Contribution of the cyclic nucleotide gated channel subunit, CNG-3, to olfactory plasticity in Caenorhabditis elegans.

In Caenorhabditis elegans, the AWC neurons are thought to deploy a cGMP signaling cascade in the detection of and response to AWC sensed odors. Prolonged exposure to an AWC sensed odor in the absence of food leads to reversible decreases in the animal's attraction to that odor. This adaptation exhibits two stages referred to as short-term and long-term adaptation. Previously, the protein kinase G (PKG), EGL-4/PKG-1, was shown necessary for both stages of adaptation and phosphorylation of its target, the beta-type cyclic nucleotide gated (CNG) channel subunit, TAX-2, was implicated in the short term stage. Here we uncover a novel role for the CNG channel subunit, CNG-3, in short term adaptation. We demonstrate that CNG-3 is required in the AWC for adaptation to short (thirty minute) exposures of odor, and contains a candidate PKG phosphorylation site required to tune odor sensitivity. We also provide in vivo data suggesting that CNG-3 forms a complex with both TAX-2 and TAX-4 CNG channel subunits in AWC. Finally, we examine the physiology of different CNG channel subunit combinations

Blood pressure screening during the May Measurement Month 2017 programme in Vietnam-South-East Asia and Australasia.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programmes worldwide. Our aim was to screen for hypertension (HTN) and cardiovascular risk factors in people aged ≥18 years in the community, thereby define the proportion of subjects with elevated BP and assess the awareness and the effectiveness of its treatment. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017. Blood pressure measurement, the definition of HTN and statistical analysis followed the standard MMM protocol. From May 2017 to June 2017, through 10 cities/provinces in Vietnam, 10 993 individuals with mean age 49.1 ± 16.2 years were screened during MMM17. After multiple imputation, 3154 (28.7%) had HTN. Of individuals not receiving antihypertensive medication, 1509 (16.1%) were hypertensive. Of individuals receiving antihypertensive medication, 620 (37.7%) had uncontrolled BP. Raised BP was also associated with additional risk factors including smoking, alcohol, overweight-obesity, and diabetes. May Measurement Month 17 was the largest BP screening campaign ever undertaken in Vietnam. Undiagnosed and uncontrolled HTN in Vietnam remains a substantial health problem. Local campaigns applying standardized methods such as MMM17, will be highly useful to screen for the significant number of individuals with raised BP and increase the awareness of HTN

Global instability in the Ghil--Sellers model

The Ghil--Sellers model, a diffusive one-dimensional energy balance model of Earth's climate, features---for a considerable range of the parameter descriptive of the intensity of the incoming radiation---two stable climate states, where the bistability results from the celebrated ice-albedo feedback. The warm state is qualitatively similar to the present climate, while the cold state corresponds to snowball conditions. Additionally, in the region of bistability, one can find unstable climate states. We find such unstable states by applying for the first time in a geophysical context the so-called edge tracking method, which has been used for studying multiple coexisting states in shear flows. This method has a great potential for studying the global instabilities in multistable systems, and for providing crucial information on the possibility of transitions when forcing is present. We examine robustness, efficiency, and accuracy properties of the edge tracking algorithm. We find that the procedure is the most efficient when taking a single bisection per cycle. Due to the strong diffusivity of the system, the transient dynamics, is approximately confined to the heteroclininc trajectory, connecting the fixed unstable and stable states, after relatively short transient times. Such a constraint dictates a functional relationship between observables. We characterize such a relationship between the global average temperature and a descriptor of nonequilibrium thermodynamics, the large scale temperature gradient between low and high latitudes. We find that a maximum of the temperature gradient is realized at the same value of the average temperature, about 270 K, largely independent of the strength of incoming solar radiation. Due to this maximum, a transient increase and nonmonotonic evolution of the temperature gradient is possible and not untypical. We also examine the structural properties of the system defined by bifurcation diagrams describing the equilibria depending on a system parameter of interest, here the solar strength. We construct new bifurcation diagrams in terms of quantities relevant for describing thermodynamic properties such as the temperature gradient and the material entropy production due to heat transport. We compare our results for the energy balance model to results for the intermediate complexity general circulation model the Planet Simulator and find an interesting qualitative agreement

