Showing papers by "University of Dundee published in 2011"

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Genome sequence and analysis of the tuber crop potato.

Abstract: Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.

Beyond Predictions: Biodiversity Conservation in a Changing Climate

Abstract: Climate change is predicted to become a major threat to biodiversity in the 21st century, but accurate predictions and effective solutions have proved difficult to formulate. Alarming predictions have come from a rather narrow methodological base, but a new, integrated science of climate-change biodiversity assessment is emerging, based on multiple sources and approaches. Drawing on evidence from paleoecological observations, recent phenological and microevolutionary responses, experiments, and computational models, we review the insights that different approaches bring to anticipating and managing the biodiversity consequences of climate change, including the extent of species' natural resilience. We introduce a framework that uses information from different sources to identify vulnerability and to support the design of conservation responses. Although much of the information reviewed is on species, our framework and conclusions are also applicable to ecosystems, habitats, ecological communities, and genetic diversity, whether terrestrial, marine, or fresh water.

AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function

Abstract: AMP-activated protein kinase (AMPK) is a sensor of energy status that maintains cellular energy homeostasis. It arose very early during eukaryotic evolution, and its ancestral role may have been in the response to starvation. Recent work shows that the kinase is activated by increases not only in AMP, but also in ADP. Although best known for its effects on metabolism, AMPK has many other functions, including regulation of mitochondrial biogenesis and disposal, autophagy, cell polarity, and cell growth and proliferation. Both tumor cells and viruses establish mechanisms to down-regulate AMPK, allowing them to escape its restraining influences on growth.

Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4

Abstract: We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10−7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

Abstract: BACKGROUND Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODS We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTS We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONS Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.).

The cytoprotective role of the Keap1–Nrf2 pathway

Abstract: An elaborate network of highly inducible proteins protects aerobic cells against the cumulative damaging effects of reactive oxygen intermediates and toxic electrophiles, which are the major causes of neoplastic and chronic degenerative diseases. These cytoprotective proteins share common transcriptional regulation, through the Keap1–Nrf2 pathway, which can be activated by various exogenous and endogenous small molecules (inducers). Inducers chemically react with critical cysteine residues of the sensor protein Keap1, leading to stabilisation and nuclear translocation of transcription factor Nrf2, and ultimately to coordinate enhanced expression of genes coding for cytoprotective proteins. In addition, inducers inhibit pro-inflammatory responses, and there is a linear correlation spanning more than six orders of magnitude of concentrations between inducer and anti-inflammatory activity. Genetic deletion of transcription factor Nrf2 renders cells and animals much more sensitive to the damaging effects of electrophiles, oxidants and inflammatory agents in comparison with their wild-type counterparts. Conversely, activation of the Keap1–Nrf2 pathway allows survival and adaptation under various conditions of stress and has protective effects in many animal models. Cross-talks with other signalling pathways broadens the role of the Keap1–Nrf2 pathway in determining the fate of the cell, impacting fundamental biological processes such as proliferation, apoptosis, angiogenesis and metastasis.

Root elongation, water stress, and mechanical impedance: a review of limiting stresses and beneficial root tip traits

Abstract: Root elongation in drying soil is generally limited by a combination of mechanical impedance and water stress. Relationships between root elongation rate, water stress (matric potential), and mechanical impedance (penetration resistance) are reviewed, detailing the interactions between these closely related stresses. Root elongation is typically halved in repacked soils with penetrometer resistances >0.8‐2 MPa, in the absence of water stress. Root elongation is halved by matric potentials drier than about ‐0.5 MPa in the absence of mechanical impedance. The likelihood of each stress limiting root elongation is discussed in relation to the soil strength characteristics of arable soils. A survey of 19 soils, with textures ranging from loamy sand to silty clay loam, found that ;10% of penetration resistances were >2 MPa at a matric potential of ‐10 kPa, rising to nearly 50% >2 MPa at ‐ 200 kPa. This suggests that mechanical impedance is often a major limitation to root elongation in these soils even under moderately wet conditions, and is important to consider in breeding programmes for drought-resistant crops. Root tip traits that may improve root penetration are considered with respect to overcoming the external (soil) and internal (cell wall) pressures resisting elongation. The potential role of root hairs in mechanically anchoring root tips is considered theoretically, and is judged particularly relevant to roots growing in biopores or from a loose seed bed into a compacted layer of soil.

