Functional effects of schizophrenia-linked genetic variants on intrinsic single-neuron excitability: A modeling study

Background: Recent genome-wide association studies (GWAS) have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cell and identify possible common alterations in behavior across SCZ-related genes. Methods: We applied a biophysically detailed multi-compartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ, and used changes in neuron model parameters to represent the effects of these variants. Results: We present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and Ca2+ transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ- related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree. Conclusions: Our results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside with the previously proposed deficits in synaptic communication and network behavior

Nucleation of a sodium droplet on C60

We investigate theoretically the progressive coating of C60 by several sodium atoms. Density functional calculations using a nonlocal functional are performed for NaC60 and Na2C60 in various configurations. These data are used to construct an empirical atomistic model in order to treat larger sizes in a statistical and dynamical context. Fluctuating charges are incorporated to account for charge transfer between sodium and carbon atoms. By performing systematic global optimization in the size range 1<=n<=30, we find that Na_nC60 is homogeneously coated at small sizes, and that a growing droplet is formed above n=>8. The separate effects of single ionization and thermalization are also considered, as well as the changes due to a strong external electric field. The present results are discussed in the light of various experimental data.Comment: 17 pages, 10 figure

Dickkopf-1 (Dkk-1) in plasma and synovial fluid is inversely correlated with radiographic severity of knee osteoarthritis patients

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis (OA) is a common degenerative joint disease causing pain, stiffness, reduced motion, swelling, crepitus, and disability. Dickkopf-1 (Dkk-1) is a critical mediator of osteoblastogenesis and regulates the joint remodeling. The aim of this study was to examine plasma and synovial fluid Dkk-1 levels of patients with primary knee OA and to investigate their relationship with disease severity.</p> <p>Methods</p> <p>Thirty-five patients aged 55-83 years with knee OA and 15 healthy individuals were recruited into this study. Disease severity was determined using weight-bearing anteroposterior radiographs of the affected knee. The radiological grading of OA in the knee was performed according to the Kellgren-Lawrence grading system. Dkk-1 levels in both plasma and synovial fluid were evaluated using enzyme-linked immunosorbent assay.</p> <p>Results</p> <p>The average concentration of circulating Dkk-1 in the knee OA patients was remarkably lower than that of healthy controls (396.0 ± 258.8, 95%CI 307.1-484.9 vs 2348.8 ± 2051.5, 95%CI 1164.3-3533.3 pg/ml, p < 0.0001). Dkk-1 levels in synovial fluid were significantly lower than in paired plasma samples (58.6 ± 31.8, 95%CI 47.7-69.6 vs 396.0 ± 258.8, 95%CI 307.1-484.9 pg/ml, p < 0.001). Furthermore, both plasma and synovial fluid Dkk-1 levels were inversely correlated with radiographic severity (r = -0.78, p < 0.001 and r = -0.42, p = 0.01, respectively). Plasma Dkk-1 levels were also significantly correlated with synovial fluid Dkk-1 levels (r = 0.72, p < 0.001).</p> <p>Conclusions</p> <p>Dkk-1 levels in plasma and synovial fluid are inversely related to the severity of joint damage in knee OA. Dkk-1 could serve as a biochemical marker for determining disease severity and might play a potential role in the pathogenesis of the degenerative process of OA.</p

Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score

Background Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. Methods and findings Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10−5 ). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer’s Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer’s Disease Center [NIA ADC], and Alzheimer’s Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62–4.24, p = 1.0 × 10−22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10−26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran–Armitage trend test, p = 1.5 × 10−10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10−6 , and Consortium to Establish a Registry for Alzheimer’s Disease score for neuritic plaques, p = 6.8 × 10−6 ) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10−6 , and hippocampus, p = 7.9 × 10−5 ). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use. Conclusions We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials

The Kolumbo submarine volcano of Santorini island is a large pool of bacterial strains with antimicrobial activity

Microbes in hydrothermal vents with their unique secondary metabolism may represent an untapped potential source of new natural products. In this study, samples were collected from the hydrothermal field of Kolumbo submarine volcano in the Aegean Sea, in order to isolate bacteria with antimicrobial activity. Eight hundred and thirty-two aerobic heterotrophic bacteria were isolated and then differentiated through BOX-PCR analysis at the strain level into 230 genomic fingerprints, which were screened against 13 different type strains (pathogenic and nonpathogenic) of Gram-positive, Gram-negative bacteria and fungi. Forty-two out of 176 bioactive-producing genotypes (76 %) exhibited antimicrobial activity against at least four different type strains and were selected for 16S rDNA sequencing and screening for nonribosomal peptide (NRPS) and polyketide (PKS) synthases genes. The isolates were assigned to genus Bacillus and Proteobacteria, and 20 strains harbored either NRPS, PKS type I or both genes. This is the first report on the diversity of culturable mesophilic bacteria associated with antimicrobial activity from Kolumbo area; the extremely high proportion of antimicrobial-producing strains suggested that this unique environment may represent a potential reservoir of novel bioactive compounds

Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer disease

Background—Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Methods and Results—Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05–1.11; P=2.86×10−8) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04–1.11; P=3.38×10−8). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. Conclusions—We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.acceptedVersio

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP

The role of steric constraints in the formation of rare aqua bridged coordination polymers: Synthesis, characterization and X-ray structures of polymeric, [Cu(2-chlorobenzoate)(2)(beta-picoline)(2)(mu-H2O)](n) and monomeric, [Cu(2-chlorobenzoate)(2)(gamma-picoline)(2)(H2O)]

Reaction of hydrated copper(II) 2-chloro-benzoate with beta-/gamma-picoline in methanol: water mixture (4:1 v/v) yielded polymeric [cu(2-chlorobenzoate)(2)(beta-picoline)(2)(mu-H2O)](n); 1 and monomeric [Cu(2-chlorobenzoate)(2)(gamma-picoline)(2)(H2O)]; 2. The newly synthesized complexes have been characterized by elemental analyses, FT-IR spectroscopy, UV-Visible spectroscopy, TGA and single crystal X-ray structure determination. X-ray crystallographic analysis revealed that both complexes crystallize in the monoclinic crystal system with space group and unit cell dimensions: (C2/c; a = 51.71 angstrom, b = 10.58 angstrom, c = 10.02 angstrom and beta = 100.5 degrees for 1 and P2(1)/c; a = 11.81 angstrom, b = 16.33 angstrom, c = 13.79 angstrom and beta = 90.77 degrees for 2. Whereas in 1 the presence of constituent and mediating water molecules running along a-axis gives rise to 1-dimensional zig-zag polymer chains, in complex 2, the presence of square pyramidal arrangement of ligands around copper(II) center results in monomeric structure. Various non-covalent interactions like O-H ... O, C-H ... O and C-H ... pi have been observed to play a decisive role in the stabilization of crystal lattices in both complexes

Diversity of actinomycetes isolated from Challenger Deep sediment (10,898 m) from the Mariana Trench

Thirty-eight actinomycetes were isolated from sediment collected from the Mariana Trench (10,898 m) using marine agar and media selective for actinomycetes, notably raffinose-histidine agar. The isolates were assigned to the class Actinobacteria using primers specific for members of this taxon. The phylogenetic analysis based on 16S rRNA gene sequencing showed that the isolates belonged to the genera Dermacoccus, Kocuria, Micromonospora, Streptomyces, Tsukamurella and Williamsia. All of the isolates were screened for genes encoding nonribosomal peptide and polyketide synthetases. Nonribosomal peptide synthetase sequences were detected in more than half of the isolates and polyketide synthases type I (PKS-I) were identified in five out of 38 strains. The Streptomyces isolates produced several unusual secondary metabolites, including a PKS-I associated product. In initial testing for piezotolerance, the Dermacoccus strain MT1.1 grew at elevated hydrostatic pressures