Stability, folding dynamics, and long-range conformational transition of the synaptic t-SNARE complex

Synaptic soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) couple their stepwise folding to fusion of synaptic vesicles with plasma membranes. In this process, three SNAREs assemble into a stable four-helix bundle. Arguably, the first and rate-limiting step of SNARE assembly is the formation of an activated binary t-SNARE complex on the plasma membrane, which then zippers with the v-SNARE on the vesicle to drive membrane fusion. However, the t-SNARE complex readily misfolds and its structure, stability, and dynamics are elusive. Using single-molecule force spectroscopy, we modeled synaptic t-SNARE complex as a parallel three-helix bundle with a small frayed Cterminus. The helical bundle sequentially folded in an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a central ionic layer, with total unfolding energy of ∼17 kBT. Peptide binding to the CTD activated the t-SNARE complex to initiate NTD zippering with the v-SNARE, a mechanism likely shared by Munc18-1. The NTD zippering then dramatically stabilized the CTD, facilitating further SNARE zippering. The subtle bidirectional tSNARE conformational switch was mediated by the ionic layer. Thus, the t-SNARE complex acts as a switch to enable fast and controlled SNARE zippering required for synaptic vesicle fusion and neurotransmission

Effects of beta-alanine supplementation on brain homocarnosine/carnosine signal and cognitive function: an exploratory study

Objectives: Two independent studies were conducted to examine the effects of 28 d of beta-alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2). Methods: In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sex-matched omnivores undertook a brain 1H-MRS exam at baseline and after beta-alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion. Results: In Study 1, there were no within-group effects of beta-alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P0.05) of beta-alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise. Conclusion: 28 d of beta-alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/ carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists

Dynamic clamp with StdpC software

Dynamic clamp is a powerful method that allows the introduction of artificial electrical components into target cells to simulate ionic conductances and synaptic inputs. This method is based on a fast cycle of measuring the membrane potential of a cell, calculating the current of a desired simulated component using an appropriate model and injecting this current into the cell. Here we present a dynamic clamp protocol using free, fully integrated, open-source software (StdpC, for spike timing-dependent plasticity clamp). Use of this protocol does not require specialist hardware, costly commercial software, experience in real-time operating systems or a strong programming background. The software enables the configuration and operation of a wide range of complex and fully automated dynamic clamp experiments through an intuitive and powerful interface with a minimal initial lead time of a few hours. After initial configuration, experimental results can be generated within minutes of establishing cell recording

Two Disease-Causing SNAP-25B Mutations Selectively Impair SNARE C-terminal Assembly

Synaptic exocytosis relies on assembly of three soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins into a parallel four-helix bundle to drive membrane fusion. SNARE assembly occurs by stepwise zippering of the vesicle-associated SNARE (v-SNARE) onto a binary SNARE complex on the target plasma membrane (t-SNARE). Zippering begins with slow N-terminal association followed by rapid C-terminal zippering, which serves as a power stroke to drive membrane fusion. SNARE mutations have been associated with numerous diseases, especially neurological disorders. It remains unclear how these mutations affect SNARE zippering, partly due to difficulties to quantify the energetics and kinetics of SNARE assembly. Here, we used single-molecule optical tweezers to measure the assembly energy and kinetics of SNARE complexes containing single mutations I67T/N in neuronal SNARE synaptosomal-associated protein of 25 kDa (SNAP-25B), which disrupt neurotransmitter release and have been implicated in neurological disorders. We found that both mutations significantly reduced the energy of C-terminal zippering by ~ 10 kBT, but did not affect N-terminal assembly. In addition, we observed that both mutations lead to unfolding of the C-terminal region in the t-SNARE complex. Our findings suggest that both SNAP-25B mutations impair synaptic exocytosis by destabilizing SNARE assembly, rather than stabilizing SNARE assembly as previously proposed. Therefore, our measurements provide insights into the molecular mechanism of the disease caused by SNARE mutations

Health-related quality of life in Huntington’s Disease patients: a comparison of proxy assessment and patient self-rating using the disease-specific Huntington’s Disease health-related quality of life questionnaire (HDQoL)

Huntington’s disease (HD) is a fatal, neurodegenerative disease for which there is no known cure. Proxy evaluation is relevant for HD as its manifestation might limit the ability of persons to report their health-related quality of life (HrQoL). This study explored patient–proxy ratings of HrQoL of persons at different stages of HD, and examined factors that may affect proxy ratings. A total of 105 patient–proxy pairs completed the Huntington’s disease health-related quality of life questionnaire (HDQoL) and other established HrQoL measures (EQ-5D and SF-12v2). Proxy–patient agreement was assessed in terms of absolute level (mean ratings) and intraclass correlation. Proxies’ ratings were at a similar level to patients’ self-ratings on an overall Summary Score and on most of the six Specific Scales of the HDQoL. On the Specific Hopes and Worries Scale, proxies on average rated HrQoL as better than patients’ self-ratings, while on both the Specific Cognitive Scale and Specific Physical and Functional Scale proxies tended to rate HrQoL more poorly than patients themselves. The patient’s disease stage and mental wellbeing (SF-12 Mental Component scale) were the two factors that primarily affected proxy assessment. Proxy scores were strongly correlated with patients’ self-ratings of HrQoL, on the Summary Scale and all Specific Scales. The patient–proxy correlation was lower for patients at moderate stages of HD compared to patients at early and advanced stages. The proxy report version of the HDQoL is a useful complementary tool to self-assessment, and a promising alternative when individual patients with advanced HD are unable to self-report

Circumstellar water vapour in M-type AGB stars: Constraints from H2O(1_10 - 1_01) lines obtained with Odin

Aims: Spectrally resolved circumstellar H2O(1_10 - 1_01) lines have been obtained towards three M-type AGB stars using the Odin satellite. This provides additional strong constrains on the properties of circumstellar H2O and the circumstellar envelope. Methods: ISO and Odin satellite H2O line data are used as constraints for radiative transfer models. Special consideration is taken to the spectrally resolved Odin line profiles, and the effect of excitation to the first excited vibrational states of the stretching modes (nu1=1 and nu3=1) on the derived abundances is estimated. A non-local, radiative transfer code based on the ALI formalism is used. Results: The H2O abundance estimates are in agreement with previous estimates. The inclusion of the Odin data sets stronger constraints on the size of the H2O envelope. The H2O(1_10 - 1_01) line profiles require a significant reduction in expansion velocity compared to the terminal gas expansion velocity determined in models of CO radio line emission, indicating that the H2O emission lines probe a region where the wind is still being accelerated. Including the nu3=1 state significantly lowers the estimated abundances for the low-mass-loss-rate objects. This shows the importance of detailed modelling, in particular the details of the infrared spectrum in the range 3 to 6 micron, to estimate accurate circumstellar H2O abundances. Conclusions: Spectrally resolved circumstellar H2O emission lines are important probes of the physics and chemistry in the inner regions of circumstellar envelopes around asymptotic giant branch stars. Predictions for H2O emission lines in the spectral range of the upcoming Herschel/HIFI mission indicate that these observations will be very important in this context.Comment: accepted in A&A, 10 pages, 8 figure

Radiative Transfer for Exoplanet Atmospheres

Remote sensing of the atmospheres of distant worlds motivates a firm understanding of radiative transfer. In this review, we provide a pedagogical cookbook that describes the principal ingredients needed to perform a radiative transfer calculation and predict the spectrum of an exoplanet atmosphere, including solving the radiative transfer equation, calculating opacities (and chemistry), iterating for radiative equilibrium (or not), and adapting the output of the calculations to the astronomical observations. A review of the state of the art is performed, focusing on selected milestone papers. Outstanding issues, including the need to understand aerosols or clouds and elucidating the assumptions and caveats behind inversion methods, are discussed. A checklist is provided to assist referees/reviewers in their scrutiny of works involving radiative transfer. A table summarizing the methodology employed by past studies is provided.Comment: 7 pages, no figures, 1 table. Filled in missing information in references, main text unchange

A False Start in the Race Against Doping in Sport: Concerns With Cycling’s Biological Passport

Professional cycling has suffered from a number of doping scandals. The sport’s governing bodies have responded by implementing an aggressive new antidoping program known as the biological passport. Cycling’s biological passport marks a departure from traditional antidoping efforts, which have focused on directly detecting prohibited substances in a cyclist’s system. Instead, the biological passport tracks biological variables in a cyclist’s blood and urine over time, monitoring for fluctuations that are thought to indirectly reveal the effects of doping. Although this method of indirect detection is promising, it also raises serious legal and scientific concerns. Since its introduction, the cycling community has debated the reliability of indirect biological-passport evidence and the clarity, consistency, and transparency of its use in proving doping violations. Such uncertainty undermines the legitimacy of finding cyclists guilty of doping based on this indirect evidence alone. Antidoping authorities should address these important concerns before continuing to pursue doping sanctions against cyclists solely on the basis of their biological passports

Multidisciplinary Collaboration in the Treatment of Patients With Type 2 Diabetes in Primary Care: Analysis Using Process Mining

[EN] Background: Public health in several countries is characterized by a shortage of professionals and a lack of economic resources. Monitoring and redesigning processes can foster the success of health care institutions, enabling them to provide a quality service while simultaneously reducing costs. Process mining, a discipline that extracts knowledge from information system data to analyze operational processes, affords an opportunity to understand health care processes. Objective: Health care processes are highly flexible and multidisciplinary, and health care professionals are able to coordinate in a variety of different ways to treat a diagnosis. The aim of this work was to understand whether the ways in which professionals coordinate their work affect the clinical outcome of patients. Methods: This paper proposes a method based on the use of process mining to identify patterns of collaboration between physician, nurse, and dietitian in the treatment of patients with type 2 diabetes mellitus and to compare these patterns with the clinical evolution of the patients within the context of primary care. Clustering is used as part of the preprocessing of data to manage the variability, and then process mining is used to identify patterns that may arise. Results: The method is applied in three primary health care centers in Santiago, Chile. A total of seven collaboration patterns were identified, which differed primarily in terms of the number of disciplines present, the participation intensity of each discipline, and the referrals between disciplines. The pattern in which the three disciplines participated in the most equitable and comprehensive manner had a lower proportion of highly decompensated patients compared with those patterns in which the three disciplines participated in an unbalanced manner. Conclusions: By discovering which collaboration patterns lead to improved outcomes, health care centers can promote the most successful patterns among their professionals so as to improve the treatment of patients. Process mining techniques are useful for discovering those collaborations patterns in flexible and unstructured health care processes.This paper was partially funded by the National Commission for Scientific and Technological Research, the Formation of Advanced Human Capital Program and the National Fund for Scientific and Technological Development (CONICYT-PCHA/Doctorado Nacional/2016-21161705 and CONICYT-FONDECYT/1150365; Chile). The authors would like to thank Ancora UC primary health care centers for their help with this research. The founding sponsors had no role in the design of the study in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.Conca, T.; Saint Pierre, C.; Herskovic, V.; Sepulveda, M.; Capurro, D.; Prieto, F.; Fernández Llatas, C. (2018). Multidisciplinary Collaboration in the Treatment of Patients With Type 2 Diabetes in Primary Care: Analysis Using Process Mining. JOURNAL OF MEDICAL INTERNET RESEARCH. 20(4). https://doi.org/10.2196/jmir.8884S204Chen, C.-C., Tseng, C.-H., & Cheng, S.-H. (2013). Continuity of Care, Medication Adherence, and Health Care Outcomes Among Patients With Newly Diagnosed Type 2 Diabetes. 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Remodeling of extra-bronchial lung vasculature following allergic airway inflammation

<p>Abstract</p> <p>Background</p> <p>We previously observed that allergen-exposed mice exhibit remodeling of large bronchial-associated blood vessels. The aim of the study was to examine whether vascular remodeling occurs also in vessels where a spill-over effect of bronchial remodeling molecules is less likely.</p> <p>Methods</p> <p>We used an established mouse model of allergic airway inflammation, where an allergic airway inflammation is triggered by inhalations of OVA. Remodeling of bronchial un-associated vessels was determined histologically by staining for α-smooth muscle actin, procollagen I, Ki67 and von Willebrand-factor. Myofibroblasts were defined as and visualized by double staining for α-smooth muscle actin and procollagen I. For quantification the blood vessels were divided, based on length of basement membrane, into groups; small (≤250 μm) and mid-sized (250–500 μm).</p> <p>Results</p> <p>We discovered marked remodeling in solitary small and mid-sized blood vessels. Smooth muscle mass increased significantly as did the number of proliferating smooth muscle and endothelial cells. The changes were similar to those previously seen in large bronchial-associated vessels. Additionally, normally poorly muscularized blood vessels changed phenotype to a more muscularized type and the number of myofibroblasts around the small and mid-sized vessels increased following allergen challenge.</p> <p>Conclusion</p> <p>We demonstrate that allergic airway inflammation in mice is accompanied by remodeling of small and mid-sized pulmonary blood vessels some distance away (at least 150 μm) from the allergen-exposed bronchi. The present findings suggest the possibility that allergic airway inflammation may cause such vascular remodeling as previously associated with lung inflammatory conditions involving a risk for development of pulmonary hypertension.</p