Regulation of the Cardiac Na+/K+ ATPase by Phospholemman

Hansraj Dhayan, Rajender Kumar, Andreas Kukol, ‘Regulation of the Cardiac Na+/K+ ATPase by Phospholemman’, in Sajal Chakraborti, Naranjan Dhalla, eds., Regulation of Membrane Na+-K+ ATPase, (Switzerland: Springer, 2016), ISBN 978-3-319-24748-9, eISBN 978-3-319-24750-2.Peer reviewe

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Social interaction style of children and adolescents with high-functioning autism spectrum disorder

Qualitative differences in social interaction style exist within the autism spectrum. In this study we examined whether these differences are associated with (1) the severity of autistic symptoms and comorbid disruptive behavior problems, (2) the child's psycho-social health, and (3) executive functioning and perspective taking skills. The social interaction style of 156 children and adolescents (6-19 years) with high-functioning autism spectrum disorder (HFASD) was determined with the Wing Subgroups Questionnaire. An active-but-odd social interaction style was positively associated with symptoms of autism, attention deficit and hyperactivity. Furthermore, an active-but-odd social interaction style was negatively associated with children's psycho-social health and positively with executive functioning problems. Social interaction style explains part of the heterogeneity among children with HFASD

Incorporating tumour pathology information into breast cancer risk prediction algorithms.

INTRODUCTION: Mutations in BRCA1 and BRCA2 confer high risks of breast cancer and ovarian cancer. The risk prediction algorithm BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) may be used to compute the probabilities of carrying mutations in BRCA1 and BRCA2 and help to target mutation screening. Tumours from BRCA1 and BRCA2 mutation carriers display distinctive pathological features that could be used to better discriminate between BRCA1 mutation carriers, BRCA2 mutation carriers and noncarriers. In particular, oestrogen receptor (ER)-negative status, triple-negative (TN) status, and expression of basal markers are predictive of BRCA1 mutation carrier status. METHODS: We extended BOADICEA by treating breast cancer subtypes as distinct disease end points. Age-specific expression of phenotypic markers in a series of tumours from 182 BRCA1 mutation carriers, 62 BRCA2 mutation carriers and 109 controls from the Breast Cancer Linkage Consortium, and over 300,000 tumours from the general population obtained from the Surveillance Epidemiology, and End Results database, were used to calculate age-specific and genotype-specific incidences of each disease end point. The probability that an individual carries a BRCA1 or BRCA2 mutation given their family history and tumour marker status of family members was computed in sample pedigrees. RESULTS: The cumulative risk of ER-negative breast cancer by age 70 for BRCA1 mutation carriers was estimated to be 55% and the risk of ER-positive disease was 18%. The corresponding risks for BRCA2 mutation carriers were 21% and 44% for ER-negative and ER-positive disease, respectively. The predicted BRCA1 carrier probabilities among ER-positive breast cancer cases were less than 1% at all ages. For women diagnosed with breast cancer below age 50 years, these probabilities rose to more than 5% in ER-negative breast cancer, 7% in TN disease and 24% in TN breast cancer expressing both CK5/6 and CK14 cytokeratins. Large differences in mutation probabilities were observed by combining ER status and other informative markers with family history. CONCLUSIONS: This approach combines both full pedigree and tumour subtype data to predict BRCA1/2 carrier probabilities. Prediction of BRCA1/2 carrier status, and hence selection of women for mutation screening, may be substantially improved by combining tumour pathology with family history of cancer.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Enhanced catecholamine transporter binding in the locus coeruleus of patients with early Parkinson disease

<p>Abstract</p> <p>Background</p> <p>Studies in animals suggest that the noradrenergic system arising from the locus coeruleus (LC) and dopaminergic pathways mutually influence each other. Little is known however, about the functional state of the LC in patients with Parkinson disease (PD).</p> <p>Methods</p> <p>We retrospectively reviewed clinical and imaging data of 94 subjects with PD at an early clinical stage (Hoehn and Yahr stage 1-2) who underwent single photon computed tomography imaging with FP-CIT ([¹²³I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane). FP-CIT binding values from the patients were compared with 15 healthy subjects: using both a voxel-based whole brain analysis and a volume of interest analysis of <it>a priori </it>defined brain regions.</p> <p>Results</p> <p>Average FP-CIT binding in the putamen and caudate nucleus was significantly reduced in PD subjects (43% and 57% on average, respectively; p < 0.001). In contrast, subjects with PD showed an increased binding in the LC (166% on average; p < 0.001) in both analyses. LC-binding correlated negatively with striatal FP-CIT binding values (caudate: contralateral, ρ = -0.28, p < 0.01 and ipsilateral ρ = -0.26, p < 0.01; putamen: contralateral, ρ = -0.29, p < 0.01 and ipsilateral ρ = -0.29, p < 0.01).</p> <p>Conclusions</p> <p>These findings are consistent with an up-regulation of noradrenaline reuptake in the LC area of patients with early stage PD, compatible with enhanced noradrenaline release, and a compensating activity for degeneration of dopaminergic nigrostriatal projections.</p

