Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Enantioselective luminescence quenching of DNA light-switch [Ru(phen) 2dppz]2+ by electron transfer to structural homologue [Ru(phendione)2dppz]2+

The quenching of the luminescence of [Ru(phen)2dppz] 2+ by structural homologue [Ru(phendione)2dppz] 2+, when both complexes are bound to DNA, has been studied for all four combinations of Δ and Λ enantiomers. Flow linear dichroism spectroscopy (LD) indicates similar binding geometries for all the four compounds, with the dppz ligand fully intercalated between the DNA base pairs. A difference in the LD spectrum observed for the lowest-energy MLCT transition suggests that a transition, potentially related to the final localization of the excited electron to the dppz ligand in [Ru(phen)2dppz]2+, is overlaid by an orthogonally polarized transition in [Ru(phendione) 2dppz]2+. This would be consistent with a low-lying LUMO of the phendione moiety of [Ru(phendione)2dppz]2+ that can accept the excited electron from [Ru(phen)2dppz]2+, thereby quenching the emission of the latter. The lifetime of excited A-[Ru(phen)2dppz]2+ is decreased moderately, from 664 to 427 ns, when bound simultaneously with the phendione complex to DNA. The 108 ns lifetime of opposite enantiomer, A-[Ru(phen)2dppz]2+, is only shortened to 94 ns. These results are consistent with an average rate constant for electron transfer of approximately 1·106 s -1 between the phenanthroline- and phendione-ruthenium complexes. At binding ratios close to saturation of DNA, the total emission of the two enantiomers is lowered equally much, but for the A enantiomer, this is not paralleled by a decrease in luminescence lifetime. A binding isotherm simulation based on a generalized McGhee - von Hippel approach shows that the Δ enantiomer binds approximately 3 times stronger to DNA both for [Ru(phendione)2dppz]2+ and [Ru(phen)2dppz] 2+. This explains the similar decrease in total emission, without the parallel decrease in lifetime for the A enantiomer. The simulation also does not indicate any significant binding cooperativity, in contrast to the case when Δ-[Rh(phi)2bipy]3+ is used as quencher. The very slow electron transfer from [Ru-(phen)2dppz]2+ to [Ru(phendione)2dppz]2+, compared to the case when [Rh(phi)2phen]3+ is the acceptor, can be explained by a much smaller driving free-energy difference. © 2005 American Chemical Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Enantioselective luminescence quenching of DNA light-switch [Ru(phen) 2dppz]2+ by electron transfer to structural homologue [Ru(phendione)2dppz]2+

The quenching of the luminescence of [Ru(phen)2dppz] 2+ by structural homologue [Ru(phendione)2dppz] 2+, when both complexes are bound to DNA, has been studied for all four combinations of Δ and Λ enantiomers. Flow linear dichroism spectroscopy (LD) indicates similar binding geometries for all the four compounds, with the dppz ligand fully intercalated between the DNA base pairs. A difference in the LD spectrum observed for the lowest-energy MLCT transition suggests that a transition, potentially related to the final localization of the excited electron to the dppz ligand in [Ru(phen)2dppz]2+, is overlaid by an orthogonally polarized transition in [Ru(phendione) 2dppz]2+. This would be consistent with a low-lying LUMO of the phendione moiety of [Ru(phendione)2dppz]2+ that can accept the excited electron from [Ru(phen)2dppz]2+, thereby quenching the emission of the latter. The lifetime of excited A-[Ru(phen)2dppz]2+ is decreased moderately, from 664 to 427 ns, when bound simultaneously with the phendione complex to DNA. The 108 ns lifetime of opposite enantiomer, A-[Ru(phen)2dppz]2+, is only shortened to 94 ns. These results are consistent with an average rate constant for electron transfer of approximately 1·106 s -1 between the phenanthroline- and phendione-ruthenium complexes. At binding ratios close to saturation of DNA, the total emission of the two enantiomers is lowered equally much, but for the A enantiomer, this is not paralleled by a decrease in luminescence lifetime. A binding isotherm simulation based on a generalized McGhee - von Hippel approach shows that the Δ enantiomer binds approximately 3 times stronger to DNA both for [Ru(phendione)2dppz]2+ and [Ru(phen)2dppz] 2+. This explains the similar decrease in total emission, without the parallel decrease in lifetime for the A enantiomer. The simulation also does not indicate any significant binding cooperativity, in contrast to the case when Δ-[Rh(phi)2bipy]3+ is used as quencher. The very slow electron transfer from [Ru-(phen)2dppz]2+ to [Ru(phendione)2dppz]2+, compared to the case when [Rh(phi)2phen]3+ is the acceptor, can be explained by a much smaller driving free-energy difference. © 2005 American Chemical Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Pertumbuhan Kelinci Hycole (Orytogalus cuniculus) dengan Bobot Badan Awal Berbeda di Anugrah Farm Kediri”. Penelitian ini merupakan bagian dari peternakan kelinci yang berada di Kabupaten Kediri.

