Role of triadin in the organization of reticulum membrane at the muscle triad.

International audienceThe terminal cisternae represent one of the functional domains of the skeletal muscle sarcoplasmic reticulum (SR). They are closely apposed to plasma membrane invaginations, the T-tubules, with which they form structures called triads. In triads, the physical interaction between the T-tubule-anchored voltage-sensing channel DHPR and the SR calcium channel RyR1 is essential because it allows the depolarization-induced calcium release that triggers muscle contraction. This interaction between DHPR and RyR1 is based on the peculiar membrane structures of both T-tubules and SR terminal cisternae. However, little is known about the molecular mechanisms governing the formation of SR terminal cisternae. We have previously shown that ablation of triadins, a family of SR transmembrane proteins that interact with RyR1, induced skeletal muscle weakness in knockout mice as well as a modification of the shape of triads. Here we explore the intrinsic molecular properties of the longest triadin isoform Trisk 95. We show that when ectopically expressed, Trisk 95 can modulate reticulum membrane morphology. The membrane deformations induced by Trisk 95 are accompanied by modifications of the microtubule network organization. We show that multimerization of Trisk 95 by disulfide bridges, together with interaction with microtubules, are responsible for the ability of Trisk 95 to structure reticulum membrane. When domains responsible for these molecular properties are deleted, anchoring of Trisk 95 to the triads in muscle cells is strongly decreased, suggesting that oligomers of Trisk 95 and microtubules contribute to the organization of the SR terminal cisternae in a triad

Impact of paternal deployment to the conflicts in Iraq and Afghanistan and paternal post-traumatic stress disorder on the children of military fathers

Background Little is known about the social and emotional well-being of children whose fathers have been deployed to the conflicts in Iraq/ Afghanistan or who have post-traumatic stress disorder (PTSD). Aims To examine the emotional and behavioural well-being of children whose fathers are or have been in the UK armed forces, in particular the effects of paternal deployment to the conflicts in Iraq or Afghanistan and paternal PTSD. Method Fathers who had taken part in a large tri-service cohort and had children aged 3–16 years were asked about the emotional and behavioural well-being of their child(ren) and assessed for symptoms of PTSD via online questionnaires and telephone interview. Results In total, 621 (67%) fathers participated, providing data on 1044 children. Paternal deployment to Iraq or Afghanistan was not associated with childhood emotional and behavioural difficulties. Paternal probable PTSD were associated with child hyperactivity. This finding was limited to boys and those under 11 years of age. Conclusions This study showed that adverse childhood emotional and behavioural well-being was not associated with paternal deployment but was associated with paternal probable PTSD

DNA copy number alterations in central primitive neuroectodermal tumors and tumors of the pineal region: an international individual patient data meta-analysis

Little is known about frequency, association with clinical characteristics, and prognostic impact of DNA copy number alterations (CNA) on survival in central primitive neuroectodermal tumors (CNS-PNET) and tumors of the pineal region. Searches of MEDLINE, Pubmed, and EMBASE—after the original description of comparative genomic hybridization in 1992 and July 2010—identified 15 case series of patients with CNS-PNET and tumors of the pineal region whose tumors were investigated for genome-wide CNA. One additional case study was identified from contact with experts. Individual patient data were extracted from publications or obtained from investigators, and CNAs were converted to a digitized format suitable for data mining and subgroup identification. Summary profiles for genomic imbalances were generated from case-specific data. Overall survival (OS) was estimated using the Kaplan-Meier method, and by univariable and multivariable Cox regression models. In their overall CNA profiles, low grade tumors of the pineal region clearly diverged from CNS-PNET and pineoblastoma. At a median follow-up of 89months, 7-year OS rates of CNS-PNET, pineoblastoma, and low grade tumors of the pineal region were 22.9±6, 0±0, and 87.5±12%, respectively. Multivariable analysis revealed that histology (CNS-PNET), age (≤2.5years), and possibly recurrent CNAs were associated with unfavorable OS. DNA copy number profiling suggests a close relationship between CNS-PNET and pineoblastoma. Low grade tumors of the pineal region differed from CNS-PNET and pineoblastoma. Due to their high biological and clinical variability, a coordinated prospective validation in future studies is necessary to establish robust risk factor

Dating Granites Using CODEX, with Application to In Situ Dating on the Moon

We have measured 87Rb–87Sr isochron ages for two granites, using the breadboard version of our Chemistry, Organics, and Dating EXperiment (CODEX), a laser-ablation resonance-ionization mass spectrometer designed for in situ geochronology on the Moon or Mars. These measurements extend the demonstrated analytical capabilities of CODEX, and indicate the value of incorporating a flight-ready version of CODEX, now under construction, into a future mission payload. We used CODEX to obtain accurate ages for the 1700 Ma Boulder Creek Granite, with 1σ statistical precision of 110 Myr, and for the 1100 Ma Pikes Peak Granite, with 1σ statistical precision of 160 Myr. To provide an end-to-end illustration of how CODEX analysis of granites can address critical lunar science questions regarding rock age and composition in situ, we describe an example mission to the lunar Gruithuisen Domes. Gruithuisen Domes appear to be volcanic edifices of granitic composition. Orbital remote sensing suggests that granitic rocks represent only a small fraction of the lunar surface, and the mere fact of their existence on the Moon is a puzzle. CODEX determination of the timing and process of their formation, both presently ill-understood, would provide important constraints on the thermal and geochemical evolution of the lunar interior

Electrophysiological evidence for an early processing of human voices

<p>Abstract</p> <p>Background</p> <p>Previous electrophysiological studies have identified a "voice specific response" (VSR) peaking around 320 ms after stimulus onset, a latency markedly longer than the 70 ms needed to discriminate living from non-living sound sources and the 150 ms to 200 ms needed for the processing of voice paralinguistic qualities. In the present study, we investigated whether an early electrophysiological difference between voice and non-voice stimuli could be observed.</p> <p>Results</p> <p>ERPs were recorded from 32 healthy volunteers who listened to 200 ms long stimuli from three sound categories - voices, bird songs and environmental sounds - whilst performing a pure-tone detection task. ERP analyses revealed voice/non-voice amplitude differences emerging as early as 164 ms post stimulus onset and peaking around 200 ms on fronto-temporal (positivity) and occipital (negativity) electrodes.</p> <p>Conclusion</p> <p>Our electrophysiological results suggest a rapid brain discrimination of sounds of voice, termed the "fronto-temporal positivity to voices" (FTPV), at latencies comparable to the well-known face-preferential N170.</p

Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum : A prospective cohort study

Funding information: This prospective cohort study was supported by a research grant from North West Hospital Group, Alkmaar, the Netherlands (Grant number: 2013T085) and by a research grant from the Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam UMC, the Netherlands (Project number: 23346). ACKNOWLEDGMENTS We thank Dr. J.P. Bestwick (employed at Queen Mary University of London, London, UK) and Professor Dr. J.H. Lazarus (employed at Cardiff School of Medicine, Cardiff, UK) for providing TSH medians from their study in the UK. Dr. J.P. Bestwick and Professor Dr. Lazarus have nothing to disclose.Peer reviewedPublisher PD

A Tri-Oceanic Perspective: DNA Barcoding Reveals Geographic Structure and Cryptic Diversity in Canadian Polychaetes

Although polychaetes are one of the dominant taxa in marine communities, their distributions and taxonomic diversity are poorly understood. Recent studies have shown that many species thought to have broad distributions are actually a complex of allied species. In Canada, 12% of polychaete species are thought to occur in Atlantic, Arctic, and Pacific Oceans, but the extent of gene flow among their populations has not been tested.Sequence variation in a segment of the mitochondrial cytochrome c oxidase I (COI) gene was employed to compare morphological versus molecular diversity estimates, to examine gene flow among populations of widespread species, and to explore connectivity patterns among Canada's three oceans. Analysis of 1876 specimens, representing 333 provisional species, revealed 40 times more sequence divergence between than within species (16.5% versus 0.38%). Genetic data suggest that one quarter of previously recognized species actually include two or more divergent lineages, indicating that richness in this region is currently underestimated. Few species with a tri-oceanic distribution showed genetic cohesion. Instead, large genetic breaks occur between Pacific and Atlantic-Arctic lineages, suggesting their long-term separation. High connectivity among Arctic and Atlantic regions and low connectivity with the Pacific further supports the conclusion that Canadian polychaetes are partitioned into two distinct faunas.Results of this study confirm that COI sequences are an effective tool for species identification in polychaetes, and suggest that DNA barcoding will aid the recognition of species overlooked by the current taxonomic system. The consistent geographic structuring within presumed widespread species suggests that historical range fragmentation during the Pleistocene ultimately increased Canadian polychaete diversity and that the coastal British Columbia fauna played a minor role in Arctic recolonization following deglaciation. This study highlights the value of DNA barcoding for providing rapid insights into species distributions and biogeographic patterns in understudied groups

Associations between hippocampal morphology, diffusion characteristics, and salivary cortisol in older men

High, unabated glucocorticoid (GC) levels are thought to selectively damage certain tissue types. The hippocampus is thought to be particularly susceptible to such effects, and though findings from animal models and human patients provide some support for this hypothesis, evidence for associations between elevated GCs and lower hippocampal volumes in older age (when GC levels are at greater risk of dysregulation) is inconclusive. To address the possibility that the effects of GCs in non-pathological ageing may be too subtle for gross volumetry to reliably detect, we analyse associations between salivary cortisol (diurnal and reactive measures), hippocampal morphology and diffusion characteristics in 88 males, aged ∼73 years. However, our results provide only weak support for this hypothesis. Though nominally significant peaks in morphology were found in both hippocampi across all salivary cortisol measures (standardised β magnitudes < 0.518, p(uncorrected) > 0.0000003), associations were both positive and negative, and none survived false discovery rate correction. We found one single significant association (out of 12 comparisons) between a general measure of hippocampal diffusion and reactive cortisol slope (β = 0.290, p = 0.008) which appeared to be driven predominantly by mean diffusivity but did not survive correction for multiple testing. The current data therefore do not clearly support the hypothesis that elevated cortisol levels are associated with subtle variations in hippocampal shape or microstructure in non-pathological older age

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)