Recent Updates on the Melanin-Concentrating Hormone (MCH) and Its Receptor System: Lessons from MCH1R Antagonists

Melanin-concentrating hormone (MCH) is a 19-amino-acid cyclic peptide which was originally found to lighten skin color in fish that is highly conserved among many species. MCH interacts with two G-protein-coupled receptors, MCH1R and MCH2R, but only MCH1R is expressed in rodents. MCH is mainly synthesized in the lateral hypothalamus and zona incerta, while MCH1R is widely expressed throughout the brain. Thus, MCH signaling is implicated in the regulation of many physiological functions. The identification of MCH1R has led to the development of small-molecule MCH1R antagonists that can block MCH signaling. MCH1R antagonists are useful not only for their potential therapeutic value, but also for understanding the physiological functions of the endogenous MCH system. Here, we review the physiological functions of the MCH system which have been investigated using MCH1R antagonists such as food intake, anxiety, depression, reward, and sleep. This will help us understand the physiological functions of the MCH system and suggest some of the potential applications of MCH1R antagonists in human disorders

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Prevalence of variations in melanoma susceptibility genes among Slovenian melanoma families

<p>Abstract</p> <p>Background</p> <p>Two high-risk genes have been implicated in the development of CM (cutaneous melanoma). Germline mutations of the CDKN2A gene are found in < 25% of melanoma-prone families and there are only seven families with mutation of the <it>CDK4 </it>gene reported to date. Beside those high penetrance genes, certain allelic variants of the <it>MC1R </it>gene modify the risk of developing the disease.</p> <p>The aims of our study were: to determine the prevalence of germline <it>CDKN2A </it>mutations and variants in members of families with familial CM and in patients with multiple primary CM; to search for possible <it>CDK4 </it>mutations, and to determine the frequency of variations in the <it>MC1R </it>gene.</p> <p>Methods</p> <p>From January 2001 until January 2007, 64 individuals were included in the study. The group included 28 patients and 7 healthy relatives belonging to 25 families, 26 patients with multiple primary tumors and 3 children with CM. Additionally 54 healthy individuals were included as a control group. Mutations and variants of the melanoma susceptibility genes were identified by direct sequencing.</p> <p>Results</p> <p>Seven families with CDKN2A mutations were discovered (7/25 or 28.0%). The L94Q mutation found in one family had not been previously reported in other populations. The D84N variant, with possible biological impact, was discovered in the case of patient without family history but with multiple primary CM. Only one mutation carrier was found in the control group. Further analysis revealed that c.540C>T heterozygous carriers were more common in the group of CM patients and their healthy relatives (11/64 vs. 2/54). One p14ARF variant was discovered in the control group and no mutations of the <it>CDK4 </it>gene were found.</p> <p>Most frequently found variants of the <it>MC1R </it>gene were T314T, V60L, V92M, R151C, R160W and R163Q with frequencies slightly higher in the group of patients and their relatives than in the group of controls, but the difference was statistically insignificant.</p> <p>Conclusion</p> <p>The present study has shown high prevalence of p16INK4A mutations in Slovenian population of familial melanoma patients (37%) and an absence of p14ARF or <it>CDK4 </it>mutations.</p

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Study protocol for a pragmatic randomised controlled trial in general practice investigating the effectiveness of acupuncture against migraine

<p>Abstract</p> <p>Background</p> <p>Migraine is a chronic neurologic disease that can severely affect the patient's quality of life. Although in recent years many randomised studies have been carried out to investigate the effectiveness of acupuncture as a treatment for migraine, it remains a controversial issue. Our aim is to determine whether acupuncture, applied under real conditions of clinical practice in the area of primary healthcare, is more effective than conventional treatment.</p> <p>Methods/Design</p> <p>The design consists of a pragmatic multi-centre, three-armed randomised controlled trial, complemented with an economic evaluation of the results achieved, comparing the effectiveness of verum acupuncture with sham acupuncture, and with a control group receiving normal care only.</p> <p>Patients eligible for inclusion will be those presenting in general practice with migraine and for whom their General Practitioner (GP) is considering referral for acupuncture. Sampling will be by consecutive selection, and by randomised allocation to the three branches of the study, in a centralised way following a 1:1:1 distribution (verum acupuncture; sham acupuncture; conventional treatment). Secondly, one patient in three will be randomly selected from each of the acupuncture (verum or sham) groups for a brain perfusion study (by single photon emission tomography). The treatment with verum acupuncture will consist of 8 treatment sessions, once a week, at points selected individually by the acupuncturist. The sham acupuncture group will receive 8 sessions, one per week, with treatment being applied at non-acupuncture points in the dorsal and lumbar regions, using the minimal puncture technique. The control group will be given conventional treatment, as will the other two groups.</p> <p>Discussion</p> <p>This trial will contribute to available evidence on acupuncture for the treatment of migraine. The primary endpoint is the difference in the number of days with migraine among the three groups, between the baseline period (the 4 weeks prior to the start of treatment) and the period from weeks 9 to 12. As a secondary aspect, we shall record the index of laterality and the percentage of change in the mean count per pixel in each region of interest measured by the brain perfusion tomography, performed on a subsample of the patients within the real and sham acupuncture groups.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN98703707.</p

Hepatitis C virus to hepatocellular carcinoma

Hepatitis C virus causes acute and chronic hepatitis and can lead to permanent liver damage and hepatocellular carcinoma (HCC) in a significant number of patients via oxidative stress, insulin resistance (IR), fibrosis, liver cirrhosis and HCV induced steatosis. HCV induced steatosis and oxidative stress causes steato-hepatitis and these pathways lead to liver injury or HCC in chronic HCV infection. Steatosis and oxidative stress crosstalk play an important role in liver damage in HCV infection. This Review illustrates viral and host factors which induce Oxidative stress, steatosis and leads toward HCC. It also expresses Molecular cascade which leads oxidative stress and steatosis to HCC

Regional Management Units for Marine Turtles: A Novel Framework for Prioritizing Conservation and Research across Multiple Scales

Background: Resolving threats to widely distributed marine megafauna requires definition of the geographic distributions of both the threats as well as the population unit(s) of interest. In turn, because individual threats can operate on varying spatial scales, their impacts can affect different segments of a population of the same species. Therefore, integration of multiple tools and techniques - including site-based monitoring, genetic analyses, mark-recapture studies and telemetry - can facilitate robust definitions of population segments at multiple biological and spatial scales to address different management and research challenges. Methodology/Principal Findings: To address these issues for marine turtles, we collated all available studies on marine turtle biogeography, including nesting sites, population abundances and trends, population genetics, and satellite telemetry. We georeferenced this information to generate separate layers for nesting sites, genetic stocks, and core distributions of population segments of all marine turtle species. We then spatially integrated this information from fine-to coarse-spatial scales to develop nested envelope models, or Regional Management Units (RMUs), for marine turtles globally. Conclusions/Significance: The RMU framework is a solution to the challenge of how to organize marine turtles into units of protection above the level of nesting populations, but below the level of species, within regional entities that might be on independent evolutionary trajectories. Among many potential applications, RMUs provide a framework for identifying data gaps, assessing high diversity areas for multiple species and genetic stocks, and evaluating conservation status of marine turtles. Furthermore, RMUs allow for identification of geographic barriers to gene flow, and can provide valuable guidance to marine spatial planning initiatives that integrate spatial distributions of protected species and human activities. In addition, the RMU framework - including maps and supporting metadata - will be an iterative, user-driven tool made publicly available in an online application for comments, improvements, download and analysis

FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics

FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1

We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics