Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity

The skin is equipped with specialized mechanoreceptors that allow the perception of the slightest brush. Indeed, some mechanoreceptors can detect even nanometer-scale movements. Movement is transformed into electrical signals via the gating of mechanically activated ion channels at sensory endings in the skin. The sensitivity of Piezo mechanically gated ion channels is controlled by stomatin-like protein-3 (STOML3), which is required for normal mechanoreceptor function. Here we identify small-molecule inhibitors of STOML3 oligomerization that reversibly reduce the sensitivity of mechanically gated currents in sensory neurons and silence mechanoreceptors $\textit{in vivo}$. STOML3 inhibitors in the skin also reversibly attenuate fine touch perception in normal mice. Under pathophysiological conditions following nerve injury or diabetic neuropathy, the slightest touch can produce pain, and here STOML3 inhibitors can reverse mechanical hypersensitivity. Thus, small molecules applied locally to the skin can be used to modulate touch and may represent peripherally available drugs to treat tactile-driven pain following neuropathy.This study was funded by DFG collaborative research grant SFB958 (projects A09 to K.P. and G.R.L., A01 to V.H. and Z02 to J.S.). Additional support was provided by a senior ERC grant (grant number 294678 to G.R.L.) and by the NeuroCure Cluster of Excellence (to V.H., G.R.L. and J.F.A.P.). K.P. was supported by a Cecile-Vogt Fellowship (MDC). S.P. was supported by a Marie Curie Fellowship from the European Union (grant number 253663 Touch in situ). C.P. received a Ph.D. fellowship from the University of Cagliari. J.F.A.P. was funded by a European Research Council (ERC) starting grant (ERC-2010-StG-260590), the DFG (FOR 1341, FOR 2143), the Berlin Institute of Health (BIH) and the European Union (FP7, 3x3Dimaging 323945). R.K. was supported by an ERC Advanced Investigator grant (294293-PAIN PLASTICITY). D.H. was funded by the Berlin Institute of Health (BIH). E.St.J.S., L.E. and M.M. were supported by an Alexander von Humboldt Fellowship

Predictors of overweight and obesity in five to seven-year-old children in Germany: Results from cross-sectional studies

BACKGROUND: Childhood obesity is a serious public health problem and epidemiological studies are important to identify predictive factors. It is the aim of this study to analyse factors associated with overweight/obesity in samples of German children. METHODS: 35,434 five to seven year-old children (50.9% boys) participated in cross-sectional studies between 1991 and 2000 in several rural and urban areas in East and West Germany. Weight and height were measured and body mass index was calculated. International cut-off points, recommended by the International Obesity Task Force, were used to classify childhood overweight and obesity. Predictive modelling was employed to analyse independently associated factors, using logistic regression to adjust for confounding. RESULTS: 15.5% were overweight, and 4.3% were obese. Female sex, other than German nationality, smoking in the living place and increasing birth weight were found to increase the odds of overweight and obesity, while increasing educational level, living space > 75 m2 and breastfeeding for more than three months were inversely associated. CONCLUSION: The findings add to the evidence informing public health action, both through health promotion strategies (promoting breastfeeding, tackling smoking) and wider societal change management (addressing children from migrant families and families with low educational level)

Maternal postnatal depression and child growth: a European cohort study

<p>Abstract</p> <p>Background</p> <p>Previous studies have reported postpartum depression to be associated with both positive and negative effects on early infant growth. This study examined the hypothesis that maternal postnatal depression may be a risk factor for later child growth faltering or overweight.</p> <p>Methods</p> <p>A total of 929 women and their children participating in a European multicenter study were included at a median age of 14 days. Mothers completed the Edinburgh postnatal depression scale (EPDS) at 2, 3 and 6 months after delivery. EPDS scores of 13 and above at any time were defined as maternal depression. Weight, length, triceps and subscapular skinfold thicknesses were measured, and body mass index (BMI) were calculated when the children were two years old and converted to standard deviation scores based on the WHO Multicentre Growth Reference Study (MGRS).</p> <p>Results</p> <p>Z-scores for weight-for-length at inclusion of infants of mothers with high EPDS scores (-0.55, SD 0.74) were lower than of those with normal scores (-0.36, SD 0.74; p = 0.013). BMI at age 24 months did not differ in the high (16.3 kg/m2, SD 1.3) and in the normal EPDS groups (16.2 kg/m2, SD 1.3; p = 0.48). All other anthropometric indices also did not differ between groups, with no change by multivariate adjustment.</p> <p>Conclusions</p> <p>We conclude that a high maternal postnatal depression score does not have any major effects on offspring growth in high income countries.</p