Role of PCSK5 Expression in Mouse Ovarian Follicle Development: Identification of the Inhibin α- and β-Subunits as Candidate Substrates

Inhibin and activin are essential dimeric glycoproteins belonging to the transforming growth factor-beta (TGFβ) superfamily. Inhibin is a heterodimer of α- and β-subunits, whereas activin is a homodimer of β-subunits. Production of inhibin is regulated during the reproductive cycle and requires the processing of pro-ligands to produce mature hormone. Furin is a subtilisin-like proprotein convertase (proconvertase) that activates precursor proteins by cleavage at basic sites during their transit through the secretory pathway and/or at the cell surface. We hypothesized that furin-like proconvertases are central regulators of inhibin α- and β-subunit processing within the ovary. We analyzed the expression of the proconvertases furin, PCSK5, PCSK6, and PCSK7 in the developing mouse ovary by real-time quantitative RT-PCR. The data showed that proconvertase enzymes are temporally expressed in ovarian cells. With the transition from two-layer secondary to pre-antral follicle, only PCSK5 mRNA was significantly elevated. Activin A selectively enhanced expression of PCSK5 mRNA and decreased expression of furin and PCSK6 in cultured two-layer secondary follicles. Inhibition of proconvertase enzyme activity by dec-RVKR-chloromethylketone (CMK), a highly specific and potent competitive inhibitor of subtilisin-like proconvertases, significantly impeded both inhibin α- and β-subunit maturation in murine granulosa cells. Overexpression of PC5/6 in furin-deficient cells led to increased inhibin α- and βB-subunit maturation. Our data support the role of proconvertase PCSK5 in the processing of ovarian inhibin subunits during folliculogenesis and suggest that this enzyme may be an important regulator of inhibin and activin bioavailability

Blood-based immune-endocrine biomarkers of treatment response in depression

Antidepressant treatment for major depressive disorder remains suboptimal with response rates of just over 50%. Although treatment guidelines, algorithms and clinical keys are available to assist the clinician, the process of finding an effective pharmacotherapy to maximise benefit for the individual patient is largely by "trial and error" and remains challenging. This highlights a clear need to identify biomarkers of treatment response to help guide personalised treatment strategies. We have carried out the largest multiplex immunoassay based longitudinal study to date, examining up to 258 serum markers involved in immune, endocrine and metabolic processes as potential biomarkers associated with treatment response in 332 depression patients recruited from four independent clinical centres. We demonstrated for the first time that circulating Apolipoprotein A-IV, Endoglin, Intercellular Adhesion Molecule 1, Tissue Inhibitor of Metalloproteinases 1, Plasminogen Activator Inhibitor 1, Thrombopoietin, Complement C3, Hepatocyte Growth Factor and Insulin-like Growth Factor-Binding Protein 2 were associated with response to different antidepressants. In addition, we showed that specific sets of immune-endocrine proteins were associated with response to Venlafaxine (serotonin-norepinephrine reuptake inhibitor), Imipramine (tricyclic antidepressant) and other antidepressant drugs. However, we were not able to reproduce the literature findings on BDNF and TNF-$\alpha$, two of the most commonly reported candidate treatment response markers. Despite the need for extensive validation studies, our preliminary findings suggest that a pre-treatment immune-endocrine profile may help to determine a patient's likelihood to respond to specific antidepressant and/or alternative treatments such as anti-inflammatory drugs, providing hope for future personalised treatment approaches.Drs Chan, Cooper and Prof. Bahn were supported by grants from the Stanley Medical Research Institute (no. 07R-1888). The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10- 000-1002) and is supported by participating universities (VU University Medical Center, Arkin, Leiden University Medical Center, University Medical Center Groningen

Thermodynamic analysis of black hole solutions in gravitating nonlinear electrodynamics

We perform a general study of the thermodynamic properties of static electrically charged black hole solutions of nonlinear electrodynamics minimally coupled to gravitation in three space dimensions. The Lagrangian densities governing the dynamics of these models in flat space are defined as arbitrary functions of the gauge field invariants, constrained by some requirements for physical admissibility. The exhaustive classification of these theories in flat space, in terms of the behaviour of the Lagrangian densities in vacuum and on the boundary of their domain of definition, defines twelve families of admissible models. When these models are coupled to gravity, the flat space classification leads to a complete characterization of the associated sets of gravitating electrostatic spherically symmetric solutions by their central and asymptotic behaviours. We focus on nine of these families, which support asymptotically Schwarzschild-like black hole configurations, for which the thermodynamic analysis is possible and pertinent. In this way, the thermodynamic laws are extended to the sets of black hole solutions of these families, for which the generic behaviours of the relevant state variables are classified and thoroughly analyzed in terms of the aforementioned boundary properties of the Lagrangians. Moreover, we find universal scaling laws (which hold and are the same for all the black hole solutions of models belonging to any of the nine families) running the thermodynamic variables with the electric charge and the horizon radius. These scale transformations form a one-parameter multiplicative group, leading to universal "renormalization group"-like first-order differential equations. The beams of characteristics of these equations generate the full set of black hole states associated to any of these gravitating nonlinear electrodynamics...Comment: 51 single column pages, 19 postscript figures, 2 tables, GRG tex style; minor corrections added; final version appearing in General Relativity and Gravitatio

Child malaria treatment decisions by mothers of children less than five years of age attending an outpatient clinic in south-west Nigeria: an application of the PEN-3 cultural model

<p>Abstract</p> <p>Background</p> <p>Using the PEN-3 cultural model, this study sought to understand mothers treatment decisions about their child febrile illness by examining positive health beliefs and practices held by mothers, examine existential (unique) practices that are indigenous to mothers and have no harmful health consequences, and explore negative beliefs and practices that limit recommended responses to febrile illness in children.</p> <p>Methods</p> <p>This qualitative study was conducted in the paediatric section of an outpatient clinic in south-west Nigeria. A total of 123 mothers with children less than five years of age with febrile illness diagnosed as malaria by physicians were individually interviewed on their treatment-seeking practices prior to visiting the clinic and their reasons for attendance at the clinic.</p> <p>Results</p> <p>For some mothers interviewed, effective treatment from the clinic for their child's febrile illness, coupled with physician's approach with malaria diagnosis and treatment practices was important in generating positive maternal treatment-seeking responses to child febrile illness. In addition, beliefs related to a child teething highlighted existential decisions with treatment-seeking for child febrile illness in this setting. Finally, the belief that febrile illness is not all that severe despite noticeable signs and symptoms was a concerning negative perception shared by some mothers in this study.</p> <p>Conclusion</p> <p>The findings highlight the need to consider not only the responses that may serve as barriers to effective treatment, but also an acknowledgment of the positive and existential responses that are equally critical in influencing mothers' management of malaria in their children.</p

Treatment-seeking behaviour for febrile illness in an area of seasonal malaria transmission in rural Ethiopia

BACKGROUND: Very little is known about the management of malaria and treatment-seeking patterns among children and adults in areas of seasonal malaria transmission particularly in east Africa. OBJECTIVES: The aim of this study was to assess treatment-seeking behaviour for reported malaria among all age groups in an area of seasonal transmission. METHODS: A community-based cross-sectional study was carried out among 2,253 households in 12 randomly selected rural kebeles in Adami Tulu district in south-central Ethiopia, during October-November 2003, using a pre-tested interviewer-administered structured questionnaire. RESULTS: Reported malaria was 14% among 12,225 people assessed during the last 14 days. Family/self-diagnosis was most common and the main first responses included visiting village-based community health workers (CHWs) (33%), public health facility (23%) and private clinic (17%). Home treatment was the least reported first response (3%). Only 13% had sought treatment within the first 24 hours of symptom onset. Early treatment-seeking pattern was reported among those who visited CHWs and practiced home treatment, with more delays among public facility users. Treatment-seeking behaviour was similar in all age groups. CONCLUSION: A considerable proportion of visits were made to CHWs and private providers, necessitating the importance of strengthening both community-based interventions and peripheral public and private facilities. Finally, the community should be informed and educated about the importance of early diagnosis and prompt treatment with effective antimalarials

Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies

<p>Abstract</p> <p>Background</p> <p>Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria.</p> <p>Methods</p> <p>Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of <it>Plasmodium falciparum </it>parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success.</p> <p>Results</p> <p>Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether.</p> <p>Conclusion</p> <p>Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy.</p