Eye guidance in natural vision: reinterpreting salience.

Abstract: Models of gaze allocation in complex scenes are derived mainly from studies of static picture viewing. The dominant framework to emerge has been image salience, where properties of the stimulus play a crucial role in guiding the eyes. However, salience-based schemes are poor at accounting for many aspects of picture viewing and can fail dramatically in the context of natural task performance. These failures have led to the development of new models of gaze allocation in scene viewing that address a number of these issues. However, models based on the picture-viewing paradigm are unlikely to generalize to a broader range of experimental contexts, because the stimulus context is limited, and the dynamic, task-driven nature of vision is not represented. We argue that there is a need to move away from this class of model and find the principles that govern gaze allocation in a broader range of settings. We outline the major limitations of salience-based selection schemes and highlight what we have learned from studies of gaze allocation in natural vision. Clear principles of selection are found across many instances of natural vision and these are not the principles that might be expected from picture-viewing studies. We discuss the emerging theoretical framework for gaze allocation on the basis of reward maximization and uncertainty reduction.

SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner.

Abstract: A disadvantage of aerobic life is the constant generation of potentially damaging reactive oxygen species (ROS). The intracellular levels of such species need to be tightly controlled in order to avoid oxidative stress. Transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in redox homeostasis since it increases the expression of many antioxidant and drug-metabolizing genes, including those encoding heme oxygenase 1 (HO-1), NADPH:quinone oxidoreductase 1, glutathione S-transferases, glutamate-cysteine ligase, and glutathione peroxidases, in response to oxidative and electrophile stressors (13). These genes all contain a common promoter enhancer called the antioxidant response element (ARE) and are transactivated by Nrf2. Because ROS play a role as intracellular signaling molecules for many physiological processes, Nrf2 can have an impact on numerous cell functions, ranging from differentiation and development to proliferation and inflammation. Therefore, Nrf2 activity influences neurodegenerative disease, cardiovascular disease, and cancer (3, 4, 14, 16, 17, 49, 53). While increased Nrf2 transcriptional activity enhances cellular antioxidant defenses and increases the capacity to detoxify drugs, it may also lead to unwanted side effects. For instance, in tumors, high levels of Nrf2 activity have been correlated with a poor prognosis (41). Indeed, high Nrf2 activity has not been favored during evolution (25), but its levels are restricted via both redox-dependent and redox-independent pathways in normal healthy cells (29). In normal cells, Keap1 (Kelch-like ECH-associated protein 1), an E3 ubiquitin ligase substrate adaptor, regulates the level of Nrf2 protein in a redox-dependent fashion (5, 20, 51). The interaction between Nrf2 and Keap1 occurs via a “two-site tethering” process, otherwise called the “hinge and latch” mechanism. In this model, two motifs, a high-affinity ETGE motif and a low-affinity DLG motif, within the N-terminal Neh2 domain of Nrf2 each interact with a separate Kelch repeat domain present in the Keap1 homodimer (40). Both the ETGE motif and the DLG motif are required for the transcription factor to be repressed by Keap1 (28). In addition to its interaction with Nrf2, Keap1 also binds Cullin 3 (Cul3), which forms a core E3 ubiquitin ligase complex through an association with Ring-box1 protein (Rbx1, also called Roc1) (5, 10, 20, 51). The Keap1-Cul3-Rbx1 complex is able to ubiquitinate Nrf2 and target it for proteasomal degradation only under normal redox conditions, and upon exposure to oxidants or electrophiles, Cys-151, Cys-273, and Cys-288 in Keap1 become modified, leading to disturbance of the interaction between Nrf2 and Keap1 (8, 21, 49, 50). Failure of Nrf2 to dock simultaneously onto both Kelch repeat domains enables it to escape ubiquitination by Cul3-Rbx1 (21, 32, 47, 50). Thus, stress-related modification of Keap1 results in Nrf2 stabilization, accumulation of the transcription factor in the nucleus, and upregulation of ARE-driven genes. Perturbation of the Nrf2-Keap1 complex by oxidants and electrophiles is considered the principal mechanism by which Nrf2 accumulates and induces the ARE-gene battery. However, other regulatory mechanisms must exist in order to explain the following: (i) how Nrf2 contributes to the basal expression of certain ARE-driven genes under normal homeostatic conditions, (ii) how Nrf2 activity returns to its low basal levels after the intracellular redox balance has been restored, and (iii) how Nrf2 activity is limited during oxidative and electrophile stress. Conventional cell signaling studies have suggested that Nrf2 might be regulated by protein phosphorylation (2, 6, 15, 18, 36, 44). Previously, we presented data suggesting that GSK-3β (glycogen synthase kinase 3β) influences the nuclear exclusion and inactivation of Nrf2 (37-39). However, the mechanistic connection between GSK-3 and Nrf2 remains largely unexplored. A number of studies have demonstrated that GSK-3 directs the ubiquitination and proteasomal degradation of various transcription factors and other proteins by SCF/β-TrCP; these include Snail (54), β-catenin (1, 22, 34), Gli2 and Gli3 (33, 48), Xom (55), Cdc 25a (19), FGD1 and -3 (11, 12), Mcl-1 (7), securin (24), prolactin receptor (46), and the phosphatase PHLPP1 (23). In these instances, GSK-3 phosphorylates a cluster of Ser/Thr residues in target proteins, which are then recognized by SCF/β-TrCP. In turn, the complex formed by SCF/β-TrCP binds the Cullin-1 (Cul1) scaffold protein to form a complete E3 ligase by association with a linker protein called Skp1 and with Rbx1. Therefore, β-TrCP is an adapter protein that contains a Skp1-binding site called F-box and a WD recognition domain for phosphorylated substrates in the consensus motif DpSGX(1-4)pS (9, 42). To date, the existence of a phosphodegron in Nrf2 has not been explored. In the present article, we report that Nrf2 is destabilized as a consequence of its phosphorylation by GSK-3 and subsequent ubiquitination by SCF/β-TrCP. This pathway represents an alternative mechanism to the Keap1-dependent degradation of Nrf2 and provides a means by which this transcription factor can be regulated in a redox-independent manner.

Mortality and Hospital Stay Associated with Resistant Staphylococcus aureus and Escherichia coli Bacteremia: Estimating the Burden of Antibiotic Resistance in Europe

Abstract: Background The relative importance of human diseases is conventionally assessed by cause-specific mortality, morbidity, and economic impact. Current estimates for infections caused by antibiotic-resistant bacteria are not sufficiently supported by quantitative empirical data. This study determined the excess number of deaths, bed-days, and hospital costs associated with blood stream infections (BSIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) and third-generation cephalosporin-resistant Escherichia coli (G3CREC) in 31 countries that participated in the European Antimicrobial Resistance Surveillance System (EARSS). Methods and findings The number of BSIs caused by MRSA and G3CREC was extrapolated from EARSS prevalence data and national health care statistics. Prospective cohort studies, carried out in hospitals participating in EARSS in 2007, provided the parameters for estimating the excess 30-d mortality and hospital stay associated with BSIs caused by either MRSA or G3CREC. Hospital expenditure was derived from a publicly available cost model. Trends established by EARSS were used to determine the trajectories for MRSA and G3CREC prevalence until 2015. In 2007, 27,711 episodes of MRSA BSIs were associated with 5,503 excess deaths and 255,683 excess hospital days in the participating countries, whereas 15,183 episodes of G3CREC BSIs were associated with 2,712 excess deaths and 120,065 extra hospital days. The total costs attributable to excess hospital stays for MRSA and G3CREC BSIs were 44.0 and 18.1 million Euros (63.1 and 29.7 million international dollars), respectively. Based on prevailing trends, the number of BSIs caused by G3CREC is likely to rapidly increase, outnumbering the number of MRSA BSIs in the near future. Conclusions Excess mortality associated with BSIs caused by MRSA and G3CREC is significant, and the prolongation of hospital stay imposes a considerable burden on health care systems. A foreseeable shift in the burden of antibiotic resistance from Gram-positive to Gram-negative infections will exacerbate this situation and is reason for concern.

