CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

Regeneration of Cryoinjury Induced Necrotic Heart Lesions in Zebrafish Is Associated with Epicardial Activation and Cardiomyocyte Proliferation

In mammals, myocardial cell death due to infarction results in scar formation and little regenerative response. In contrast, zebrafish have a high capacity to regenerate the heart after surgical resection of myocardial tissue. However, whether zebrafish can also regenerate lesions caused by cell death has not been tested. Here, we present a simple method for induction of necrotic lesions in the adult zebrafish heart based on cryoinjury. Despite widespread tissue death and loss of cardiomyocytes caused by these lesions, zebrafish display a robust regenerative response, which results in substantial clearing of the necrotic tissue and little scar formation. The cellular mechanisms underlying regeneration appear to be similar to those activated in response to ventricular resection. In particular, the epicardium activates a developmental gene program, proliferates and covers the lesion. Concomitantly, mature uninjured cardiomyocytes become proliferative and invade the lesion. Our injury model will be a useful tool to study the molecular mechanisms of natural heart regeneration in response to necrotic cell death

Happiness Through Vacationing: Just a Temporary Boost or Long-Term Benefits?

Does vacationing add to our happiness in the long run? This question was addressed in a study of 3,650 Dutch citizens who reported their leisure travel every 3 months during 2 years and rated their happiness at the end of each year. Participants who had been on vacation appeared to be marginally happier, in terms of hedonic level of affect, than those who had not. This difference in Affect balance between vacationers and non-vacationers is probably due to a very minor causal effect of vacationing on hedonic level of affect. Possibly, vacationing is positively reminisced and these memories allow for the prevalence of more positive affect in people's lives. Happiness did not predict vacationing. The effect of holiday trips on vacationers' happiness is mostly short-lived; among vacationers, happiness was unrelated to the number of trips and days spent on vacation. A separate analysis of vacationers, who value vacationing most, yielded the same results. Implications for future research are discussed

Bloodstream and endovascular infections due to Abiotrophia defectiva and Granulicatella species

BACKGROUND: Abiotrophia and Granulicatella species, previously referred to as nutritionally variant streptococci (NVS), are significant causative agents of endocarditis and bacteraemia. In this study, we reviewed the clinical manifestations of infections due to A. defectiva and Granulicatella species that occurred at our institution between 1998 and 2004. METHODS: The analysis included all strains of NVS that were isolated from blood cultures or vascular graft specimens. All strains were identified by 16S rRNA sequence analysis. Patients' medical charts were reviewed for each case of infection. RESULTS: Eleven strains of NVS were isolated during the 6-year period. Identification of the strains by 16S rRNA showed 2 genogroups: Abiotrophia defectiva (3) and Granulicatella adiacens (6) or "para-adiacens" (2). The three A. defectiva strains were isolated from immunocompetent patients with endovascular infections, whereas 7 of 8 Granulicatella spp. strains were isolated from immunosuppressed patients, mainly febrile neutropenic patients. We report the first case of "G. para-adiacens" bacteraemia in the setting of febrile neutropenia. CONCLUSION: We propose that Granulicatella spp. be considered as a possible agent of bacteraemia in neutropenic patients

A prospective cohort study of dietary patterns of non-western migrants in the Netherlands in relation to risk factors for cardiovascular diseases: HELIUS-Dietary Patterns

<p>Abstract</p> <p>Background</p> <p>In Western countries the prevalence of cardiovascular disease (CVD) is often higher in non-Western migrants as compared to the host population. Diet is an important modifiable determinant of CVD. Increasingly, dietary patterns rather than single nutrients are the focus of research in an attempt to account for the complexity of nutrient interactions in foods. Research on dietary patterns in non-Western migrants is limited and may be hampered by a lack of validated instruments that can be used to assess the habitual diet of non-western migrants in large scale epidemiological studies. The ultimate aims of this study are to (1) understand whether differences in dietary patterns explain differences in CVD risk between ethnic groups, by developing and validating ethnic-specific Food Frequency Questionnaires (FFQs), and (2) to investigate the determinants of these dietary patterns. This paper outlines the design and methods used in the HELIUS-Dietary Patterns study and describes a systematic approach to overcome difficulties in the assessment and analysis of dietary intake data in ethnically diverse populations.</p> <p>Methods/Design</p> <p>The HELIUS-Dietary Patterns study is embedded in the HELIUS study, a Dutch multi-ethnic cohort study. After developing ethnic-specific FFQs, we will gather data on the habitual intake of 5000 participants (18-70 years old) of ethnic Dutch, Surinamese of African and of South Asian origin, Turkish or Moroccan origin. Dietary patterns will be derived using factor analysis, but we will also evaluate diet quality using hypothesis-driven approaches. The relation between dietary patterns and CVD risk factors will be analysed using multiple linear regression analysis. Potential underlying determinants of dietary patterns like migration history, acculturation, socio-economic factors and lifestyle, will be considered.</p> <p>Discussion</p> <p>This study will allow us to investigate the contribution of the dietary patterns on CVD risk factors in a multi-ethnic population. Inclusion of five ethnic groups residing in one setting makes this study highly innovative as confounding by local environment characteristics is limited. Heterogeneity in the study population will provide variance in dietary patterns which is a great advantage when studying the link between diet and disease.</p