Pentafluorosulfanyl (SF(5)) as a superior (19)F magnetic resonance reporter group: signal detection and biological activity of teriflunomide derivatives

Fluorine ((19)F) magnetic resonance imaging (MRI) is severely limited by a low signal-to noise ratio (SNR), and tapping it for (19)F drug detection in vivo still poses a significant challenge. However, it bears the potential for label-free theranostic imaging. Recently, we detected the fluorinated dihydroorotate dehydrogenase (DHODH) inhibitor teriflunomide (TF) noninvasively in an animal model of multiple sclerosis (MS) using (19)F MR spectroscopy (MRS). In the present study, we probed distinct modifications to the CF(3) group of TF to improve its SNR. This revealed SF(5) as a superior alternative to the CF(3) group. The value of the SF(5) bioisostere as a (19)F MRI reporter group within a biological or pharmacological context is by far underexplored. Here, we compared the biological and pharmacological activities of different TF derivatives and their (19)F MR properties (chemical shift and relaxation times). The (19)F MR SNR efficiency of three MRI methods revealed that SF(5)-substituted TF has the highest (19)F MR SNR efficiency in combination with an ultrashort echo-time (UTE) MRI method. Chemical modifications did not reduce pharmacological or biological activity as shown in the in vitro dihydroorotate dehydrogenase enzyme and T cell proliferation assays. Instead, SF(5)-substituted TF showed an improved capacity to inhibit T cell proliferation, indicating better anti-inflammatory activity and its suitability as a viable bioisostere in this context. This study proposes SF(5) as a novel superior (19)F MR reporter group for the MS drug teriflunomide

Pandemic Influenza A H1N1 2009 Infection versus Vaccination: A Cohort Study Comparing Immune Responses in Pregnancy

Background: With the emergence of H1N1 pandemic (pH1N1) influenza, the CDC recommended that pregnant women be one of five initial target groups to receive the 2009 monovalent H1N1 vaccine, regardless of prior infection with this influenza strain. We sought to compare the immune response of pregnant women to H1N1 infection versus vaccination and to determine the extent of passive immunity conferred to the newborn. Methods/Findings: During the 2009-2010 influenza season, we enrolled a cohort of women who either had confirmed pH1N1 infection during pregnancy, did not have pH1N1 during pregnancy but were vaccinated against pH1N1, or did not have illness or vaccination. Maternal and umbilical cord venous blood samples were collected at delivery. Hemagglutination inhibition assays (HAI) for pH1N1 were performed. Data were analyzed using linear regression analyses. HAIs were performed for matched maternal/cord blood pairs for 16 women with confirmed pH1N1 infection, 14 women vaccinated against pH1N1, and 10 women without infection or vaccination. We found that pH1N1 vaccination and wild-type infection during pregnancy did not differ with respect to (1) HAI titers at delivery, (2) HAI antibody decay slopes over time, and (3) HAI titers in the cord blood. Conclusions: Vaccination against pH1N1 confers a similar HAI antibody response as compared to pH1N1 infection durin

Enzyme Promiscuity in Enolase Superfamily. Theoretical Study of o-Succinylbenzoate Synthase Using QM/MM Methods

The promiscuous activity of the enzyme o-succinylbenzoate synthase (OSBS) from the actinobacteria Amycolatopsis is investigated by means of QM/MM methods, using both density functional theory and semiempirical Hamiltonians. This enzyme catalyzes not only the dehydration of 2-succinyl-6R-hydroxy-2,4-cyclohexadiene-1R-carboxylate but also catalyzes racemization of different acylamino acids, with N-succinyl-R-phenylglycine being the best substrate. We investigated the molecular mechanisms for both reactions exploring the potential energy surface. Then, molecular dynamics simulations were performed to obtain the free energy profiles and the averaged interaction energies of enzymatic residues with the reacting system. Our results confirm the plausibility of the reaction mechanisms proposed in the literature, with a good agreement between theoretical and experimentally derived activation free energies. Our simulations unravel the role played by the different residues in each of the two possible reactions. The presence of flexible loops in the active site and the selection of structural modifications in the substrate seem to be key elements to promote the promiscuity of this enzyme.This work was supported by the Spanish Ministerio de Economia y Competitividad project CTQ2012-36253-C03-03 ́ and FEDER funds. K.S. thanks the Polish National Science Center (NCN) for Grant 2011/02/A/ST4/00246. The authors acknowledge computational facilities of the Servei d’Informatica ̀ de la Universitat de Valencia in the ̀ “Tirant” supercomputer, which is part of the Spanish Supercomputing Network

Installing hydrolytic activity into a completely <i>de novo </i>protein framework

The design of enzyme-like catalysts tests our understanding of sequence-to-structure/function relationships in proteins. Here we install hydrolytic activity predictably into a completely de novo and thermostable α-helical barrel, which comprises seven helices arranged around an accessible channel. We show that the lumen of the barrel accepts 21 mutations to functional polar residues. The resulting variant, which has cysteine–histidine–glutamic acid triads on each helix, hydrolyses p-nitrophenyl acetate with catalytic efficiencies that match the most-efficient redesigned hydrolases based on natural protein scaffolds. This is the first report of a functional catalytic triad engineered into a de novo protein framework. The flexibility of our system also allows the facile incorporation of unnatural side chains to improve activity and probe the catalytic mechanism. Such a predictable and robust construction of truly de novo biocatalysts holds promise for applications in chemical and biochemical synthesis

Vaccination coverage and timeliness in three South African areas: a prospective study

<p>Abstract</p> <p>Background</p> <p>Timely vaccination is important to induce adequate protective immunity. We measured vaccination timeliness and vaccination coverage in three geographical areas in South Africa.</p> <p>Methods</p> <p>This study used vaccination information from a community-based cluster-randomized trial promoting exclusive breastfeeding in three South African sites (Paarl in the Western Cape Province, and Umlazi and Rietvlei in KwaZulu-Natal) between 2006 and 2008. Five interview visits were carried out between birth and up to 2 years of age (median follow-up time 18 months), and 1137 children were included in the analysis. We used Kaplan-Meier time-to-event analysis to describe vaccination coverage and timeliness in line with the Expanded Program on Immunization for the first eight vaccines. This included Bacillus Calmette-Guérin (BCG), four oral polio vaccines and 3 doses of the pentavalent vaccine which protects against diphtheria, pertussis, tetanus, hepatitis B and Haemophilus influenzae type B.</p> <p>Results</p> <p>The proportion receiving all these eight recommended vaccines were 94% in Paarl (95% confidence interval [CI] 91-96), 62% in Rietvlei (95%CI 54-68) and 88% in Umlazi (95%CI 84-91). Slightly fewer children received all vaccines within the recommended time periods. The situation was worst for the last pentavalent- and oral polio vaccines. The hazard ratio for incomplete vaccination was 7.2 (95%CI 4.7-11) for Rietvlei compared to Paarl.</p> <p>Conclusions</p> <p>There were large differences between the different South African sites in terms of vaccination coverage and timeliness, with the poorer areas of Rietvlei performing worse than the better-off areas in Paarl. The vaccination coverage was lower for the vaccines given at an older age. There is a need for continued efforts to improve vaccination coverage and timeliness, in particular in rural areas.</p> <p>Trial registration number</p> <p>ClinicalTrials.gov: <a href="http://clinicaltrials.gov/ct2/show/NCT00397150">NCT00397150</a></p