Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions

Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, represent- ing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated posi- tions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular path- ways associated with aetiological variation in complex disease

Measurement of K-S(0) and K*(0) in p plus p, d plus Au, and Cu plus Cu collisions at root s(NN)=200 GeV

The PHENIX experiment at the Relativistic Heavy Ion Collider has performed a systematic study of K-S(0) and K*(0) meson production at midrapidity in p + p, d + Au, and Cu + Cu collisions at root s(NN) = 200 GeV. The K-S(0) and K*(0) mesons are reconstructed via their K-S(0) -\u3e pi(0)(-\u3e gamma gamma) pi(0)(-\u3e gamma gamma) and K*(0) -\u3e K-+/-pi(-/+) decay modes, respectively. The measured transverse-momentum spectra are used to determine the nuclear modification factor of K-S(0) and K*(0) mesons in d + Au and Cu + Cu collisions at different centralities. In the d + Au collisions, the nuclear modification factor of K-S(0) and K*(0) mesons is almost constant as a function of transverse momentum and is consistent with unity, showing that cold-nuclear-matter effects do not play a significant role in the measured kinematic range. In Cu + Cu collisions, within the uncertainties no nuclear modification is registered in peripheral collisions. In central collisions, both mesons show suppression relative to the expectations from the p + p yield scaled by the number of binary nucleon-nucleon collisions in the Cu + Cu system. In the p(T) range 2-5 GeV/c, the strange mesons (K-S(0), K*(0)) similarly to the phi meson with hidden strangeness, show an intermediate suppression between the more suppressed light quark mesons (pi(0)) and the nonsuppressed baryons (p, (p) over bar). At higher transverse momentum, p(T) \u3e 5 GeV/c, production of all particles is similarly suppressed by a factor of approximate to 2

A Novel Potentiometric Solid‐State Iodide Sensor

A simple and highly selective potentiometric solid‐state iodide sensor was fabricated. The sensor relies on a very thin film of silver‐tin oxide, which can be easily regenerated when necessary. The calibration plot for iodide determination was linear in the concentration range from 1.0×10−6 to 1.8×10−2 M iodide. The slope was affected by pH and ranged from 57.1 mV/decade to 64.8 mV/decade. The selectivity coefficients of the sensor determined by the two‐solution method showed excellent selectivities toward possible interfering anions, except for cyanide and sulfide. The response time of the sensor was less than 10 s

Cu (II) ion-selective electrodes based on Cu (II) complex with cyclized salophen

Several versions of Cu (II) ion selective electrodes (ISE), based on cyclized N, N!-bis (salicylidene)-o-phenylenediamine (salophen) complexes with Cu (II), were fabricated for determination of Cu (II) in aqueous solutions. The response of the ISE was optimized by variation of membrane composition and evaluation of various experimental conditions. Near Nernstian slopes (~ 28–32 mV/decade) were obtained for some preparations. The linear range of the ISE ranged from 5• 10–5 to 1• 10–2 m Cu (II). Coated-wire and coated disc ISE resulted practically in a similar response as screen printed electrodes (SPE). The potentiometric selectivity coefficients (Kij) for all electrodes were determined for Na+, NH4+, Ca2+, Mg2+, Ni2+, Pb2+, Zn2+, Cd2+, Co2+, Fe3+, Hg2+, CO3 2–, H2PO4–, HPO4 2–, SO4 2–, CH3COO–, Br–, I–, NO3–, and SCN–. The selectivity coefficients were in the range from 10–2 to 10–3 for all ions

Coated-wire and coated-disc Cu (II) ion-selective electrodes based on Cu (II) complex with cyclized salophen

Coated-wire and coated-disc ion selective electrodes (ISE) based on cyclized N,N ′-bis(salicylidene)-o-phenylenediamine (salophen) complex with Cu(II) were fabricated for determination of Cu(II) in aqueous solutions. The response of the ISE was optimized by variation of membrane composition and evaluation of the various experimental conditions. Near Nernstian slopes (˜28 mV/decade) were obtained. The linear range of the ISE ranged from 5 × 10−5 to 1 × 10−2 M Cu(II).The potentiometric selectivity coefficients (K ij ) were determined for , Ca2+, Mg2+, Ni2+, Pb2+, Zn2+, Cd2+, Co2+, Fe3+, Hg2+, , CH3COO−, Br−, I−, , and SCN−. The selectivity coefficients were in the range from 10−2 to 10−3 for all ions tested except Hg2+, I−, and to less extent Fe3+. The fabricated ISE using the Cu(II)-salophen complex are reliable and stable

