Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene.

BACKGROUND AND AIMS: Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects. RESULTS: The ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∼14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C (p = 0.004), and higher risk of coronary heart disease (CHD) (p = 0.04). The SNP is in modest linkage disequilibrium (r(2) > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p = 1.36 × 10(-05)). CONCLUSIONS: Both rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering

Optimasi Formula Dan Karakterisasi Sifat Fisikokimia Biskuit Dari Tepung Labu Kuning (Cucurbita moschata)

Biskuit merupakan kue kering yang berukuran kecil, memiliki rasa manis yang berbahan dasar tepung terigu dan melalui proses pemanggangan. Penggunaan tepung terigu dapat disubstitusikan dengan tepung labu kuning. Manfaat tepung labu kuning yaitu mengandung nilai gizi tinggi seperti karoten yang berperan dalam meningkatkan aktivitas antioksidan pada biskuit. Selain itu, manfaat dari penggunaan susu kedelai yaitu memiliki nilai zat gizi seperti lesitin yang berperan dalam pembentukan ketahanan tekstur dan sebagai antioksidan. Tujuan penelitian untuk mengetahui 1) optimasi formula pada biskuit tepung labu kuning 2) karakterisasi sifat fisikokimia dari perlakuan terbaik biskuit tepung labu kuning. Pada penelitian ini dilakukan optimasi formula menggunakan metode Response Surface Methodology (RSM) rancangan metode Central Composite Design dengan software Design Expert 13 dengan batas bawah dan batas atas pada tepung labu kuning yaitu 40 g dan 55 g, serta pada susu kedelai 8 g dan 23 g. Selanjutnya, dilakukan uji verifikasi menggunakan software Minitab 19 menggunakan analisis Paired T-test dengan tingkat kesalahan kurang dari 5% (p value<0,05). Kemudian, hasil perlakuan terbaik biskuit tepung labu kuning dilakukan uji karakterisasi sifat fisikokimia yang meliputi uji kekerasan menggunakan alat tensile strength, uji warna menggunakan alat color reader, aktivitas antioksidan IC50 menggunakan metode DPPH dan total flavonoid metode kalorimetri - AlCl3 dengan quercetin. Hasil menunjukan bahwa formula optimum dari biskuit tepung labu kuning yang diprediksi oleh software Design Expert 13 yaitu proporsi tepung labu kuning sebesar 40,658% dan susu kedelai sebesar 12,911% dengan respon aktivitas antioksidan IC50 sebesar 117,178 ppm dan kekerasan sebesar 8,319 N. Setelah dilakukan verifikasi, didapatkan hasil pada respon kekerasan dan aktivitas antioksidan IC50 adalah tidak berbeda nyata dengan p value> 0,05. Hasil analisis pada produk akhir yaitu biskuit tepung labu kuning memiliki karakteristik kecerahan (L*) 49,68, kemerahan (a*) +20,10, kekuningan (b*) 27,99, flavonoid sebesar 1,419 mg GAE/g, aktivitas antioksidan IC50 sebesar 100,073 yang termasuk kedalam golongan sedang dan kekerasan sebesar 8,2 N

Distinct pathways drive anterior hypoblast specification in the implanting human embryo.

Acknowledgements: The authors thank patients at CARE, Herts & Essex, Bourn Hall Fertility and King’s Fertility Clinics for their generous donations, as well as the embryologists and members of each clinic for facilitating donations. We thank G. Serapio-García for advice on Bayesian statistical analysis and the bioinformaticians and data scientists who made their code, packages and vignettes available. This work is supported by Wellcome Trust (207415/Z/17/Z) and Open Atlas and NOMIS awards to M.Z.-G. B.A.T.W. was supported by the Gates Cambridge Trust. C.W.G. was supported by a Leverhulme Trust Early Career Fellowship. L.K.I.-S. was supported by the Rosetrees Trust.Funder: NOMIS Stiftung (NOMIS Foundation); doi: https://doi.org/10.13039/501100008483Funder: Open AtlasFunder: Gates Cambridge Trust; doi: https://doi.org/10.13039/501100005370Funder: Leverhulme Trust; doi: https://doi.org/10.13039/501100000275Funder: Rosetrees Trust; doi: https://doi.org/10.13039/501100000833Development requires coordinated interactions between the epiblast, which generates the embryo proper; the trophectoderm, which generates the placenta; and the hypoblast, which forms both the anterior signalling centre and the yolk sac. These interactions remain poorly understood in human embryogenesis because mechanistic studies have only recently become possible. Here we examine signalling interactions post-implantation using human embryos and stem cell models of the epiblast and hypoblast. We find anterior hypoblast specification is NODAL dependent, as in the mouse. However, while BMP inhibits anterior signalling centre specification in the mouse, it is essential for its maintenance in human. We also find contrasting requirements for BMP in the naive pre-implantation epiblast of mouse and human embryos. Finally, we show that NOTCH signalling is important for human epiblast survival. Our findings of conserved and species-specific factors that drive these early stages of embryonic development highlight the strengths of comparative species studies.Open Atlas NOMIS Gates Cambridge Trust Leverhulme Trust Rosetrees Trus

Distinct pathways drive anterior hypoblast specification in the implanting human embryo.

Development requires coordinated interactions between the epiblast, which generates the embryo proper; the trophectoderm, which generates the placenta; and the hypoblast, which forms both the anterior signalling centre and the yolk sac. These interactions remain poorly understood in human embryogenesis because mechanistic studies have only recently become possible. Here we examine signalling interactions post-implantation using human embryos and stem cell models of the epiblast and hypoblast. We find anterior hypoblast specification is NODAL dependent, as in the mouse. However, while BMP inhibits anterior signalling centre specification in the mouse, it is essential for its maintenance in human. We also find contrasting requirements for BMP in the naive pre-implantation epiblast of mouse and human embryos. Finally, we show that NOTCH signalling is important for human epiblast survival. Our findings of conserved and species-specific factors that drive these early stages of embryonic development highlight the strengths of comparative species studies.Open Atlas NOMIS Gates Cambridge Trust Leverhulme Trust Rosetrees Trus