Introduction to the SPARC Reanalysis Intercomparison Project (S-RIP) and overview of the reanalysis systems

The climate research community uses atmospheric reanalysis data sets to understand a wide range of processes and variability in the atmosphere, yet different reanalyses may give very different results for the same diagnostics. The Stratosphere–troposphere Processes And their Role in Climate (SPARC) Reanalysis Intercomparison Project (S-RIP) is a coordinated activity to compare reanalysis data sets using a variety of key diagnostics. The objectives of this project are to identify differences among reanalyses and understand their underlying causes, to provide guidance on appropriate usage of various reanalysis products in scientific studies, particularly those of relevance to SPARC, and to contribute to future improvements in the reanalysis products by establishing collaborative links between reanalysis centres and data users. The project focuses predominantly on differences among reanalyses, although studies that include operational analyses and studies comparing reanalyses with observations are also included when appropriate. The emphasis is on diagnostics of the upper troposphere, stratosphere, and lower mesosphere. This paper summarizes the motivation and goals of the S-RIP activity and extensively reviews key technical aspects of the reanalysis data sets that are the focus of this activity. The special issue The SPARC Reanalysis Intercomparison Project (S-RIP) in this journal serves to collect research with relevance to the S-RIP in preparation for the publication of the planned two (interim and full) S-RIP reports

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

GABAB receptor activation desensitizes postsynaptic GABAB and A1 adenosine responses in rat hippocampal neurones

Whole-cell recordings of EPSCs and G-protein-activated inwardly rectifying (GIRK) currents were made from cultured hippocampal neurones to determine the effect of long-term agonist treatment on the presynaptic and postsynaptic responses mediated by GABAB receptors (GABABRs). GABABR-mediated presynaptic inhibition was unaffected by agonist (baclofen) treatment for up to 48 h, and was desensitized by about one-half after 96 h. In contrast, GABABR-mediated GIRK currents were desensitized by a similar amount after only 2 h of agonist treatment. In addition, presynaptic inhibition mediated by A1 adenosine receptors (A1Rs) was unaffected by prolonged GABABR activation, whereas A1R-mediated GIRK currents were desensitized. Desensitization of postsynaptic GABABR and A1R responses was blocked by the GABABR antagonist (1-(S)-3,4-dichlorophenylethyl)amino-2-(S) hydroxypropyl-p-benzyl-phosphonic acid (CGP 55845A), but not by the A1R antagonist cyclopentyldipropylxanthine (DPCPX). GIRK current amplitude could be partially restored after baclofen treatment by either coapplication of baclofen and adenosine, or intracellular infusion of the non-hydrolysable GTP analog 5′-guanylylimidodiphosphate (Gpp(NH)p). Short-term (4–24 h) baclofen treatment also significantly desensitized the inhibition of postsynaptic voltage-gated calcium channels by activation of GABABRs or A1Rs. These results show that responses mediated by GABABRs and A1Rs desensitize differently in presynaptic and postsynaptic compartments, and demonstrate the heterologous desensitization of postsynaptic A1R responses

A magnetic resonance imaging-based workflow for planning radiation therapy for prostate cancer

Dose planning for prostate radiation therapy is performed using computed tomography (CT) scans that provide the electron density information needed for individual patients' radiation dose calculations

Nanoscale Carbon Modified α‑MnO₂ Nanowires: Highly Active and Stable Oxygen Reduction Electrocatalysts with Low Carbon Content

Carbon-coated α-MnO₂ nanowires (C-MnO₂ NWs) were prepared from α-MnO₂ NWs by a two-step sucrose coating and pyrolysis method. This method resulted in the formation of a thin, porous, low mass-percentage amorphous carbon coating (<5 nm, ≤1.2 wt % C) on the nanowire with an increase in single-nanowire electronic conductivity of roughly 5 orders of magnitude (α-MnO₂, 3.2 × 10^–6 S cm^–1; C-MnO₂, 0.52 S cm^–1) and an increase in surface Mn³⁺ (average oxidation state: α-MnO₂, 3.88; C-MnO₂, 3.66) while suppressing a phase change to Mn₃O₄ at high temperature. The enhanced physical and electronic properties of the C-MnO₂ NWsenriched surface Mn³⁺ and high conductivityare manifested in the electrocatalytic activity toward the oxygen reduction reaction (ORR), where a 13-fold increase in specific activity (α-MnO₂, 0.13 A m^–2; C-MnO₂, 1.70 A m^–2) and 6-fold decrease in charge transfer resistance (α-MnO₂, 6.2 kΩ; C-MnO₂, 0.9 kΩ) were observed relative to the precursor α-MnO₂ NWs. The C-MnO₂ NWs, composed of ∼99 wt % MnO₂ and ∼1 wt % carbon coating, also demonstrated an ORR onset potential within 20 mV of commercial 20% Pt/C and a chronoamperometric current/stability equal to or greater than 20% Pt/C at high overpotential (0.4 V vs RHE) and high temperature (60 °C) with no additional conductive carbon

Leveraging Accelerometry as a Prognostic Indicator for Increase in Opioid Withdrawal Symptoms

Treating opioid use disorder (OUD) is a significant healthcare challenge in the United States. Remaining abstinent from opioids is challenging for individuals with OUD due to withdrawal symptoms that include restlessness. However, to our knowledge, studies of acute withdrawal have not quantified restlessness using involuntary movements. We hypothesized that wearable accelerometry placed mid-sternum could be used to detect withdrawal-related restlessness in patients with OUD. To study this, 23 patients with OUD undergoing active withdrawal participated in a protocol involving wearable accelerometry, opioid cues to elicit craving, and non-invasive Vagal Nerve Stimulation (nVNS) to dampen withdrawal symptoms. Using accelerometry signals, we analyzed how movements correlated with changes in acute withdrawal severity, measured by the Clinical Opioid Withdrawal Scale (COWS). Our results revealed that patients demonstrating sinusoidal&ndash;i.e., predominantly single-frequency oscillation patterns in their motion almost exclusively demonstrated an increase in the COWS, and a strong relationship between the maximum power spectral density and increased withdrawal over time, measured by the COWS (R = 0.92, p = 0.029). Accelerometry may be used in an ambulatory setting to indicate the increased intensity of a patient&rsquo;s withdrawal symptoms, providing an objective, readily-measurable marker that may be captured ubiquitously