Cyclo­hexa­nespiro-2′-[2′,3′,6′,7′-tetra­hydro-1′H-cyclo­penta­[d]pyrimidin]-4′(5′H)-one

The title compound, C12H18N2O, was synthesized by the reaction of cyclo­hexa­none and 2-amino­cyclo­pent-1-enecarbonitrile. In the mol­ecule of the title compound, the six-carbon ring displays a chair conformation, the six-membered 1,3-diaza ring and the cyclo­pentene ring both assume envelope conformations. Supra­molecular aggregation is achieved by N—H⋯O hydrogen bonds

Self-mask fabrication of uniformly orientated SiGe island/SiGe/Si hetero-nanowire arrays with controllable sizes

National Natural Science Foundation of China [61176050, 61036003, 61176092]; Fundamental Research Funds for the Fujian province of China [2012H0038]; National Basic Research Program of China [2012CB933503, 2013CB632103]; Fundamental Research Funds for the Central Universities [2010121056]We report the synthesis of SiGe island/SiGe/Si hetero-nanowire arrays using laser-induced SiGe islands as templates followed by Ar ion beam etching (IBE). Firstly, single crystal SiGe islands with an average aspect ratio of 0.96 are prepared by pulse laser irradiation of amorphous Ge film on Si substrate. It is interesting to note that these SiGe islands can serve as masks, and uniformly orientated SiGe island/SiGe/Si nanowires can be fabricated by Ar IBE. Moreover, the diameters of the hetero-nanowires can be well-controlled by the size of the SiGe islands determined by the energy density of the pulse laser during the crystallization. Our experiments show the unique nonlithographic self-mask method and demonstrate the mass production of SiGe island/SiGe/Si hetero-nanowire arrays which may find applications in nanodevices

Emilin1 gene and essential hypertension: a two-stage association study in northern Han Chinese population

<p>Abstract</p> <p>Background</p> <p>Elastogenesis of elastic extracellular matrix (ECM) which was recognized as a major component of blood vessels has been believed for a long time to play only a passive role in the dynamic vascular changes of typical hypertension. Emilin1 gene participated in the transcription of ECM's formation and was recognized to modulate links TGF-β maturation to blood pressure homeostasis in animal study. Recently relevant advances urge further researches to investigate the role of Emilin1 gene in regulating TGF-β signals involved in elastogenesis and vascular cell defects of essential hypertension (EH).</p> <p>Methods</p> <p>We designed a two-stage case-control study and selected three single nucleotide polymorphisms (SNPs), rs3754734, rs2011616 and rs2304682 from the HapMap database, which covered Emilin1 gene. Totally 2,586 subjects were recruited from the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). In stage 1, all the three SNPs of the Emilin1 gene were genotyped and tested within a subsample including 503 cases and 490 controls, significant SNPs would enter into stage 2 including 814 cases with hypertension and 779 controls and analyze on the basis of testing total 2,586 subjects.</p> <p>Results</p> <p>In stage 1, single locus analyses showed that SNPs rs3754734 and rs2011616 had significant association with EH (P < 0.05). In stage 2, weak association for dominant model were observed by age stratification and odds ratio (ORs) of TG+GG vs. TT of rs3754734 were 0.768 (0.584-1.009), 0.985 (0.735-1.320) and 1.346 (1.003-1.806) in < 50, 50-59 and ≥ 60 years group and ORs of GA+AA vs. GG of rs2011616 were 0.745 (0.568-0.977), 1.013 (0.758-1.353) and 1.437 (1.072-1.926) in < 50, 50-59 and ≥ 60 years group respectively. Accordingly, significant interactions were detected between genotypes of rs3754734 and rs2011616 and age for EH, and ORs were 1.758 (1.180-2.620), P = 0.006 and 1.903 (1.281-2.825), P = 0.001, respectively. Results of haplotypes analysis showed that there weren't any haplotypes associated with EH directly, but the interaction of hap2 (GA) and age-group found to be significant after being adjusted for the covariates, OR was 1.220 (1.031-1.444), P value was 0.020.</p> <p>Conclusion</p> <p>Our findings don't support positive association of Emilin1 gene with EH, but the interaction of age and genotype variation of rs3754734 and rs2011616 might increase the risk to hypertension.</p

Potential candidates for liver resection in liver-confined advanced HCC: a Chinese multicenter observational study

BackgroundAdvanced hepatocellular carcinoma (HCC) is characterized as symptomatic tumors [performance status (PS) score of 1-2], vascular invasion and extrahepatic spread, but patients with PS1 alone may be eliminated from this stage. Although liver resection is used for liver-confined HCC, its role in patients with PS1 alone remains controversial. Therefore, we aimed to explore its application in such patients and identify potential candidates.MethodsEligible liver-confined HCC patients undergoing liver resection were retrospectively screened in 15 Chinese tertiary hospitals, with limited tumor burden, liver function and PS scores. Cox-regression survival analysis was used to investigate the prognostic factors and develop a risk-scoring system, according to which patients were substratified using fitting curves and the predictive values of PS were explored in each stratification.ResultsFrom January 2010 to October 2021, 1535 consecutive patients were selected. In the whole cohort, PS, AFP, tumor size and albumin were correlated with survival (adjusted P&lt;0.05), based on which risk scores of every patient were calculated and ranged from 0 to 18. Fitting curve analysis demonstrated that the prognostic abilities of PS varied with risk scores and that the patients should be divided into three risk stratifications. Importantly, in the low-risk stratification, PS lost its prognostic value, and patients with PS1 alone achieved a satisfactory 5-year survival rate of 78.0%, which was comparable with that PS0 patients (84.6%).ConclusionSelected patients with PS1 alone and an ideal baseline condition may benefit from liver resection and may migrate forward to BCLC stage A

Identify optimal HAP series scores for unresectable HCC patients undergoing TACE plus sorafenib: A Chinese multicenter observational study

BackgroundHepatoma arterial-embolization prognostic (HAP) series scores have been proposed for prognostic prediction in patients with unresectable hepatocellular carcinoma (uHCC) undergoing transarterial chemoembolization (TACE). However, their prognostic value in TACE plus sorafenib (TACE-S) remains unknown. Here, we aim to evaluate their prognostic performance in such conditions and identify the best model for this combination therapy.MethodsBetween January 2012 and December 2018, consecutive patients with uHCC receiving TACE-S were recruited from 15 tertiary hospitals in China. Cox regression analyses were used to investigate the prognostic values of baseline factors and every scoring system. Their prognostic performance and discriminatory performance were evaluated and confirmed in subgroup analyses.ResultsA total of 404 patients were enrolled. In the whole cohort, the median follow-up period was 44.2 (interquartile range (IQR), 33.2–60.7) months, the median overall survival (OS) time was 13.2 months, and 336 (83.2%) patients died at the end of the follow-up period. According to multivariate analyses, HAP series scores were independent prognostic indicators of OS. In addition, the C-index, Akaike information criterion (AIC) values, and time-dependent area under the receiver operating characteristic (ROC) curve (AUC) indicated that modified HAP (mHAP)-III had the best predictive performance. Furthermore, the results remained consistent in most subsets of patients.ConclusionHAP series scores exhibited good predictive ability in uHCC patients accepting TACE-S, and the mHAP-III score was found to be superior to the other HAP series scores in predicting OS. Future prospective high-quality studies should be conducted to confirm our results and help with treatment decision-making

Genome-Wide Association Meta-analysis Identifies Novel Variants Associated With Fasting Plasma Glucose in East Asians

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk