Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

Longer pregnancy and slower fetal development in women with latent "asymptomatic" toxoplasmosis

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to confirm that women with latent toxoplasmosis have developmentally younger fetuses at estimated pregnancy week 16 and to test four exclusive hypotheses that could explain the observed data.</p> <p>Methods</p> <p>In the present retrospective cohort study we analysed by the GLM (general linear model) method data from 730 <it>Toxoplasma</it>-free and 185 <it>Toxoplasma</it>-infected pregnant women.</p> <p>Results</p> <p>At pregnancy week 16 estimated from the date of the last menstruation, the mothers with latent toxoplasmosis had developmentally younger fetuses based on ultrasound scan (<it>P </it>= 0.014). Pregnancy of <it>Toxoplasma</it>-positive compared to <it>Toxoplasma</it>-negative women was by about 1.3 days longer, as estimated both from the date of the last menstruation (<it>P </it>= 0.015) and by ultrasonography (<it>P </it>= 0.025).</p> <p>Conclusion</p> <p>The most parsimonious explanation for the observed data is retarded fetal growth during the first weeks of pregnancy in <it>Toxoplasma</it>-positive women. The phenomenon was only detectable in multiparous women, suggesting that the immune system may play some role in it.</p

Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Malaria paediatric hospitalization between 1999 and 2008 across Kenya

<p>Abstract</p> <p>Background</p> <p>Intervention coverage and funding for the control of malaria in Africa has increased in recent years, however, there are few descriptions of changing disease burden and the few reports available are from isolated, single site observations or are of reports at country-level. Here we present a nationwide assessment of changes over 10 years in paediatric malaria hospitalization across Kenya.</p> <p>Methods</p> <p>Paediatric admission data on malaria and non-malaria diagnoses were assembled for the period 1999 to 2008 from in-patient registers at 17 district hospitals in Kenya and represented the diverse malaria ecology of the country. These data were then analysed using autoregressive moving average time series models with malaria and all-cause admissions as the main outcomes adjusted for rainfall, changes in service use and populations-at-risk within each hospital's catchment to establish whether there has been a statistically significant decline in paediatric malaria hospitalization during the observation period.</p> <p>Results</p> <p>Among the 17 hospital sites, adjusted paediatric malaria admissions had significantly declined at 10 hospitals over 10 years since 1999; had significantly increased at four hospitals, and remained unchanged in three hospitals. The overall estimated average reduction in malaria admission rates was 0.0063 cases per 1,000 children aged 0 to 14 years per month representing an average percentage reduction of 49% across the 10 hospitals registering a significant decline by the end of 2008. Paediatric admissions for all-causes had declined significantly with a reduction in admission rates of greater than 0.0050 cases per 1,000 children aged 0 to 14 years per month at 6 of 17 hospitals. Where malaria admissions had increased three of the four sites were located in Western Kenya close to Lake Victoria. Conversely there was an indication that areas with the largest declines in malaria admission rates were areas located along the Kenyan coast and some sites in the highlands of Kenya.</p> <p>Conclusion</p> <p>A country-wide assessment of trends in malaria hospitalizations indicates that all is not equal, important variations exist in the temporal pattern of malaria admissions between sites and these differences require more detailed investigation to understand what is required to promote a clinical transition across Africa.</p

Asymptotic W-symmetries in three-dimensional higher-spin gauge theories

We discuss how to systematically compute the asymptotic symmetry algebras of generic three-dimensional bosonic higher-spin gauge theories in backgrounds that are asymptotically AdS. We apply these techniques to a one-parameter family of higher-spin gauge theories that can be considered as large N limits of SL(N) x SL(N) Chern-Simons theories, and we provide a closed formula for the structure constants of the resulting infinite-dimensional non-linear W-algebras. Along the way we provide a closed formula for the structure constants of all classical W_N algebras. In both examples the higher-spin generators of the W-algebras are Virasoro primaries. We eventually discuss how to relate our basis to a non-primary quadratic basis that was previously discussed in literature.Comment: 61 page

Obesity and nutrition behaviours in Western and Palestinian outpatients with severe mental illness

Extent: 7p.Background: While people with severe mental illness have been found to be more overweight and obese in Western nations, it is unknown to what extent this occurs in Middle Eastern nations and which eating behaviours contribute to obesity in Middle Eastern nations. Method: A total of 665 responses were obtained from patients with serious mental illness attending out-patient clinics in Western developed countries (Germany, UK and Australia; n = 518) and Palestine (n = 147). Patients were evaluated by ICD-10 clinical diagnosis, anthropometric measurements and completed a self-report measure of frequencies of consuming different food items and reasons for eating. Nutritional habits were compared against a Western normative group. Results: More participants from Palestine were overweight or obese (62%) compared to Western countries (47%). In the Western sample, obese patients reported consuming more low-fat products (OR 2.54, 95% CI 1.02-6.33) but also greater eating due to negative emotions (OR 1.84, 95% CI 1.31-2.60) than patients with a healthy body-mass index. In contrast, obese patients from Palestine reported increased consumption of unhealthy snacks (OR 3.73 95% CI 1.16-12.00). Conclusion: Patients with mental illness have poorer nutritional habits than the general population, particularly in Western nations. Separate interventions to improve nutritional habits and reduce obesity are warranted between Western nations and Palestine.David Jakabek, Frances Quirk, Martin Driessen, Yousef Aljeesh and Bernhard T Baun

The strengths and difficulties questionnaire as a predictor of parent-reported diagnosis of autism spectrum disorder and attention deficit hyperactivity disorder

notes: PMCID: PMC3848967This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The Strengths and Difficulties Questionnaire (SDQ) is widely used as an international standardised instrument measuring child behaviour. The primary aim of our study was to examine whether behavioral symptoms measured by SDQ were elevated among children with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) relative to the rest of the population, and to examine the predictive value of the SDQ for outcome of parent-reported clinical diagnosis of ASD/ADHD. A secondary aim was to examine the extent of overlap in symptoms between children diagnosed with these two disorders, as measured by the SDQ subscales. A cross-sectional secondary analysis of data from the Millennium Birth Cohort (n = 19,519), was conducted. Data were weighted to be representative of the UK population as a whole. ADHD or ASD identified by a medical doctor or health professional were reported by parents in 2008 and this was the case definition of diagnosis; (ADHD n = 173, ASD n = 209, excluding twins and triplets). Study children's ages ranged from 6.3-8.2 years; (mean 7.2 years). Logistic regression was used to examine the association between the parent-reported clinical diagnosis of ASD/ADHD and teacher and parent-reported SDQ subscales. All SDQ subscales were strongly associated with both ASD and ADHD. There was substantial co-occurrence of behavioral difficulties between children diagnosed with ASD and those diagnosed with ADHD. After adjustment for other subscales, the final model for ADHD, contained hyperactivity/inattention and impact symptoms only and had a sensitivity of 91% and specificity of 90%; (AUC) = 0.94 (95% CI, 0.90-0.97). The final model for ASD was composed of all subscales except the 'peer problems' scales, indicating of the complexity of behavioural difficulties that may accompany ASD. A threshold of 0.03 produced model sensitivity and specificity of 79% and 93% respectively; AUC = 0.90 (95% CI, 0.86-0.95). The results support changes to DSM-5 removing exclusivity clauses.ESRCNational Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsul

Deconstructing the DGAT1 enzyme: membrane interactions at substrate binding sites

Diacylglycerol acyltransferase 1 (DGAT1) is a key enzyme in the triacylglyceride synthesis pathway. Bovine DGAT1 is an endoplasmic reticulum membrane-bound protein associated with the regulation of fat content in milk and meat. The aim of this study was to evaluate the interaction of DGAT1 peptides corresponding to putative substrate binding sites with different types of model membranes. Whilst these peptides are predicted to be located in an extramembranous loop of the membrane-bound protein, their hydrophobic substrates are membrane-bound molecules. In this study, peptides corresponding to the binding sites of the two substrates involved in the reaction were examined in the presence of model membranes in order to probe potential interactions between them that might influence the subsequent binding of the substrates. Whilst the conformation of one of the peptides changed upon binding several types of micelles regardless of their surface charge, suggesting binding to hydrophobic domains, the other peptide bound strongly to negatively-charged model membranes. This binding was accompanied by a change in conformation, and produced leakage of the liposome-entrapped dye calcein. The different hydrophobic and electrostatic interactions observed suggest the peptides may be involved in the interactions of the enzyme with membrane surfaces, facilitating access of the catalytic histidine to the triacylglycerol substrates

Do real interest rates converge across Latin american countries?

In this study, we apply the Sequential Panel Selection Method (SPSM), pro- posed by Chortareas and Kapetanios (Journal of Banking and Finance 33:390–404, 2009), to investigate and assess the non-stationary properties of the real interest rate parity (RIRP) for fourteen Latin American countries. Utilizing the SPSM, we can classify the entire panel into a group of stationary series and a group of non-stationary series. We clearly identify how many and which series in the panel are stationary processes and provide robust evidence that clearly indicate RIRP holds true for ten countries. Our findings note that these countries’ real interest rate convergence is a mean reversion toward RIRP equilib- rium values in a non-linear way. Our results have important policy implications for these Latin American countries under study.info:eu-repo/semantics/publishedVersio

Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle

Activation of 5-HT4 receptors in failing ventricles elicits a cAMP-dependent positive inotropic response which is mainly limited by the cGMP-inhibitable phosphodiesterase (PDE) 3. However, PDE4 plays an additional role which is demasked by PDE3 inhibition. The objective of this study was to evaluate the effect of cGMP generated by particulate and soluble guanylyl cyclase (GC) on the 5-HT4-mediated inotropic response. Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats, exhibiting heart failure 6 weeks after surgery. Contractility was measured in left ventricular preparations. Cyclic GMP was measured by EIA. In ventricular preparations, ANP or BNP displayed no impact on 5-HT4-mediated inotropic response. However, CNP increased the 5-HT4-mediated inotropic response as well as the β1-adrenoceptor (β1-AR)-mediated response to a similar extent as PDE3 inhibition by cilostamide. Pretreatment with cilostamide eliminated the effect of CNP. Inhibition of nitric oxide (NO) synthase and soluble GC by l-NAME and ODQ, respectively, attenuated the 5-HT4-mediated inotropic response, whereas the NO donor Sin-1 increased this response. The effects were absent during PDE3 inhibition, suggesting cGMP-dependent inhibition of PDE3. However, in contrast to the effects on the 5-HT4 response, Sin-1 inhibited whereas l-NAME and ODQ enhanced the β1-AR-mediated inotropic response. cGMP generated both by particulate (NPR-B) and soluble GC increases the 5-HT4-mediated inotropic response in failing hearts, probably through inhibition of PDE3. β1-AR and 5-HT4 receptor signalling are subject to opposite regulatory control by cGMP generated by soluble GC in failing hearts. Thus, cGMP from different sources is functionally compartmented, giving differential regulation of different Gs-coupled receptors