Relationships between motion on isentropic surfaces from 3-H rawinsonde data and radar echoes

Vertical motion in insentropic surfaces obtained at 3-h intervals conducted on 11 and 12 May, 1974 is related to convection indicated by radar echoes. Temporal and spatial changes in vertical motion are shown and demonstrated to be associated with areas of convection. Large vertical motion was calculated, and it is shown that vertical motion changes as much as 20 cm s (-1) in a horizontal distance of 300 km. The rate of change of vertical motion is demonstrated to be as large a 8 cm s (-1)h(-1) from data taken at 3-h intervals, while data taken at 12-h intervals the same day displayed a maximum rate of change of 2 cm s(-1)n(-1). Radar observations confirmed that the intensity of convection varies as a result of the atmospheric variability as detected by 3-h data but is invisible in data taken at 12-h intervals

First report of Laternula elliptica in the Antarctic intertidal zone

Many Antarctic marine invertebrates are considered to be highly stenothermal, subjected to loss of functionality at increased temperatures and so at high risk of mortality in a rapidly warming environment. The bivalve Laternula elliptica is often used as a model taxon to test these theories. Here, we report the first instance L. elliptica from an intertidal site. Genetic analysis of the tissue confirms the species identity. A total of seven animals ranging in length from 6 to 85 mm were collected from 3 × 0.25 m2 quadrats of intertidal sediments at St Martha Cove on James Ross Island, Eastern Antarctic Peninsula. Ambient temperatures of 7.5 °C within the sediment and 10 °C (air) were recorded. This raises questions as to the current perception that “many Antarctic marine invertebrates cannot adapt to higher temperatures”

CLIPPER: an add-on to the Trans-Proteomic Pipeline for the automated analysis of TAILS N-terminomics data

Data analysis in proteomics is complex and with the extra challenges involved in the interpretation of data from N-terminomics experiments, this can be daunting. Therefore, we have devised a rational pipeline of steps to approach N-terminomics data analysis in a statistically-based and valid manner. We have automated these steps in CLIPPER, an add-on to the Trans-Proteomic Pipeline (TPP). Applying CLIPPER to the analysis of N-terminomics data generated by terminal amine isotopic labeling of substrates (TAILS) enables high confidence peptide to protein assignment, protein N-terminal characterization and annotation, and for protease analysis readily allows protease substrate discovery with high confidenc

Discovery of noncanonical translation initiation sites through mass spectrometric analysis of protein N termini

Translation initiation generally occurs at AUG codons in eukaryotes, although it has been shown that non-AUG or non-canonical translation initiation can also occur. However, the evidence for noncanonical translation initiation sites (TISs) is largely indirect and based on ribosome profiling (Ribo-seq) studies. Here, using a strategy specifically designed to enrich N termini of proteins, we demonstrate that many human proteins are translated at noncanonical TISs. The large majority of TISs that mapped to 5' untranslated regions were noncanonical and led to N-terminal extension of annotated proteins or translation of upstream small open reading frames (uORF). It has been controversial whether the amino acid corresponding to the start codon is incorporated at the TIS or methionine is still incorporated. We found that methionine was incorporated at almost all noncanonical TISs identified in this study. Comparison of the TISs determined through mass spectrometry with ribosome profiling data revealed that about two-thirds of the novel annotations were indeed supported by the available ribosome profiling data. Sequence conservation across species and a higher abundance of noncanonical TISs than canonical ones in some cases suggests that the noncanonical TISs can have biological functions. Overall, this study provides evidence of protein translation initiation at noncanonical TISs and argues that further studies are required for elucidation of functional implications of such noncanonical translation initiation

Factor Xa subsite mapping by proteome-derived peptide libraries improved using WebPICS, a resource for proteomic identification of cleavage sites

Proteomic identification of protease cleavage site specificity (PICS) is a recent proteomic approach for the easy mapping of protease subsite preferences that determines both the prime- and non-prime side specificity concurrently. Here we greatly facilitate user access by providing an automated and simple web-based data-analysis resource termed WebPics (http://clipserve.clip.ubc.ca/pics/). We demonstrate the utility of WebPics analysis of PICS data by determining the substrate specificity of factor Xa from P6-P6', an important blood coagulation protease that proteolytically generates thrombin from prothrombin. PICS confirms existing data on non-prime site specificity and refines our knowledge of factor Xa prime-site selectivit

Noise sensitivities in dogs: an exploration of signs in dogs with and without musculoskeletal pain using qualitative content analysis

