Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

Integer Programming on Domains Containing Inseparable Ordered Paris

Using the integer programming approach introduced by Sethuraman, Teo, and Vohra (2003), we extend the analysis of the preference domains containing an inseparable ordered pair, initiated by Kalai and Ritz (1978). We show that these domains admit not only Arrovian social welfare functions \without ties," but also Arrovian social welfare functions \with ties," since they satisfy the strictly decomposability condition introduced by Busetto, Codognato, and Tonin (2012). Moreover, we go further in the comparison between Kalai and Ritz (1978)'s inseparability and Arrow (1963)'s single-peak restrictions, showing that the former condition is more \respectable," in the sense of Muller and Satterthwaite (1985).

Predators promote defence of rhizosphere bacterial populations by selective feeding on non-toxic cheaters.

Soil pseudomonads increase their competitiveness by producing toxic secondary metabolites, which inhibit competitors and repel predators. Toxin production is regulated by cell-cell signalling and efficiently protects the bacterial population. However, cell communication is unstable, and natural populations often contain signal blind mutants displaying an altered phenotype defective in exoproduct synthesis. Such mutants are weak competitors, and we hypothesized that their fitness depends on natural communities on the exoproducts of wild-type bacteria, especially defence toxins. We established mixed populations of wild-type and signal blind, non-toxic gacS-deficient mutants of Pseudomonas fluorescens CHA0 in batch and rhizosphere systems. Bacteria were grazed by representatives of the most important bacterial predators in soil, nematodes (Caenorhabditis elegans) and protozoa (Acanthamoeba castellanii). The gacS mutants showed a negative frequency-dependent fitness and could reach up to one-third of the population, suggesting that they rely on the exoproducts of the wild-type bacteria. Both predators preferentially consumed the mutant strain, but populations with a low mutant load were resistant to predation, allowing the mutant to remain competitive at low relative density. The results suggest that signal blind Pseudomonas increase their fitness by exploiting the toxins produced by wild-type bacteria, and that predation promotes the production of bacterial defence compounds by selectively eliminating non-toxic mutants. Therefore, predators not only regulate population dynamics of soil bacteria but also structure the genetic and phenotypic constitution of bacterial communities.

El suro com a adsorbent del plom i el poloni

S’ha estudiat la utilització del suro com a adsorbent de metalls i radionúclids, com el plom i el poloni. Aquesta metodologia es pot aplicar en diferents camps, principalment per la separació d’aquests elements tant per a la seva posterior anàlisi com per l’eliminació i descontaminació en medis naturals. El suro és un bon adsorbent del plom, ja que de promig n’adsorbeix un 80%, i existeix dependència amb la relació superfície – volum del suro. La capacitat de càrrega màxima, a partir de les vuit hores, correspon al suro de diàmetre de partícula de 0.5 a 1 mm, amb un valor proper a 6·10-2 mmol Pb/g suro. El poloni presenta una eficiència d’adsorció menor a la del plom, d’un 50% del poloni present en la solució de càrrega inicial. Del present treball es pot concloure que el suro és un bon material adsorbent per a metalls i/o radionúclids, i per tan pot ser emprat com a una tècnica de separació i/o recuperació alternativa a les actualment establertes, sent més econòmica i biodegradable.

Characterisation of microbial communities colonising the hyphal surfaces of arbuscular mycorrhizal fungi.

Arbuscular mycorrhizal fungi (AMF) are symbiotic soil fungi that are intimately associated with the roots of the majority of land plants. They colonise the interior of the roots and the hyphae extend into the soil. It is well known that bacterial colonisation of the rhizosphere can be crucial for many pathogenic as well as symbiotic plant-microbe interactions. However, although bacteria colonising the extraradical AMF hyphae (the hyphosphere) might be equally important for AMF symbiosis, little is known regarding which bacterial species would colonise AMF hyphae. In this study, we investigated which bacterial communities might be associated with AMF hyphae. As bacterial-hyphal attachment is extremely difficult to study in situ, we designed a system to grow AMF hyphae of Glomus intraradices and Glomus proliferum and studied which bacteria separated from an agricultural soil specifically attach to the hyphae. Characterisation of attached and non-attached bacterial communities was performed using terminal restriction fragment length polymorphism and clone library sequencing of 16S ribosomal RNA (rRNA) gene fragments. For all experiments, the composition of hyphal attached bacterial communities was different from the non-attached communities, and was also different from bacterial communities that had attached to glass wool (a non-living substratum). Analysis of amplified 16S rRNA genes indicated that in particular bacteria from the family of Oxalobacteraceae were highly abundant on AMF hyphae, suggesting that they may have developed specific interactions with the fungi.

Is there a common factor for vision?

In cognition, common factors play a crucial role. For example, different types of intelligence are highly correlated, pointing to a common factor, which is often called g. One might expect that a similar common factor would also exist for vision. Surprisingly, no one in the field has addressed this issue. Here, we provide the first evidence that there is no common factor for vision. We tested 40 healthy students' performance in six basic visual paradigms: visual acuity, vernier discrimination, two visual backward masking paradigms, Gabor detection, and bisection discrimination. One might expect that performance levels on these tasks would be highly correlated because some individuals generally have better vision than others due to superior optics, better retinal or cortical processing, or enriched visual experience. However, only four out of 15 correlations were significant, two of which were nontrivial. These results cannot be explained by high intraobserver variability or ceiling effects because test-retest reliability was high and the variance in our student population is commensurate with that from other studies with well-sighted populations. Using a variety of tests (e.g., principal components analysis, Bayes theorem, test-retest reliability), we show the robustness of our null results. We suggest that neuroplasticity operates during everyday experience to generate marked individual differences. Our results apply only to the normally sighted population (i.e., restricted range sampling). For the entire population, including those with degenerate vision, we expect different results.

Discharge properties of single neurons in the dorsal nucleus of the lateral lemniscus of the rat.

The aim of the present study was to characterize the discharge properties of single neurons in the dorsal nucleus of the lateral lemniscus (DNLL) of the rat. In the absence of acoustic stimulation, two types of spontaneous discharge patterns were observed: units tended to fire in a bursting or in a nonbursting mode. The distribution of units in the DNLL based on spontaneous firing rate followed a rostrocaudal gradient: units with high spontaneous rates were most commonly located in the rostral part of the DNLL, whereas in the caudal part units had lower spontaneous discharge rates. The most common response pattern of DNLL units to 200 ms binaural noise bursts contained a prominent onset response followed by a lower but steady-state response and an inhibitory response in the early-off period. Thresholds of response to noise bursts were on average higher for DNLL units than for units recorded in the inferior colliculus under the same experimental conditions. The DNLL units were arranged according to a mediolateral sensitivity gradient with the lowest threshold units in the most lateral part of the nucleus. In the rat, as in other mammals, the most common DNLL binaural input type was an excitatory response to contralateral ear stimulation and inhibitory response to ipsilateral ear stimulation (EI type). Pure tone bursts were in general a more effective stimulus compared to noise bursts. Best frequency (BF) was established for 97 DNLL units and plotted according to their spatial location. The DNLL exhibits a loose tonotopic organization, where there is a concentric pattern with high BF units located in the most dorsal and ventral parts of the DNLL and lower BF units in the middle part of the nucleus.

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We describe here the potential of viral-mediated gene transfer for the modeling and treatment of Huntington's disease, focusing in particular on strategies for the tissue-specific targeting of various CNS cells. The protocols described here cover the design of lentiviral vectors, strategies for modifying their tropism, including the use of various envelopes and tissue-specific promoters, and the potential of miRNA to regulate transgene expression.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

The search for new antimalarial drugs from plants used to treat fever and malaria or plants ramdomly selected: a review

In this review we discuss the ongoing situation of human malaria in the Brazilian Amazon, where it is endemic causing over 610,000 new acute cases yearly, a number which is on the increase. This is partly a result of drug resistant parasites and new antimalarial drugs are urgently needed. The approaches we have used in the search of new drugs during decades are now reviewed and include ethnopharmocology, plants randomly selected, extracts or isolated substances from plants shown to be active against the blood stage parasites in our previous studies. Emphasis is given on the medicinal plant Bidens pilosa, proven to be active against the parasite blood stages in tests using freshly prepared plant extracts. The anti-sporozoite activity of one plant used in the Brazilian endemic area to prevent malaria is also described, the so called "Indian beer" (Ampelozizyphus amazonicus, Rhamnaceae). Freshly prepared extracts from the roots of this plant were totally inactive against blood stage parasites, but active against sporozoites of Plasmodium gallinaceum or the primary exoerythrocytic stages reducing tissue parasitism in inoculated chickens. This result will be of practical importance if confirmed in mammalian malaria. Problems and perspectives in the search for antimalarial drugs are discussed as well as the toxicological and clinical trials to validate some of the active plants for public health use in Brazil.

Emissió ràdio a baixa freqüència en fenòmens eruptius i en fonts esteses de raigs gamma d'alta i molt alta energia

La tasca investigadora presentada en aquesta memòria s'ha centrat en les fonts galàctiques de raigs gamma de molt alta energia LS I +61 303, HESS J1708-410 i HESS J1858+020. La primera és una binària de raigs gamma molt estudiada, formada per una estrella massiva i un objecte compacte. S'ha proposat un escenari on l'objecte compacte seria un púlsar jove, i la interacció del seu vent amb el vent de l'estrella generaria els raigs gamma. De totes formes, no s'ha detectat polsos procedents d'aquest putatiu púlsar. L'investigador va realitzar observacions en fase a 1280 MHz amb el radiotelescopi GMRT, sense trobar-hi polsos, cosa que implica un estricte límit superior de 0,38 mJy a la densitat mitjana de flux polsat en un putatiu púlsar amb un període major que 2 mil•lisegons en el sistema binari LS I +61 303. Per altra banda, HESS J1708-410 i HESS J1858+020 són dues fonts esteses de raigs gamma de molt alta energia de les quals no es coneix cap contrapart a d'altres longituds d'ona. L'investigador les va observar amb el GMRT, quatre vegades HESS J1708-410 (dues a 610 MHz i dues a 1400 MHz) i dues vegades HESS J1858+020 (una a cada freqüència). En les imatges realitzades amb aquestes dades no hi ha emissió estesa coincident amb les regions d'emissió de raigs gamma. HESS J1858+020 se solapa parcialment amb una font estesa que podria ser un SNR. De confirmar-se la falta de contrapartida ràdio de HESS J1708-410, estaríem parlant d'un accelerador hadrònic extraordinàriament eficient, d'una classe desconeguda fins ara.

Frequency of Strongyloides stercoralis Infection in Alcoholics

Several studies have shown that chronic alcoholics have increased susceptibility to infections due to higher exposure to infectious agents as well as breakdown in their immune defenses. As Strongyloides stercoralis infection is usually more relevant in immunocompromised patients, the aim of this study was to evaluate the frequency of S. stercoralis infection in alcoholics. Thus, coproparasitological examination was carried out in 145 subjects, from which 45 were chronic alcoholics (mean age of 45.7 ± 11.0 years), 10 were nonalcoholic cirrhotic patients (mean age of 50.2 ± 13.1 years), and 90 were asymptomatic nonalcoholic subjects (mean age of 46.7 ± 10.1 years), which served as controls. From the alcoholics, 9 had hepatic cirrhosis, 9 had chronic pancreatitis and 27 had neither cirrhosis nor pancreatitis. For the diagnosis of strongyloidiasis, the Baermann-Moraes and Lutz methods were used in three fecal samples from each subject. Samples were collected at alternated days, and three slides of each sample were analyzed for each method, thus totalizing 2,610 slides examined. The frequency of strongyloidiasis in the total alcoholic group (33.3%) and in the subgroups of alcoholics, i.e., patients with hepatic cirrhosis (44.4%), with chronic pancreatitis (33.3%), and those with no cirrhosis or pancreatitis (29.6%) was statistically higher than that found in the control group (5.5%). None of the individuals with nonalcoholic hepatic cirrhosis had S. stercoralis infection. Our results showed that the chronic alcoholism itself is an important factor that predisposes to strongyloidiasis.

Variants in MTNR1B influence fasting glucose levels.

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.