Development of a novel solid-state pH sensor based on tin oxide thin film

A solid-state pH sensor was fabricated using a transparent conductive tin oxide film on a glass substrate. The coating of the glass substrate was achieved by a novel simple chemical vapor deposition (CVD) procedure. The response time of the pH sensor was substantially reduced when a thin graphite film was deposited onto the tin oxide conductive film. The sensor slope was found to increase as the temperature of the solution was increased. The performance of the sensor was investigated in the pH range from 0.3 to 11.0. A straight-line calibration graph was achieved throughout the whole range tested, especially when the solution temperature was 80℃. The working pH range was found to decrease on the expense of the lower range as the temperature was decreased. Results obtained by the suggested sensor compares very well with conventional pH electrodes where the square of the correlation coefficient

Formation of ortho-cyano-aminothiophenolate ligands with versatile binding modes via facile carbon-sulfur bond cleavage of 2-aminobenzothiazoles at mercury(II) centres

Mercuric acetate and 2-aminobenzothiazoles react to give novel ortho-cyano-aminothiophenolate complexes via sulfur–carbon bond cleavage and H2 loss.</p

Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72.

A hexanucleotide (GGGGCC) expansion in C9ORF72 gene is the most common genetic change seen in familial Frontotemporal Lobar Degeneration (FTLD) and familial Motor Neurone Disease (MND). Pathologically, expansion bearers show characteristic p62 positive, TDP-43 negative inclusion bodies within cerebellar and hippocampal neurons which also contain dipeptide repeat proteins (DPR) formed from sense and antisense RAN (repeat associated non ATG-initiated) translation of the expanded repeat region itself. ‘Inappropriate’ formation, and aggregation, of DPR might therefore confer neurotoxicity and influence clinical phenotype. Consequently, we compared the topographic brain distribution of DPR in 8 patients with Frontotemporal dementia (FTD), 6 with FTD + MND and 7 with MND alone (all 21 patients bearing expansions in C9ORF72) using a polyclonal antibody to poly-GA, and related this to the extent of TDP-43 pathology in key regions of cerebral cortex and hippocampus. There were no significant differences in either the pattern or severity of brain distribution of DPR between FTD, FTD + MND and MND groups, nor was there any relationship between the distribution of DPR and TDP-43 pathologies in expansion bearers. Likewise, there were no significant differences in the extent of TDP-43 pathology between FTLD patients bearing an expansion in C9ORF72 and non-bearers of the expansion. There were no association between the extent of DPR pathology and TMEM106B or APOE genotypes. However, there was a negative correlation between the extent of DPR pathology and age at onset. Present findings therefore suggest that although the presence and topographic distribution of DPR may be of diagnostic relevance in patients bearing expansion in C9ORF72 this has no bearing on the determination of clinical phenotype. Because TDP-43 pathologies are similar in bearers and non-bearers of the expansion, the expansion may act as a major genetic risk factor for FTLD and MND by rendering the brain highly vulnerable to those very same factors which generate FTLD and MND in sporadic disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2051-5960-2-70) contains supplementary material, which is available to authorized users

pH measurement as quality control on human post mortem brain tissue: a study of the BrainNet Europe consortium

AIMS: Most brain diseases are complex entities. Although animal models or cell culture experiments mimic some disease aspects, human post mortem brain tissue remains essential to advance our understanding of brain diseases using biochemical and molecular techniques. Post mortem artefacts must be properly understood, standardized, and either eliminated or factored into such experiments. Here we examine the influence of several premortem and post mortem factors on pH, and discuss the role of pH as a biochemical marker for brain tissue quality. METHODS: We assessed brain tissue pH in 339 samples from 116 brains provided by 8 different European and 2 Australian brain bank centres. We correlated brain pH with tissue source, post mortem delay, age, gender, freezing method, storage duration, agonal state and brain ischaemia. RESULTS: Our results revealed that only prolonged agonal state and ischaemic brain damage influenced brain tissue pH next to repeated freeze/thaw cycles. CONCLUSIONS: pH measurement in brain tissue is a good indicator of premortem events in brain tissue and it signals limitations for post mortem investigations