Noise sensitivity is a common behaviour problem in dogs. In humans, there is a well-established relationship between painful conditions and the development of fear-related avoidance responses. Whilst it is likely that a relationship exists between noise sensitivity and pain in dogs, this does not appear to have been investigated. The aim of this study was to explore the signs of noise sensitivity in dogs with and without musculoskeletal pain by comparing case histories using qualitative content analysis. Data were extracted from the clinical records of 20 cases of dogs presenting with noise sensitivity seen by clinical animal behaviourists at the University of Lincoln, composed of 2 groups—10 “clinical cases” with pain and 10 “control cases” without pain. Loud noises as a trigger of noise sensitivity were a common theme in both groups but ubiquitous among “clinical cases.” In “clinical cases” (i.e., those where pain was identified), the age of onset of the noise sensitivity was on average nearly 4 years later than “control cases.” In addition, strong themes emerged relating to widespread generalisation to associated environments and avoidance of other dogs in the “clinical cases,” which did not appear in the “control cases.” “Clinical cases” responded well to treatment once the involvement of pain had been identified. Veterinarians and behaviourists should carefully assess dogs with noise sensitivities for pain-related problems especially if presenting with these characteristics

Molecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection.

The interplay between a highly polymorphic set of MHC-I alleles and molecular chaperones shapes the repertoire of peptide antigens displayed on the cell surface for T cell surveillance. Here, we demonstrate that the molecular chaperone TAP-binding protein related (TAPBPR) associates with a broad range of partially folded MHC-I species inside the cell. Bimolecular fluorescence complementation and deep mutational scanning reveal that TAPBPR recognition is polarized toward the α2 domain of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the α2 domain. Conversely, thermodynamic measurements of TAPBPR binding for a representative set of properly conformed, peptide-loaded molecules suggest a narrower MHC-I specificity range. Using solution NMR, we find that the extent of dynamics at "hotspot" surfaces confers TAPBPR recognition of a sparsely populated MHC-I state attained through a global conformational change. Consistently, restriction of MHC-I groove plasticity through the introduction of a disulfide bond between the α1/α2 helices abrogates TAPBPR binding, both in solution and on a cellular membrane, while intracellular binding is tolerant of many destabilizing MHC-I substitutions. Our data support parallel TAPBPR functions of 1) chaperoning unstable MHC-I molecules with broad allele-specificity at early stages of their folding process, and 2) editing the peptide cargo of properly conformed MHC-I molecules en route to the surface, which demonstrates a narrower specificity. Our results suggest that TAPBPR exploits localized structural adaptations, both near and distant to the peptide-binding groove, to selectively recognize discrete conformational states sampled by MHC-I alleles, toward editing the repertoire of displayed antigens

Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials

BACKGROUND: Chlorpromazine (CPZ) remains one of the most common drugs used for people with schizophrenia worldwide, and a benchmark against which other treatments can be evaluated. Quantitative reviews are rare; this one evaluates the effects of chlorpromazine in the treatment of schizophrenia in comparison with placebo. METHODS: We sought all relevant randomised controlled trials (RCT) comparing chlorpromazine to placebo by electronic and reference searching, and by contacting trial authors and the pharmaceutical industry. Data were extracted from selected trials and, where possible, synthesised and random effects relative risk (RR), the number needed to treat (NNT) and their 95% confidence intervals (CI) calculated. RESULTS: Fifty RCTs from 1955–2000 were included with 5276 people randomised to CPZ or placebo. They constitute 2008 person-years spent in trials. Meta-analysis of these trials showed that chlorpromazine promotes a global improvement (n = 1121, 13 RCTs, RR 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10), although a considerable placebo response is also seen. People allocated to chlorpromazine tended not to leave trials early in both the short (n = 945, 16 RCTs, RR 0.74 CI 0.5 to 1.1) and medium term (n = 1861, 25 RCTs, RR 0.79 CI 0.6 to 1.1). There were, however, many adverse effects. Chlorpromazine is sedating (n = 1242, 18 RCTs, RR 2.3 CI 1.7 to 3.1, NNH 6 CI 5 to 8), increases a person's chances of experiencing acute movement disorders, Parkinsonism and causes low blood pressure with dizziness and dry mouth. CONCLUSION: It is understandable why the World Health Organization (WHO) have endorsed and included chlorpromazine in their list of essential drugs for use in schizophrenia. Low- and middle-income countries may have more complete evidence upon which to base their practice compared with richer nations using recent innovations