Reproductive ecology of Dusky Flycatchers in montane meadows of the central Sierra Nevada

Avian species with expansive ranges or those that occupy more than one vegetative association may vary in aspects of their life histories across their ranges. The distribution of Dusky Flycatchers encompasses a variety of vegetative associations, including riparian communities. However, much of the literature on this species details studies conducted in upland areas. Our objectives were to describe the breeding ecology and fecundity of Dusky Flycatchers nesting in montane meadows of the central Sierra Nevada, California. We monitored 36 territories and located 37 Dusky Flycatcher nests in 8 meadows. Average clutch size was 3.9 eggs. Egg laying, incubation, and nestling stages were 4, 15.4, and 16.4 days, respectively. Eighteen nests successfully fledged young, with an average of 3.3 fledglings per successful nest. Nest success was 43% and nest predation was the leading cause of nest failure. Estimated annual fecundity was 1.62 fledglings per pair; however, because all renesting attempts were not located, this should be viewed as the minimum annual fecundity. Dusky Flycatchers we monitored may have had higher fecundity than those nesting in upland areas because riparian areas often have higher arthropod abundances. While the importance of riparian conservation to riparian-obligate bird species is obvious, our study indicates that these areas also may be of value to Dusky Flycatchers that breed in riparian areas and upland areas.     

First reports of Draba pennellii and Draba pedicellata (Cruciferae) in Utah, and new distribution records for Draba kassii, Draba novolympica, and Hackelia ibapensis (Boraginaceae).

The discovery of Draba pennellii Rollins and D. pedicellata (Rollins & R.A. Price) Windham var. pedicellata, both previously known only from Nevada, is reported here from the Deep Creek Mountains of western Utah. The documentation of significant populations of D. pennellii and D. pedicellata var. pedicellata in Utah is important for accurate botanical inventories and floristic studies in both Utah and Nevada. New distribution records for D. kassii S.L. Welsh, D. novolympica Payson & St. John, and Hackelia ibapensis L.M. Shultz & J.S. Shultz are described, and the significance of these range extensions and new populations is discussed.     

Status of introduced fishes in certain spring systems in southern Nevada

We record eight species of exotic fishes as established, reproducing populations in certain springs in Clark, Lincoln, and Nye counties. Nevada. These include an unidentified species of Hypostomus, Cyprinus carpio, Poecilia mexicana, Poecilia reticulata, a Xiphophorus hybrid, and Cichlasoma nigrofasciatum. Tilapia mariae, established in a spring near the Overton Arm of Lake Mead, and Tilapia zilli, established in a golf course pond in Pahrump Valley, are recorded for the first time from Nevada waters. Though populations of transplanted Gambusia affinis persist, other populations of Poecilia latipinna are apparently no longer extant. Cichlasoma severum, Notemigonus crysoleucas, Poecilia latipinna, and Carassius auratus were apparently eradicated from Rogers Spring in 1963.     

Common variants on 8p12 and 1q24.2 confer risk of schizophrenia

Schizophrenia is a severe mental disorder affecting ～1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10(-10)) and 1q24.2 (rs10489202, P = 9.50 × 10(-9)). Our findings provide new insights into the pathogenesis of schizophrenia.     

A rare variant in MYH6 is associated with high risk of sick sinus syndrome

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10?2?. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.     

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10??) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.     

Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection

Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance.     

Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.     

Objectivity, abstraction, and the individual: the influence of Søren Kierkegaard on Paul Feyerabend

This paper explores the influence of Søren Kierkegaard upon Paul Feyerabend by examining their common criticisms of totalising accounts of human nature. Both complained that philosophical and scientific theories of human nature which were methodologically committed to objectivity and abstraction failed to capture the richness of human experience. Kierkegaard and Feyerabend argued that philosophy and the science were threatening to become obstacles to human development by imposing abstract theories of human nature and reality which denied the complexities of both. In both cases, this took the form of asserting an ‘existential’ criterion for the assessment of philosophical and scientific theories. Kierkegaard also made remarks upon the inappropriateness of applying natural scientific methods to human beings which Feyerabend later expanded and developed in his criticisms of the inability of the ‘scientific worldview’ to accommodate the values necessary to a flourishing human life. I conclude by noting some differences between Kierkegaard and Feyerabend’s positions and by affirming the value of existential criticisms of scientific knowledge.     

An abundant, truncated human sulfonylurea receptor 1 splice variant has prodiabetic properties and impairs sulfonylurea action

An alternatively spliced form of human sulfonylurea receptor (SUR) 1 mRNA lacking exon 2 (SUR1Δ2) has been identified. The omission of exon 2 caused a frame shift and an immediate stop codon in exon 3 leading to translation of a 5.6-kDa peptide that comprises the N-terminal extracellular domain and the first transmembrane helix of SUR1. Based on a weak first splice acceptor site in the human SUR1 gene (ABCC8), RT-PCR revealed a concurrent expression of SUR1Δ2 and SUR1. The SUR1Δ2/(SUR1 + SUR1Δ2) mRNA ratio differed between tissues, and was lowest in pancreas (46%), highest in heart (88%) and negatively correlated with alternative splice factor/splicing factor 2 (ASF/SF2) expression. In COS-7 cells triple transfected with SUR1Δ2/SUR1/Kir6.2, the SUR1Δ2 peptide co-immunoprecipitated with Kir6.2, thereby displacing two of four SUR1 subunits on the cell surface. The ATP sensitivity of these hybrid ATP-sensitive potassium channels (K_ATP) channels was reduced by about sixfold, as shown with single-channel recordings. RINm5f rat insulinoma cells, which genuinely express SUR1 but not SUR1Δ2, exhibited a strongly increased K_ATP channel current upon transfection with SUR1Δ2. This led to inhibition of glucose-induced depolarization, calcium flux, insulin release and glibenclamide action. A non-mutagenic SNP on nucleotide position 333 (Pro69Pro) added another exonic splicing enhancer sequence detected by ASF/SF2, reduced relative abundance of SUR1Δ2 and slightly protected from non-insulin dependent diabetes in homozygotic individuals. Thus, SUR1Δ2 represents an endogenous K_ATP-channel modulator with prodiabetic properties in islet cells. Its predominance in heart may explain why high-affinity sulfonylurea receptors are not found in human cardiac tissue.