Vacationers Happier, but Most not Happier After a Holiday

The aim of this study was to obtain a greater insight into the association between vacations and happiness. We examined whether vacationers differ in happiness, compared to those not going on holiday, and if a holiday trip boosts post-trip happiness. These questions were addressed in a pre-test/post-test design study among 1,530 Dutch individuals. 974 vacationers answered questions about their happiness before and after a holiday trip. Vacationers reported a higher degree of pre-trip happiness, compared to non-vacationers, possibly because they are anticipating their holiday. Only a very relaxed holiday trip boosts vacationers’ happiness further after return. Generally, there is no difference between vacationers’ and non-vacationers’ post-trip happiness. The findings are explained in the light of set-point theory, need theory and comparison theory

Whole Genome Sequencing Reveals Local Transmission Patterns of Mycobacterium bovis in Sympatric Cattle and Badger Populations

Whole genome sequencing (WGS) technology holds great promise as a tool for the forensic epidemiology of bacterial pathogens. It is likely to be particularly useful for studying the transmission dynamics of an observed epidemic involving a largely unsampled &lsquo;reservoir' host, as for bovine tuberculosis (bTB) in British and Irish cattle and badgers. BTB is caused by Mycobacterium bovis, a member of the M. tuberculosis complex that also includes the aetiological agent for human TB. In this study, we identified a spatio-temporally linked group of 26 cattle and 4 badgers infected with the same Variable Number Tandem Repeat (VNTR) type of M. bovis. Single-nucleotide polymorphisms (SNPs) between sequences identified differences that were consistent with bacterial lineages being persistent on or near farms for several years, despite multiple clear whole herd tests in the interim. Comparing WGS data to mathematical models showed good correlations between genetic divergence and spatial distance, but poor correspondence to the network of cattle movements or within-herd contacts. Badger isolates showed between zero and four SNP differences from the nearest cattle isolate, providing evidence for recent transmissions between the two hosts. This is the first direct genetic evidence of M. bovis persistence on farms over multiple outbreaks with a continued, ongoing interaction with local badgers. However, despite unprecedented resolution, directionality of transmission cannot be inferred at this stage. Despite the often notoriously long timescales between time of infection and time of sampling for TB, our results suggest that WGS data alone can provide insights into TB epidemiology even where detailed contact data are not available, and that more extensive sampling and analysis will allow for quantification of the extent and direction of transmission between cattle and badgers

The signatures of Anthropocene defaunation: cascading effects of the seed dispersal collapse

Anthropogenic activity is driving population declines and extinctions of large-bodied, fruit-eating animals worldwide. Loss of these frugivores is expected to trigger negative cascading effects on plant populations if remnant species fail to replace the seed dispersal services provided by the extinct frugivores. A collapse of seed dispersal may not only affect plant demography (i.e., lack of recruitment), but should also supress gene flow via seed dispersal. Yet little empirical data still exist demonstrating the genetic consequences of defaunation for animal-dispersed plant species. Here, we first document a significant reduction of seed dispersal distances along a gradient of human-driven defaunation, with increasing loss of large- and medium-bodied frugivores. We then show that local plant neighbourhoods have higher genetic similarity and smaller effective population sizes when large seed dispersers become extinct (i.e., only small frugivores remain) or are even partially downgraded (i.e., medium-sized frugivores providing less efficient seed dispersal). Our results demonstrate that preservation of large frugivores is crucial to maintain functional seed dispersal services and their associated genetic imprints, a central conservation target. Early signals of reduced dispersal distances that accompany the Anthropogenic defaunation forecast multiple, cascading effects on plant populations