Specialised information processing deficits and distinct metabolomics profiles following TM-domain disruption of Nrg1

While there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signalling in schizophrenia. The present study focused on specialised behavioural and characterisation of hitherto un-characterised information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across two different sites and protocols, Nrg1 mutants demonstrated deficits in pre-pulse inhibition, a measure of sensorimotor gating that is disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second-, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in the ‘what-where-when’ cognitive paradigm, Nrg1 mutants displayed sex-specific (males only) disruption of ‘what-when’ performance, indicative of impaired episodic memory. Differential metabolomic profiling revealed that these behavioural phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioural changes in adulthood

The distribution of heartwater in the highveld of Zimbabwe, 1980-1997

Heartwater, the tick-borne disease caused by the rickettsia Cowdria ruminantium has historically been confined to the southern and western lowvelds of Zimbabwe. Since 1986, however, cases of heartwater have been diagnosed with increasing frequency in the central and eastern regions of the previously heartwater-free highveld plateau. During the same period, collections of the two major tick vectors of heartwater in Zimbabwe, Amblyomma hebraeum and Amblyomma variegatum, were made for the first time in these areas, suggesting that spread of these ticks was responsible for the changed distribution of the disease. The factors associated with this spread have not been determined, but increased cattle and wildlife movement and reduced intensity of dipping undoubtedly play important roles. Currently, the distribution of heartwater and its vectors in the highveld is still largely restricted to the central and eastern regions. The northern regions of the highveld appear to be predominantly uninfected, though it is likely that, eventually, heartwater will spread further with considerable impact on livestock production in Zimbabwe.The articles have been scanned in colour with a HP Scanjet 5590; 600dpi. Adobe Acrobat X Pro was used to OCR the text and also for the merging and conversion to the final presentation PDF-format.United States Agency tor International Development.mn201

Evidence for surface uplift of the Atlas Mountains and the surrounding peripheral plateaux: Combining apatite fission-track results and geomorphic indicators in the Western Moroccan Meseta (coastal Variscan Paleozoic basement)

This work represents an initial attempt to link the evolution of the topography in relation to the general tectonic framework of western Morocco. For this purpose, in a section of the Western Moroccan Meseta different tools are combined in order to attain the general objective. Apatite fission-track (AFT) data of granitic rocks of the Rabat–Khenifra area give ages around 200 Ma with track length distributions which are compatible with the thermal models already established for the area. An inverse correlation between AFT ages and elevation is observed which is compatible with previous models indicating northward tilting of the whole Western Moroccan Meseta which is younger than 20–25 Ma. In order to test this possibility a detailed analysis of the topography at different scales in the Western Moroccan Meseta has been performed. Results indicate that two open folds with different amplitudes are recognized and that the one with wider wavelength could correspond to a lithospheric fold as previously stated by other authors on the basis of independent geological arguments. The northward tilting proposed based on the AFT data agrees with the results obtained in the analysis of the topography which reinforces the presence of a very open fold with a wavelength of 200–300 km in the north-western limb of the Western Moroccan Meseta

48 Altered gut microbiota in stable patients with cystic fibrosis (CF) compared to controls and its relationship with intravenous (IV) antibiotic usage and lung function

peer-reviewedObjective CF is associated with altered digestive function and thus nutrient availability for gut microbes in addition to altered gut microbiota, compared with healthy controls. Equally intensive antibiotic and nutritional therapy may further compound this. We present results from the largest CF gut microbiota study to date

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Abundance patterns of cubozoans on and near the Great Barrier Reef

The ecology of cubozoans is poorly understood and there are few quantitative studies on their distribution patterns. Sampling was designed to test first for variation in abundance with distance across the continental shelf in waters of the Great Barrier Reef, Australia. Second, we tested for the possible influence of islands versus submerged reefs on the abundances of cubozoan jellyfishes. Jellyfishes were collected after attraction to tethered night lights. Additional sampling focused on turbid near-shore waters. Carybdeid jellyfishes were found at mainland, inner, and mid-shelf reefs during summers between 2007 and 2010. No cubozoan medusae were found at outer reef sites. Copula sivickisi and Carukia barnesi were more abundant near reefs with islands than at fully submerged reefs. There was no evidence of lunar periodicity in abundance for these cubozoan taxa. Chironex fleckeri medusae were only found close to shore near the mainland, but they were rarely observed when riverine runoff was high. All taxa were characterized by high spatial and temporal variation and there was some evidence for small populations at spatial scales of less than one kilometer. "Blooms" and related intensity of predation and risk to humans are most likely at small spatial scales

An epidemiological study of renal pathology in tuberous sclerosis complex

Objectives: To report the frequency of renal symptoms and complications of patients with tuberous sclerosis complex (TSC), to describe the ultrasonographic appearance of the kidneys in a population-based sample, and to investigate the relationship between a history of renal haemorrhage and renal lesions identified by ultrasonography.Patients and Methods: As part of an epidemiological study, 179 patients with TSC were identified as living in the Wessex Region in the South of England. Patients were interviewed and examined in their homes, to elicit the presence of renal symptoms or a history of renal complications. Renal ultrasonography was used in consenting patients in their homes.Results: There was a history of renal complications in 16 (9%) patients; 149 consented to interview and examination, and 19 gave a history of renal symptoms in the previous year; 124 had renal ultrasonography; 86 (69%) had renal angiomyolipomas and 37 (30%) had renal cysts. Large lesions (>3 cm in diameter) were strongly associated with a history of symptomatic bleeding, although significant haemorrhage occurred in a 6-year-old child with small angiomyolipomas.Conclusions: The formation of angiomyolipoma in TSC is common. Polycystic kidney disease, renal carcinoma and renal failure, although rare, occur in TSC. Most patients with angiomyolipomas have neither complications nor symptoms. There was no appreciable difference between the sexes in the risk of developing these lesions. Although less commonly seen in the very young, there is no identifiable relationship after adolescence between age and the risk of having a renal angiomyolipoma. Bleeding tends to occur from large lesions (>3 cm) but most such patients have remained asymptomatic to date