Distinct Regions of the Large Extracellular Domain of Tetraspanin CD9 Are Involved in the Control of Human Multinucleated Giant Cell Formation

Multinucleated giant cells, formed by the fusion of monocytes/macrophages, are features of chronic granulomatous inflammation associated with infections or the persistent presence of foreign material. The tetraspanins CD9 and CD81 regulate multinucleated giant cell formation: soluble recombinant proteins corresponding to the large extracellular domain (EC2) of human but not mouse CD9 can inhibit multinucleated giant cell formation, whereas human CD81 EC2 can antagonise this effect. Tetraspanin EC2 are all likely to have a conserved three helix sub-domain and a much less well-conserved or hypervariable sub-domain formed by short helices and interconnecting loops stabilised by two or more disulfide bridges. Using CD9/CD81 EC2 chimeras and point mutants we have mapped the specific regions of the CD9 EC2 involved in multinucleated giant cell formation. These were primarily located in two helices, one in each sub-domain. The cysteine residues involved in the formation of the disulfide bridges in CD9 EC2 were all essential for inhibitory activity but a conserved glycine residue in the tetraspanin-defining ‘CCG’ motif was not. A tyrosine residue in one of the active regions that is not conserved between human and mouse CD9 EC2, predicted to be solvent-exposed, was found to be only peripherally involved in this activity. We have defined two spatially-distinct sites on the CD9 EC2 that are required for inhibitory activity. Agents that target these sites could have therapeutic applications in diseases in which multinucleated giant cells play a pathogenic role

Discovery of permuted and recently split transfer RNAs in Archaea

Background: As in eukaryotes, precursor transfer RNAs in Archaea often contain introns that are removed in tRNA maturation. Two unrelated archaeal species display unique pre-tRNA processing complexity in the form of split tRNA genes, in which two to three segments of tRNAs are transcribed from different loci, then trans-spliced to form a mature tRNA. Another rare type of pre-tRNA, found only in eukaryotic algae, is permuted, where the 3 ’ half is encoded upstream of the 5 ’ half, and must be processed to be functional. Results: Using an improved version of the gene-finding program tRNAscan-SE, comparative analyses and experimental verifications, we have now identified four novel trans-spliced tRNA genes, each in a different species of the Desulfurococcales branch of the Archaea: tRNA Asp(GUC) in Aeropyrum pernix and Thermosphaera aggregans, and tRNA Lys(CUU) in Staphylothermus hellenicus and Staphylothermus marinus. Each of these includes features surprisingly similar to previously studied split tRNAs, yet comparative genomic context analysis and phylogenetic distribution suggest several independent, relatively recent splitting events. Additionally, we identified the first examples of permuted tRNA genes in Archaea: tRNA iMet(CAU) and tRNA Tyr(GUA) in Thermofilum pendens, which appear to be permuted in the same arrangement seen previously in red alga. Conclusions: Our findings illustrate that split tRNAs are sporadically spread across a major branch of the Archaea

Molecular architecture of the Nup84–Nup145C–Sec13 edge element in the nuclear pore complex lattice

Nuclear pore complexes (NPCs) facilitate all nucleocytoplasmic transport. These massive protein assemblies are modular, with a stable structural scaffold supporting more dynamically attached components. The scaffold is made from multiple copies of the heptameric Y complex and the heteromeric Nic96 complex. We previously showed that members of these core subcomplexes specifically share an ACE1 fold with Sec31 of the COPII vesicle coat, and we proposed a lattice model for the NPC based on this commonality. Here we present the crystal structure of the heterotrimeric 134-kDa complex of Nup84–Nup145C–Sec13 of the Y complex. The heterotypic ACE1 interaction of Nup84 and Nup145C is analogous to the homotypic ACE1 interaction of Sec31 that forms COPII lattice edge elements and is inconsistent with the alternative 'fence-like' NPC model. We construct a molecular model of the Y complex and compare the architectural principles of COPII and NPC lattices.National Institutes of Health (U.S.) (Grant GM77537)Pew Charitable Trusts (Scholar Award