Large-scale mapping of mutations affecting zebrafish development

BACKGROUND: Large-scale mutagenesis screens in the zebrafish employing the mutagen ENU have isolated several hundred mutant loci that represent putative developmental control genes. In order to realize the potential of such screens, systematic genetic mapping of the mutations is necessary. Here we report on a large-scale effort to map the mutations generated in mutagenesis screening at the Max Planck Institute for Developmental Biology by genome scanning with microsatellite markers. RESULTS: We have selected a set of microsatellite markers and developed methods and scoring criteria suitable for efficient, high-throughput genome scanning. We have used these methods to successfully obtain a rough map position for 319 mutant loci from the Tübingen I mutagenesis screen and subsequent screening of the mutant collection. For 277 of these the corresponding gene is not yet identified. Mapping was successful for 80 % of the tested loci. By comparing 21 mutation and gene positions of cloned mutations we have validated the correctness of our linkage group assignments and estimated the standard error of our map positions to be approximately 6 cM. CONCLUSION: By obtaining rough map positions for over 300 zebrafish loci with developmental phenotypes, we have generated a dataset that will be useful not only for cloning of the affected genes, but also to suggest allelism of mutations with similar phenotypes that will be identified in future screens. Furthermore this work validates the usefulness of our methodology for rapid, systematic and inexpensive microsatellite mapping of zebrafish mutations

Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention. © 2014

Assessment of prostate-specific antigen screening: an evidence-based report by the German Institute for Quality and Efficiency in Health Care

Context Prostate-specific antigen (PSA) testing increases prostate cancer diagnoses and reduces long-term disease-specific mortality, but also results in overdiagnoses and treatment-related harms. Objective To systematically assess the benefits and harms of population-based PSA screening and the potential net benefit to inform health policy decision-makers in Germany. Evidence Acquisition We performed a protocol-guided comprehensive literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. All steps were performed by one or two investigators; any discrepancies were resolved by consensus. To allow subgroup analyses for identifying the optimal screening parameters, the eight national trials conducted under the umbrella of the European Randomised study of Screening for Prostate Cancer (ERSPC) were included as individual trials. Evidence Synthesis We included a total 11 randomised controlled trials (RCTs) with a total of 416 000 study participants. For all-cause mortality, we found neither benefit nor harm. PSA screening was associated with a reduced risk of both prostate cancer mortality and the development of metastases. For the outcomes of health-related quality of life, adverse effects and the consequences of false-negative screening results there was no difference; however, this was due to the lack of eligible RCT data. Finally, PSA screening was associated with large numbers of overdiagnoses with adverse downstream consequences of unnecessary treatment (e.g. incontinence, erectile dysfunction) and large numbers of false-positive PSA tests leading to biopsies associated with a small but not negligible risk of complications. Limitations of this assessment include the clinical heterogeneity and methodological limitations of the underlying studies. Conclusions The benefits of PSA-based prostate cancer screening do not outweigh its harms. We failed to identify eligible screening studies of newer biomarkers, PSA derivatives or modern imaging modalities, which may alter the balance of benefit to harm. Patient Summary In the present study, we reviewed the evidence on the PSA blood test to screen men without symptoms for prostate cancer. We found that the small benefits experienced by some men do not outweigh the harms to many more men

The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

Aims/hypothesis Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetes-associated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT(1)R) subtype. However, its actions via the angiotensin II type 2 receptor (AT(2)R) subtype are still poorly understood. This study is the first to investigate the role of the novel selective AT(2)R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA). Methods Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate buffer), C21 (1 mg/kg per day), candesartan cilexetil (4 mg/kg per day) or C21 + candesartan cilexetil over a 20 week period. In vitro models of DAA using human aortic endothelial cells and monocyte cultures treated with C21 were also performed. At the end of the experiments, assessment of plaque content and markers of oxidative stress, inflammation and fibrosis were conducted. Results C21 treatment significantly attenuated aortic plaque deposition in a mouse model of DAA in vivo, in association with a decreased infiltration of macrophages and mediators of inflammation, oxidative stress and fibrosis. On the other hand, combination therapy with C21 and candesartan (AT(1)R antagonist) appeared to have a limited additive effect in attenuating the pathology of DAA when compared with either treatment alone. Similarly, C21 was found to confer profound anti-atherosclerotic actions at the in vitro level, particularly in the setting of hyperglycaemia. Strikingly, these atheroprotective actions of C21 were completely blocked by the AT(2)R antagonist PD123319. Conclusions/interpretation Taken together, these findings provide novel mechanistic and potential therapeutic insights into C21 as a monotherapy agent against DAA

