Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

DNA methylation-based measures of biological age:meta-analysis predicting time to death

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p ≤ 8.2 x 10-9), independent of chronological age, even after adjusting for additional risk factors (p < 5.4 x 10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p≤ 7.5 x 10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality

Synthesis, radiolabelling and biodistribution studies of triazole derivatives for targeting melanoma

Abstract: Molecular probes that target specific markers expressed in solid tumours are in demand for cancer imaging and radionuclide therapy applications. The synthesis, characterization, and in vivo evaluation of radioiodinated triazoles designed as probes to target melanoma is described here. Compounds were prepared using a thermal click reaction between ethynylstannane and methyl 2-azidoacetate resulting in preferential formation of the corresponding 1,4-tin triazole. The primary amine of various targeting vectors was then coupled to the resulting tin triazole methyl ester. These precursors were labelled with no carrier added 123I or 125I and purified by high performance liquid chromatography to give isolated radiochemical yields between 6% and 51%, and radiochemical purities of >95% in all cases. Among the evaluated compounds, N-(2-diethylamino-ethyl)-2-(4-iodo-[1,2,3]triazol-1-yl)acetamide (7a) and N-(1-benzylpiperidin-4-yl)-2-(4-iodo-1H-1,2,3-triazol-1-yl)acetamide (7d) showed the most promising in vivo data and their 123I-labelled forms were used in single photon emission computed tomography-computed tomography (SPECT-CT) imaging studies. The imaging data showed excellent tumour visualization with a very high signal to noise ratio.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

The DGS Corpus Project: Development of a Corpus Based Electronic Dictionary German Sign Language – German

With a target size of 400 hours video from 300 informants, the DGS (German Sign Language) Corpus Project (2009-2023) is the first project that will create a DGS corpus comparable in size to spoken language corpora. In addition to making a large language resource available for research, the project will develop a comprehensive DGS dictionary based on corpus data, significantly advancing state of the art in corpus-based sign language lexicography. Data collection is done with a mobile studio that over the course of three years will be moved to twelve different locations all over Germany. To obtain language data coming as close to natural language use of DGS as possible, two informants coming from the same region interact with each other in a large variety of tasks lasting six hours altogether. The mix of tasks (including warm-ups etc.) is the result of a pilot phase with extensive testing of various elicitation formats and materials. The studio setup was chosen to make the informants feel as comfortable as possible without compromising recording quality. The 7-cameras setup (HD and stereoscopic cameras) promises to deliver videos suitable for manual transcription and image processing that over the course of the project is expected to deliver semi-automatic annotation to increase the effectiveness of the transcription process. As a first step to make the corpus data accessible, translations into German will be produced. The next step is a basic transcription, providing a sign-by-sign segmentation and type-token matching. More detailed transcription (including grammatical information, use of space, eye gaze) will be carried out in a third phase. As limited resources do not allow the whole corpus to be transcribed in detail, it will mainly be the lexicographical workflow determining which parts of the corpus need to be transcribed in detail. Both the transcription and lexicographic work will be carried out within the iLex environment which will steadily be extended over the course of the project in order to make use of synergies with other projects running in parallel (such as Dicta-Sign on semi-automated annotation) or to match new challenges from new linguistic research questions. With more than 20 people working concurrently with corpus data, it is evident that quality assurance has a central role in the project. Intensive transcriber trainings and coding manuals as well as experiments on formalizing inter- and intra-transcriber agreements for coding conventions used (such as HamNoSys) are only the first steps taken. In addition, researchers as well as student coworkers are invited to carry out pilot data experiments on annotation data and metadata to see if data analyses are possible within the existing data model and annotation conventions long before enough data become available to make these studies really feasible. Feedback from these experiments allow us to continually evolve the transcription process and adapt the transcription environment. It is essential for the success of the project that the language community is involved in the project beyond those people participating as informants. The task of contact persons in each region is therefore not limited to finding informants for the data recordings, but also to raise public awareness within the Deaf community. A web portal focusing on the community’s interests in the project (including viewing the corpus video material as a resource for cultural heritage) will also encourage people to provide feedback. In the dictionary context, this might include feedback on individual signs’ regional distribution. Ideas to make this portal not only attractive to contact persons and informants, but to the community at large, include offering consultation hours for questions about the language

Correction: A 99mTc-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule trans-Cyclooctene Derivatives.

[This corrects the article DOI: 10.1371/journal.pone.0167425.]

Erfahrungen und Empfehlungen aus der Beratung bei Datenmanagementplänen

Datenmanagementpläne werden zunehmend zu einem Teil des wissenschaftlichen Forschungsprozesses. Der vorliegende Bericht fasst die Erfahrungen zum Beratungsprozess von Forschenden bei der Erstellung eines Datenmanagementplans durch zentrale oder dezentrale Ansprechpartnerinnen und -partner zusammen. Die Autorinnen und Autoren aus Universitäten und außeruniversitären Forschungseinrichtungen haben darin ihre Expertise aus mehrjähriger Erfahrung zusammengetragen. Die entstandenen Empfehlungen und Best Practices sollen andere Einrichtungen bei der Beratung von Forschenden unterstützen. Der Bericht entstand im Rahmen der DINI/nestor-AG Forschungsdaten in der Unter-AG Datenmanagementpläne, die zum Ziel hat, Wissen, (Weiterbildungs-)Materialien und Erfahrungen zum Thema auszutauschen sowie weiterzuentwickeln. (DIPF/Orig.