DDAO Controlled Synthesis of Organo-Modified Silica Nanoparticles with Encapsulated Fluorescent Boron Dipyrrins and Study of Their Uptake by Cancerous Cells

The design of cargo carriers with high biocompatibility, unique morphological characteristics, and capability of strong bonding of fluorescent dye is highly important for the development of a platform for smart imaging and diagnostics. In this paper, BODIPY-doped silica nanoparticles were prepared through a "one-pot" soft-template method using a sol-gel process. Several sol-gel precursors have been used in sol-gel synthesis in the presence of soft-template to obtain the silica-based materials with the most appropriate morphological features for the immobilization of BODIPY molecules. Obtained silica particles have been shown to be non-cytotoxic and can be effectively internalized into the cervical cancer cell line (HeLa). The described method of synthesis allows us to obtain silica-based carriers with an immobilized fluorescent dye that provide the possibility for real-time imaging and detection of these carriers

An exploratory phenome wide association study linking asthma and liver disease genetic variants to electronic health records from the Estonian Biobank

<div><p>The Estonian Biobank, governed by the Institute of Genomics at the University of Tartu (Biobank), has stored genetic material/DNA and continuously collected data since 2002 on a total of 52,274 individuals representing ~5% of the Estonian adult population and is increasing. To explore the utility of data available in the Biobank, we conducted a phenome-wide association study (PheWAS) in two areas of interest to healthcare researchers; asthma and liver disease. We used 11 asthma and 13 liver disease-associated single nucleotide polymorphisms (SNPs), identified from published genome-wide association studies, to test our ability to detect established associations. We confirmed 2 asthma and 5 liver disease associated variants at nominal significance and directionally consistent with published results. We found 2 associations that were opposite to what was published before (rs4374383:AA increases risk of NASH/NAFLD, rs11597086 increases ALT level). Three SNP-diagnosis pairs passed the phenome-wide significance threshold: rs9273349 and E06 (thyroiditis, p = 5.50x10^-8); rs9273349 and E10 (type-1 diabetes, p = 2.60x10^-7); and rs2281135 and K76 (non-alcoholic liver diseases, including NAFLD, p = 4.10x10^-7). We have validated our approach and confirmed the quality of the data for these conditions. Importantly, we demonstrate that the extensive amount of genetic and medical information from the Estonian Biobank can be successfully utilized for scientific research.</p></div

Comparison of Antibody Repertoires Produced by HIV-1 Infection, Other Chronic and Acute Infections, and Systemic Autoimmune Disease

Background Antibodies (Abs) produced during HIV-1 infection rarely neutralize a broad range of viral isolates; only eight broadly-neutralizing (bNt) monoclonal (M)Abs have been isolated. Yet, to be effective, an HIV-1 vaccine may have to elicit the essential features of these MAbs. The V genes of all of these bNt MAbs are highly somatically mutated, and the VH genes of five of them encode a long (≥20 aa) third complementarity-determining region (CDR-H3). This led us to question whether long CDR-H3s and high levels of somatic mutation (SM) are a preferred feature of anti-HIV bNt MAbs, or if other adaptive immune responses elicit them in general. Methodology and Principal Findings We assembled a VH-gene sequence database from over 700 human MAbs of known antigen specificity isolated from chronic (viral) infections (ChI), acute (bacterial and viral) infections (AcI), and systemic autoimmune diseases (SAD), and compared their CDR-H3 length, number of SMs and germline VH-gene usage. We found that anti-HIV Abs, regardless of their neutralization breadth, tended to have long CDR-H3s and high numbers of SMs. However, these features were also common among Abs associated with other chronic viral infections. In contrast, Abs from acute viral infections (but not bacterial infections) tended to have relatively short CDR-H3s and a low number of SMs, whereas SAD Abs were generally intermediate in CDR-H3 length and number of SMs. Analysis of VH gene usage showed that ChI Abs also tended to favor distal germline VH-genes (particularly VH1-69), especially in Abs bearing long CDR-H3s. Conclusions and Significance The striking difference between the Abs produced during chronic vs. acute viral infection suggests that Abs bearing long CDR-H3s, high levels of SM and VH1-69 gene usage may be preferentially selected during persistent infection

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

Эпидемиология и результаты терапии первой линии ВИЧ-ассоциированной лимфомы Ходжкина

Introduction. The risk of developing Hodgkin lymphoma (HL) with HIV infection is higher than in the general population, and the course of the disease itself is more aggressive. Currently, there is no unified approach to the treatment of HIV-related HL, and data on its epidemiology in the Russian Federation are limited.The objective was to study epidemiological characteristics, the used therapeutic tactics and the results of treatment for HIV-related HL.Methods and materials. The multicenter retrospective study included 46 patients with HIV- related HL treated in 9 centers of the Russian Federation. Descriptive statistics methods were used, the analysis of overall survival (OS) and progression-free survival (PFS) was performed using the Kaplan–Meier method.Results. HIV-related HL is more often represented by an advanced stage, B-symptoms, and extranodal lesions. The ABVD regimen was used as the first-line therapy in 60 % for HIV-related HL. The overall response to therapy was 81.6 %, and the 2-year OS and PFS were 85 % and 49 %, respectively. Factors that worsened OS were CD4+˂266 cells/mcL and general somatic status ECOG≥2. Введение. Вероятность развития лимфомы Ходжкина (ЛХ) на фоне ВИЧ-инфекции выше, чем в общей популяции, а течение заболевания имеет более агрессивный характер. В настоящий момент отсутствует единый подход к терапии ЛХ на фоне ВИЧ, а данные об ее эпидемиологии в Российской Федерации ограничены.Цель – изучить эпидемиологическую характеристику, применяемую терапевтическую тактику и результаты лечения лимфомы Ходжкина на фоне ВИЧ-инфекции.Методы и материалы. В многоцентровое ретроспективное исследование были включены 46 пациентов с диагнозом «ЛХ» на фоне ВИЧ, получавших лечение в девяти центрах Российской Федерации. Применяли методы описательной статистки, анализ общей выживаемости (ОВ) и беспрогрессивной выживаемости (БПВ) выполняли с использованием метода Каплана – Мейера.Результаты. ЛХ на фоне ВИЧ чаще представлена распространенной стадией, В-симптомами и экстранодальным поражением. В качестве терапии первой линии ЛХ на фоне ВИЧ в 60 % случаев использовалась схема ABVD. Общий ответ на терапию составил 81,6 %, а 2-летняя ОВ и БПВ составили 85 и 49 % соответственно. Факторами, снижающими ОВ, являлись уровень CD4+&lt;266 кл/мкл и общесоматический статус ECOG≥2. Ключевые слова: лимфома Ходжкина, ВИЧ, CD4+, ECOG, многоцентровое исследование, терапия первой линии&gt;˂ 266 кл/мкл и общесоматический статус ECOG≥2.

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries