of high osmostress. We show that RTG2, the main upstream regulator of the RTG pathway, contributes to osmoadaptation in an HOG1-dependent manner and that, with RTG3, it is notably involved in a late phase of growth. Our data demonstrate that impairment of RTG signaling causes a decrease in mitochondrial respiratory capacity exclusively under os-mostress. Overall, these results suggest that HOG1 and the RTG pathway may interact sequentially in the stress signaling cascade and that the RTG pathway may play a role in inter-organellar metabolic communication for osmoadaptation

Cirurgia neuroendoscópica para tratamento da hidrocefalia unilateral secundária à obstrução inflamatória do forame de Monro

OBJECTIVE: Unilateral hydrocephalus (UH) is characterized by enlargement of just one lateral ventricle. In this paper, the authors will demonstrate their experiences in the neuroendoscopic management of this uncommon type of hydrocephalus. METHOD: The authors retrospectively reviewed a serie of almost 800 neuroendoscopic procedures performed from September 1995 to July 2010 and selected seven adult patients with UH. Clinical and radiological charts were reviewed and analyzed. RESULTS: Six patients had intraventricular neurocysticercosis and one patient had congenital stenosis of the foramen of Monro. Headaches were the most common symptom. A septostomy restored cerebrospinal fluid circulation. During follow-up period (65.5 months, range 3-109) no patient has presented clinical recurrence as well as no severe complications have been observed. CONCLUSION: UH is a rare condition. A successful treatment can be accomplished through a neuroendoscopic approach avoiding the use of ventricular shunts.OBJETIVO: Hidrocefalia unilateral (HU) é caracterizada pelo alargamento de apenas um dos ventrículos laterais. Neste estudo, os autores demonstraram sua experiência no manejo deste tipo incomum de hidrocefalia. MÉTODO: Foram revisados, de uma série de quase 800 cirurgias neuroendoscópicas realizadas entre Setembro de 1995 e Julho de 2010, sete pacientes adultos com diagnóstico de HU. Dados clínicos e radiológicos foram analisados. RESULTADOS: Seis pacientes tinham neurocisticercose intraventricular e um apresentava uma estenose congênita do forame de Monro. Cefaléia foi o sintoma clínico mais comum. Uma septostomia restabeleceu o fluxo liquórico. Durante o seguimento (65,5 meses, de 3-109), nenhum paciente apresentou recorrência clínica assim como nenhuma complicação grave foi observada. CONCLUSÃO: HU é uma condição rara. O tratamento satisfatório pode ser alcançado por meio de uma abordagem neuroendoscópica evitando, desta maneira, o uso de sistemas de derivação ventricular.Federal University of São Paulo Division of Neurosurgery Department of Neurology and NeurosurgeryUNIFESP, Division of Neurosurgery Department of Neurology and NeurosurgerySciEL

E-Cadherin Destabilization Accounts for the Pathogenicity of Missense Mutations in Hereditary Diffuse Gastric Cancer

E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated). Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo

Exploring the endocannabinoidome in genetically obese (ob/ob) and diabetic (db/db) mice: Links with inflammation and gut microbiota

Background: Obesity and type 2 diabetes are two interrelated metabolic disorders characterized by insulin resistance and a mild chronic inflammatory state. We previously observed that leptin (ob/ob) and leptin receptor (db/db) knockout mice display a distinct inflammatory tone in the liver and adipose tissue. The present study aimed at investigating whether alterations in these tissues of the molecules belonging to the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system, whose functions are important in the context of metabolic disorders and inflammation, could reflect their different inflammatory phenotypes. Results: The basal eCBome lipid and gene expression profiles, measured by targeted lipidomics and qPCR transcriptomics, respectively, in the liver and subcutaneous or visceral adipose tissues, highlighted a differentially altered eCBome tone, which may explain the impaired hepatic function and more pronounced liver inflammation remarked in the ob/ob mice, as well as the more pronounced inflammatory state observed in the subcutaneous adipose tissue of db/db mice. In particular, the levels of linoleic acid-derived endocannabinoid-like molecules, of one of their 12-lipoxygenase metabolites and of Trpv2 expression, were always altered in tissues exhibiting the highest inflammation. Correlation studies suggested the possible interactions with some gut microbiota bacterial taxa, whose respective absolute abundances were significantly different between ob/ob and the db/db mice. Conclusions: The present findings emphasize the possibility that bioactive lipids and the respective receptors and enzymes belonging to the eCBome may sustain the tissue-dependent inflammatory state that characterizes obesity and diabetes, possibly in relation with gut microbiome alterations

Contamination Control and Assay Results for the Majorana Demonstrator Ultra Clean Components

The MAJORANA DEMONSTRATOR is a neutrinoless double beta decay experiment utilizing enriched Ge-76 detectors in 2 separate modules inside of a common solid shield at the Sanford Underground Research Facility. The DEMONSTRATOR has utilized world leading assay sensitivities to develop clean materials and processes for producing ultra-pure copper and plastic components. This experiment is now operating, and initial data provide new insights into the success of cleaning and processing. Post production copper assays after the completion of Module 1 showed an increase in U and Th contamination in finished parts compared to starting bulk material. A revised cleaning method and additional round of surface contamination studies prior to Module 2 construction have provided evidence that more rigorous process control can reduce surface contamination. This article describes the assay results and discuss further studies to take advantage of assay capabilities for the purpose of maintaining ultra clean fabrication and process design.Comment: Proceedings of Low Radioactivity Techniques (LRT May 2017, Seoul

Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature

<p>Abstract</p> <p>Background</p> <p>The frequency of E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has not been well established. The goal of this study was to assess the worldwide frequency of <it>CDH1 </it>germline mutations in gastric cancers coming from low- and high-risk areas.</p> <p>Methods</p> <p>English articles using MEDLINE access (from 1998 to 2011). Search terms included <it>CDH1</it>, E-cadherin, germline mutation, gastric cancer, hereditary, familial and diffuse histotype.</p> <p>The study included all E-cadherin germline mutations identified in gastric cancer patients; somatic mutations and germline mutations reported in other tumors were excluded.</p> <p>The method of this study was scheduled in accordance with the "PRISMA statement for reporting systematic reviews and meta-analyses". Countries were classified as low- or middle/high risk-areas for gastric carcinoma incidence. Statistical analysis was performed to correlate the <it>CDH1 </it>mutation frequency with gastric cancer incidence areas.</p> <p>Results</p> <p>A total of 122 E-cadherin germline mutations have been identified; the majority (87.5%) occurred in gastric cancers coming from low-risk areas. In high-risk areas, we identified 16 mutations in which missense mutations were predominant. (68.8%). We verified a significant association between the mutation frequency and the gastric cancer risk area (<it>p </it>< 0.001: overall identified mutations in low- vs. middle/high-risk areas).</p> <p>Conclusions</p> <p>E-cadherin genetic screenings performed in low-risk areas for gastric cancer identified a higher frequency of <it>CDH1 </it>germline mutations. This data could open new approaches in the gastric cancer prevention test; before proposing a proband candidate for the <it>CDH1 </it>genetic screening, geographic variability, alongside the family history should be considered.</p