Kelinci adalah salah satu ternak yang baik dalam produktivitasnya. Ternak kelinci mempunyai sifat jarak beranak yang singkat sehingga dapat menghasilkan jumlah anak yang banyak dalam waktu yang singkat sehingga dapat memiliki potensi dikembangkan di Indonesia sebagai penghasil protein. Potensi ternak kelinci Hycole yang pada rumpun kelinci pedaging yang unggul dapat dikembangkan di Indonesia kemampuan pertumbuhan cepat dan produktivitas yang baik. Penelitian ini bertujuan untuk mengetahui bobot badan awal yang berbeda terhadap laju pertumbuhan kelinci Hycole yang dapat ditinjau dari pertambahan bobot badan kumulatif, absolut dan relatif. Hasil dari penelitian ini harapan dapat digunakan sebagai media informasi dalam akademisi dan peternak kelinci Hycole mengenai pertumbuhan berat badan kelinci Hycole yang paling efektif. Penelitian dilakukan di Anugrah Farm milik saudara Dwi Hariyono, S.Pt. yang terletak di Jalan Merpati No. 123 RT 02/RW 04 Dusun Pule Utara, Kecamatan Kandat, Kabupaten Kediri. Penelitian dilaksanakan dalam waktu 1 bulan pada 21 Agustus 2023 sampai 21 September 2023. Bahan penelitian yang digunakan adalah kelinci Hycole jenis kelamin jantan sebanyak 21 ekor. Perlakuan yang dilakukan adalah pengelompokan bobot badan awal menjadi 3 kelompok yaitu kelompok kelinci Hycole besar, sedang dan kecil. Pengelompokan kelinci besar dengan bobot badan sebesar 1210 g- 1640 g, kelinci sedang dengan bobot sebesar 1090 g – 1200 g dan kelinci kecil 855 g – 995 g. Pakan yang diberikan adalah pelet bermerek King Rabbit yang diproduksi oleh PT. Jingkrak Intergrated Farms dengan kode PK-01. Metode penelitian yang dilakukan adalah survei dan wawancara dengan pengumpulan data primer dan sekunder. Analisa data menggunakan One Way ANOVA (Analysis of Variance). Analisa ini dilakukan untuk mempelajari pengaruh dari perlakuan. Apabila hasil penelitian menunjukkan perbedaan yang nyata antar perlakuan terhadap pertambahan bobot badan, dilanjutkan dengan uji BNT (berbeda nyata terkecil). Hasil penelitian kelinci Hycole jantan dengan bobot awal berbeda yang ditinjau dari pertambahan bobot badan kumulatif, absolut dan relatif menunjukan perbedaan nyata. Hasil penelitian menunjukan kelompok kelinci Hycole kelompok besar memberikan hasil tertinggi pada pertambahan bobot badan kumulatif sebesar 26.48 ± 2.26 g/ekor/hari. Pada pertambahan bobot terbesar pada kelompok kelinci Hycole kelompok besar pada pertambahan bobot badan absolut sebesar 35.31 ± 3.01 g/ekor/hari. Pertambahan bobot badan berbanding lurus dengan bobot badan awal, hal ini dapat dipengaruhi oleh genetik, lingkungan dan ransum. Kelompok kelinci besar dapat penyerapan nutrisi yang baik dibandingkan kelompok kelinci kecil. Bobot badan awal ternak mempengaruhi faktor terhadap pertambahan bobot badan. Kelinci dengan bobot badan awal besar memiliki perbedaan proporsi jaringan utama karkas (otot, lemak, dan lemak) pada umur yang sama dibandingkan kelinci dengan bobot awal kecil. Kelinci Hycole memiliki ukuran tulang tubuh kelinci yang besar maka memungkinkan perkembangan karkas yang lebih luas sehingga memiliki massa tubuh yang lebih besar. Kelompok kelinci kecil terbesar pada pertambahan bobot badan relatif adalah kelompok kelinci Hycole kecil sebesar 70.06 ± 4.62%. Hal tersebut terjadi karena pertambahan bobot badan relatif merupakan hasil bobot badan kelinci akhir kemudian dikurangi bobot badan awal dibagi bobot kelinci awal dan dikali 100%, sehingga jika kelinci Hycole dengan pertambahan bobot badan yang sama namun bobot badan awal kecil maka akan menghasilkan persentase pertambahan bobot badan relatif yang besar dengan perhitungan pertambahan bobot badan relatif. Kesimpulan dari penelitian adalah bobot awal kelompok kelinci Hycole laju pertumbuhan kelinci Hycole jantan ditinjau dari pertambahan bobot badan kumulatif, pertambahan bobot badan absolut dan pertambahan bobot badan relatif. Pada penelitian ini didapatkan bahwa laju pertumbuhan kelinci besar memiliki pengaruh terhadap hasil akhir yang besar. Berdasarkan penelitian diatas disarankan untuk peternak kelinci dalam bibit kelinci dengan bobot yang besar untuk menghasilkan bobot badan akhir besar untuk efisien dan efektif dalam penggemukannya. Tujuan pemeliharaan pengemukan, lebih disarankan untuk memilih bibit kelinci pada umur 2 bulan, dikarena laju pertumbuhan yang lebih tinggi setelah pasca sapih