Verbundprojekt SIMULTAN (Sinkhole instability: integrated multi-scale monitoring and analysis; Subrosion und Erdfall-Instabilität: integrierte multi-skalige Überwachung und Analyse) - Schlussbericht zum BMBF-Verbundvorhaben - Förderkennzeichen FKZ 03G0843 (A bis J)

Das Verbundprojekt SIMULTAN erforscht die Früherkennung für Instabilität, Unruhe und Kollaps von Erdfällen. Der neuartige Forschungsansatz kombiniert strukturelle, geophysikalische, petrophysikalische und hydrologische Kartierungsmethoden, die von Sensorentwicklung und mulit-skaliger Überwachung flankiert werden, und umfasst eine Informationsplattform. Kollapsprozesse an Erdfällen finden generell in den obersten wenigen 100 Metern der Erdkruste statt. Individuelle Prozesskomponenten können einfach sein und verstanden werden. Aber es wechselwirken auch Prä-Kollapsprozesse und Vorläufer auf unterschiedlichen raum-zeitlichen Skalen und mit kleinen Variationen miteinander. Dies erfordert innovative, multi-skalige Beobachtungen, Analysen und integrierte Früherkennungskonzepte, besonders für urbane Bereiche, die bisher noch nicht vollständig entwickelt verfügbar sind und auch noch nicht als automatische operationelle Systeme arbeiten. Zur Identifizierung und Quantifizierung von Subrosionsbereichen zeigten sich bohrlochseismische Verfahren mit kombinierten P- und S-Wellen als zielführend. Als besonderer Indikator, der sich auch für Langzeitmonitoring eignet, hat sich dabei das ungewöhnliche Konversionsverhalten der Wellen in Subrosionszonen gezeigt. Neue Prozessingverfahren zur Detektion kleiner seismischer Ereignisse und für emergente Einsätze unterstützen den Ansatz von angepassten Arraymessungen. Geodätisch-gravimetrische Überwachungsnetze sind auch unter urbanen Bedingungen geeignet, durch Subrosion verursachte Oberflächendeformationen und Massenverlagerungen räumlich-zeitlich zu erfassen und zu überwachen. Nivellements liefern bezüglich der Oberflächendeformation höchste Genauigkeiten; zugleich sind sie vergleichsweise kostengünstig zu realisieren. Die Integration von GNSS hat in Verbindung mit dem Nivellement die räumliche Auflösung im Untersuchungsgebiet zusätzlich gestützt und hat das Potenzial, diese großräumig zu kontrollieren. Gravimetrische Messungen sind mit einem sehr hohen Aufwand verbunden. Die Kombination oberflächengeophysikalischer Verfahren mit einer vertikal hochaufgelösten direct push-basierten Erkundung im Raum mit einem maßgeschneiderten hydrogeologischen Monitoring bietet eine zuverlässige Grundlage für numerische Prozessmodellierungen und ermöglichen es, erdfallrelevante Prozesse abzubilden und zu erfassen. Karstaquifer- und geomechanische Modellierungen konnten die Prozesse in den Fokusgebieten erfolgreich abbilden, sobald diese mit realistischen Werten unterlegt wurden. Es zeigt sich somit insgesamt, dass sowohl flächenhafte Messungen und zeitlich wiederholte Kampagnen sehr vorteilhaft sind, da sie es erlauben, Fehler zu verringern und beanspruchte Bereiche einzugrenzen. Erst dieses integrierte Vorgehen ermöglicht es, potenzielle Wegsamkeiten im Untergrund hochauflösender als bisher abzubilden und zu bewerten. Als solches stellt es ein Instrumentarium zur Charakterisierung und angepassten Überwachung von Untergrundbereichen im Allgemeinen zur Verfügung. Diese Ergebnisse und Szenarien stehen der Öffentlichkeit auf einer Informationsplattform zur Verfügung (http://simultan.gfz-potsdam.de).BMBF - Bundesministerium für Bildung und Forschung - Projektträger Jülich/Sonderprogramm GEOTECHNOLOGIEN (Frühwarnsysteme)/03G0843 (A bis J)/E

Inspiration Geschichte : Publikation der Arbeitsgemeinschaft des Kunsthandwerks Hamburg e.V.

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