Interpretative phenomenological analysis: a discussion and critique.

Abstract: Aim The aim of this article is to examine the approach of interpretative phenomenological analysis (IPA) and to add to discussions regarding the contribution that the approach can make to healthcare research. Background Interpretative phenomenological analysis is an approach to qualitative, experiential research that has been gaining in momentum and popularity over the past 10-15 years. The approach has its roots in psychology and recognises the central role of the analyst in understanding the experiences of participants. IPA involves a two-stage interpretation process whereby the researcher attempts to interpret how the participants make sense of their experience. Data sources Interpretative phenomenological analysis is discussed and critiqued in relation to other phenomenological approaches; benefits, potential limitations and rigour of studies using the method are explored. Review methods This is a methodology discussion that compares and contrasts IPA with other phenomenological approaches. Conclusion Interpretative phenomenological analysis offers an adaptable and accessible approach to phenomenological research intended to give a complete and in-depth account that privileges the individual. It enables nurses to reach, hear and understand the experiences of participants. Findings from IPA studies can influence and contribute to theory. Implications for research and practice Achieving a greater understanding of experiences in health care and illness can improve service provision. It is only by understanding meanings that nurses can influence health behaviour and lifestyles.

Germline mutations in RAD51D confer susceptibility to ovarian cancer

Abstract: Nazneen Rahman and colleagues show that germline inactivating mutations in RAD51D confer susceptibility to ovarian cancer. They further show that RAD51D-deficient cells are sensitive to PARP inhibition, suggesting a possible strategy for treating cancers arising in RAD51D mutation carriers.

Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy

Abstract: Background IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. Objective To investigate the association between filaggrin loss-of-function mutations and peanut allergy. Methods Case-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL −1 ) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. Results Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients ( P = 3.0 × 10 −6 ; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study ( P = 5.4 × 10 −5 ; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant ( P = .0008) after controlling for coexistent atopic dermatitis. Conclusion Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel.

Abstract: BACKGROUND AND AIM Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel. METHODOLOGY Data references were identified through indexed journals and non-indexed sources. In this work, 13,000 articles were reviewed and 860 were selected based on their relevance. RESULTS Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (â?¤ 0.5%) estimates were from northern European countries and the highest (â?¥ 3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well-established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel. CONCLUSION Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood-borne infections in the region.

Expected value and prediction error abnormalities in depression and schizophrenia.

Abstract: The dopamine system has been linked to anhedonia in depression and both the positive and negative symptoms of schizophrenia, but it remains unclear how dopamine dysfunction could mechanistically relate to observed symptoms. There is considerable evidence that phasic dopamine signals encode prediction error (differences between expected and actual outcomes), with reinforcement learning theories being based on prediction error-mediated learning of associations. It has been hypothesized that abnormal encoding of neural prediction error signals could underlie anhedonia in depression and negative symptoms in schizophrenia by disrupting learning and blunting the salience of rewarding events, and contribute to psychotic symptoms by promoting aberrant perceptions and the formation of delusions. To test this, we used model based functional magnetic resonance imaging and an instrumental reward-learning task to investigate the neural correlates of prediction errors and expected-reward values in patients with depression (n=15), patients with schizophrenia (n=14) and healthy controls (n=17). Both patient groups exhibited abnormalities in neural prediction errors, but the spatial pattern of abnormality differed, with the degree of abnormality correlating with syndrome severity. Specifically, reduced prediction errors in the striatum and midbrain were found in depression, with the extent of signal reduction in the bilateral caudate, nucleus accumbens and midbrain correlating with increased anhedonia severity. In schizophrenia, reduced prediction error signals were observed in the caudate, thalamus, insula and amygdala-hippocampal complex, with a trend for reduced prediction errors in the midbrain, and the degree of blunting in the encoding of prediction errors in the insula, amygdala-hippocampal complex and midbrain correlating with increased severity of psychotic symptoms. Schizophrenia was also associated with disruption in the encoding of expected-reward values in the bilateral amygdala-hippocampal complex and parahippocampal gyrus, with the degree of disruption correlating with psychotic symptom severity. Neural signal abnormalities did not correlate with negative symptom severity in schizophrenia. These findings support the suggestion that a disruption in the encoding of prediction error signals contributes to anhedonia symptoms in depression. In schizophrenia, the findings support the postulate of an abnormality in error-dependent updating of inferences and beliefs driving psychotic symptoms. Phasic dopamine abnormalities in depression and schizophrenia are suggested by our observation of prediction error abnormalities in dopamine-rich brain areas, given the evidence for dopamine encoding prediction errors. The findings are consistent with proposals that psychiatric syndromes reflect different disorders of neural valuation and incentive salience formation, which helps bridge the gap between biological and phenomenological levels of understanding.

Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.

Abstract: Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ~75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

Abstract: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2

Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. We employed a new, parallel, compound-centric approach to identify a potent and selective LRRK2 inhibitor, LRRK2-IN-1, and demonstrated that inhibition of LRRK2 induces dephosphorylation of Ser910 and Ser935 and accumulation of LRRK2 within aggregate structures. LRRK2-IN-1 will serve as a versatile tool to pharmacologically interrogate LRRK2 biology and study its role in Parkinson's disease.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.

Abstract: Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Control of blackleg and tuber soft rot of potato caused by Pectobacterium and Dickeya species: a review.

Abstract: This paper briefly reviews research on the causative agents of blackleg and soft rot diseases of potato, namely Pectobacterium and Dickeya species, and the disease syndrome, including epidemiological and aetiological aspects. It critically evaluates control methods used in practice based on the avoidance of the contamination of plants, in particular the use of seed testing programmes and the application of hygienic procedures during crop production. It considers the perspective of breeding and genetic modification to introduce resistance. It also evaluates the application of physical and chemical tuber treatments to reduce inoculum load and examines the possibility of biocontrol using antagonistic bacteria and bacteriophages.

Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics.

Abstract: The human large intestine harbors a complex microbiota containing many hundreds of different bacterial species. Although structure/function relationships between different components of the microbiota are unclear, this complex multicellular entity plays an important role in maintaining homeostasis in the body. Many of the physiologic properties of the microbiota can be attributed to fermentation and the production of short-chain fatty acids (SCFAs), particularly acetate, propionate, and butyrate. In healthy people, fermentation processes are largely controlled by the amounts and different types of substrate, particularly complex carbohydrates that are accessible to bacteria in the colonic ecosystem. However, other factors impact on bacterial metabolism in the large gut, including large bowel transit time, the availability of inorganic terminal electron acceptors, such as nitrate and sulfate, and gut pH. They all affect the types and levels of SCFA that can be formed by the microbiota. This is important because to a large extent, acetate, propionate, and butyrate have varying physiologic effects in different body tissues. Prebiotics such as galactooligosaccharides together with inulins and their fructooligosaccharide derivatives have been shown to modify the species composition of the colonic microbiota, and in various degrees, to manifest several health-promoting properties related to enhanced mineral absorption, laxation, potential anticancer properties, lipid metabolism, and anti-inflammatory and other immune effects, including atopic disease. Many of these phenomena can be linked to their digestion and SCFA production by bacteria in the large gut.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Abstract: Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin. © 2011 Nature America, Inc. All rights reserved.

European guidelines on managing adverse effects of medication for ADHD.

Abstract: The safety of ADHD medications is not fully known. Concerns have arisen about both a lack of contemporary-standard information about medications first licensed several decades ago, and signals of possible harm arising from more recently developed medications. These relate to both relatively minor adverse effects and extremely serious issues such as sudden cardiac death and suicidality. A guidelines group of the European Network for Hyperkinetic Disorders (EUNETHYDIS) has therefore reviewed the literature, recruited renowned clinical subspecialists and consulted as a group to examine these concerns. Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations. However, several areas require further study to allow a more precise understanding of these risks.