Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.</p

CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Comunicación corta. El N-(2-cloro-4-piridil)-N-fenilurea (4CPPU) mejora la regeneración in vitro vía organogénesis directa de segmentos de epicótilo deCitrus aurantium L. en comparación con otras citoquininas de uso común

The effect of three concentrations of five different cytokinins, i.e. 6-benzylamino purine, 2-isopentyl adenine, kinetin (Kin), thidiazuron and N-(2-chloro-4-pyridyl)-N-phenylurea (4-CPPU), was evaluated on the in vitro direct shoot organogenesis of epicotyl explants of sour orange (Citrus aurantium L.). The basal medium used was that of Murashige and Tucker and epicotyl explants were incubated in medium supplemented with the prementioned cytokinins for 45 days. The addition of Kin and 4-CPPU in the medium enhanced the direct shoot organogenesis of sour orange epicotyl segments. The concentration of each of these two cytokinins which gave the best results, was combined with indole-3-acetic acid (IAA) or α-naphthalene acetic acid (α-NAA) at concentrations ranging from 0.01 mg L–1 to 0.2 mg L–1. The inclusion of IAA at 0.2 mg L–1 in the medium with 4-CPPU at 0.05 mg L–1 resulted in 100% successful direct shoot organogenesis, while the combination of Kin at 0.25 mg L–1 with IAA or α-NAA each at 0.01 mg L–1 presented equally high organogenesis percentages (91.7%). The incubation of the produced shoots, in medium supplemented with either indole-3-butyric acid or α-NAA resulted in high rooting percentages (up to 90%) and the rooted explants were successfully acclimatized under mist (85%). Although 4-CPPU has been used in in vitro cultureof various species, this is the first report on its use in the direct shoot organogenesis of citrus species and could be ofgreat value in citrus genetic transformation protocols using epicotyl segments, since this cytokinin resulted in theabsolute organogenesis percentage.&nbsp;Se evalu&oacute; el efecto de tres concentraciones de cinco diferentes citoquininas [6-bencilaminopurina; 2-isopentil adenina; kinetina (Kin), tidiazur&oacute;n y N-(2-cloro-4-piridil)-N-fenilurea (4-CPPU)], en la organog&eacute;nesis directa in vitro deexplantes de epic&oacute;tilo de naranjo amargo (Citrus aurantium L.). Se incubaron durante 45 d&iacute;as explantes de epic&oacute;tiloen medio Murashige y Tucker suplementado con las cinco citoquininas. La adici&oacute;n de Kin y 4-CPPU en el medio aument&oacute;la organog&eacute;nesis directa de segmentos de epic&oacute;tilo de naranjo amargo. Se combin&oacute; la concentraci&oacute;n que dio mejores resultados de cada uno de estas dos citoquininas con &aacute;cido indol-3-ac&eacute;tico (IAA) o con &aacute;cido &alpha;-naftaleno ac&eacute;tico (&alpha;-NAA) en concentraciones desde 0,01 hasta 0,2 mg L&ndash;1. La inclusi&oacute;n de IAA a 0,2 mg L&ndash;1 en el medio con 4-CPPU a 0,05 mg L&ndash;1 result&oacute; en un 100% de &eacute;xito en la organog&eacute;nesis directa, mientras que la combinaci&oacute;n de Kin a 0,25 mg L&ndash;1 con IAA o &alpha;-NAA, ambas a 0,01 mg L&ndash;1, result&oacute; en un 91,7% de organog&eacute;nesis. La incubaci&oacute;n de los&nbsp;brotes producidos en medio suplementado con &aacute;cido indol-3-but&iacute;rico &oacute; &alpha;-NAA result&oacute; en altos porcentajes de enraizamiento (hasta un 90%) y los explantes enraizados se aclimataron con &eacute;xito (85%) en un mist. Se ha utilizado el 4-CPPU en el cultivo in vitro de diferentes especies, pero este es el primer informe sobre su uso en la organog&eacute;nesis directa de c&iacute;tricos y podr&iacute;a ser de gran valor en los protocolos de transformaci&oacute;n gen&eacute;tica de segmentos de epic&oacute;tilo de c&iacute;tricos, ya que esta citoquinina produjo un 100% de organog&eacute;nesis

N-(2-chloro-4-pyridyl)-N-phenylurea (4-CPPU) enhances "in vitro" direct shoot organogenesis of "Citrus aurantium" L. epicotyl segments compared to other commonly used cytokinins: short comunication

The effect of three concentrations of five different cytokinins, i.e. 6-benzylamino purine, 2-isopentyl adenine, kinetin (Kin), thidiazuron and N-(2-chloro-4-pyridyl)-N-phenylurea (4-CPPU), was evaluated on the in vitro direct shoot organogenesis of epicotyl explants of sour orange (Citrus aurantium L.). The basal medium used was that of Murashige and Tucker and epicotyl explants were incubated in medium supplemented with the prementioned cytokinins for 45 days. The addition of Kin and 4-CPPU in the medium enhanced the direct shoot organogenesis of sour orange epicotyl segments. The concentration of each of these two cytokinins which gave the best results, was combined with indole-3-acetic acid (IAA) or á-naphthalene acetic acid (á-NAA) at concentrations ranging from 0.01 mg L�1 to 0.2 mg L�1. The inclusion of IAA at 0.2 mg L�1 in the medium with 4-CPPU at 0.05 mg L�1 resulted in 100% successful direct shoot organogenesis, while the combination of Kin at 0.25 mg L�1 with IAA or á-NAA each at 0.01 mg L�1 presented equally high organogenesis percentages (91.7%). The incubation of the produced shoots, in medium supplemented with either indole-3-butyric acid or á-NAA resulted in high rooting percentages (up to 90%) and the rooted explants were successfully acclimatized under mist (85%). Although 4-CPPU has been used in in vitro culture of various species, this is the first report on its use in the direct shoot organogenesis of citrus species and could be of great value in citrus genetic transformation protocols using epicotyl segments, since this cytokinin resulted in the absolute organogenesis percentage.Se evaluo el efecto de tres concentraciones de cinco diferentes citoquininas [6-bencilaminopurina; 2-isopentil adenina; kinetina (Kin), tidiazuron y N-(2-cloro-4-piridil)-N-fenilurea (4-CPPU)], en la organogenesis directa in vitro de explantes de epicotilo de naranjo amargo (Citrus aurantium L.). Se incubaron durante 45 dias explantes de epicotilo en medio Murashige y Tucker suplementado con las cinco citoquininas. La adicion de Kin y 4-CPPU en el medio aumento la organogenesis directa de segmentos de epicotilo de naranjo amargo. Se combino la concentracion que dio mejores resultados de cada uno de estas dos citoquininas con acido indol-3-acetico (IAA) o con acido �¿-naftaleno acetico (�¿-NAA) en concentraciones desde 0,01 hasta 0,2 mg L.1. La inclusion de IAA a 0,2 mg L.1 en el medio con 4-CPPU a 0,05 mg L.1 resulto en un 100% de exito en la organogenesis directa, mientras que la combinacion de Kin a 0,25 mg L.1 con IAA o �¿-NAA, ambas a 0,01 mg L.1, resulto en un 91,7% de organogenesis. La incubacion de los brotes producidos en medio suplementado con acido indol-3-butirico o �¿-NAA resulto en altos porcentajes de enraizamiento (hasta un 90%) y los explantes enraizados se aclimataron con exito (85%) en un mist. Se ha utilizado el 4- CPPU en el cultivo in vitro de diferentes especies, pero este es el primer informe sobre su uso en la organogenesis directa de citricos y podria ser de gran valor en los protocolos de transformacion genetica de segmentos de epicotilo de citricos, ya que esta citoquinina produjo un 100% de organogenesis

-572 G/C single nucleotide polymorphism of interleukin-6 and sepsis predisposition in chronic renal disease

Single nucleotide polymorphisms (SNPs) of interleukin (IL)-6 are associated with the development of chronic renal disease (CRD). Their impact for sepsis in the field of CRD was investigated. One control cohort of 115 patients with CRD without infection and another case cohort of 198 patients with CRD and sepsis were enrolled. Genotyping at the −174 (rs1800795) and −572 positions of IL-6 (rs1800796) was done by restriction fragment length polymorphism. Circulating IL-6 was measured by an enzyme immunoassay. The GG genotype of rs1800796 was more frequent among cases (78.3 %) than controls (62.6 %). No difference in the genotype frequencies of rs1800795 between cases and controls were found. Odds ratio for sepsis was 2.07 (95%CI 1.24–3.44, p = 0.005) with the GG genotype of rs1800796, which was confirmed by logistic regression analysis taking into consideration the presence of chronic comorbidities. All-cause mortality until day 28 was similar between patients with the GG genotype and the GC/CC genotypes of rs1800796, but death caused from cardiovascular events not-related with infection was more frequent with the GG genotype (14.6 % vs 2.4 %, p = 0.031). Circulating IL-6 was greater among patients of the GC/CC genotypes of rs1800796 and multiple organ dysfunction (p = 0.013). The GG genotype of rs1800796 predisposes to sepsis in CRD and to 28-day mortality by sepsis-unrelated cardiovascular phenomena. © 2015, Springer-Verlag Berlin Heidelberg