Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana.

Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana-a Southern African country that is regionally underrepresented in genomic databases. Using whole-exome sequencing data from 164 Batswana and comparisons with 150 similarly sequenced HIV-positive Ugandan children, we found that 13%-25% of variation observed among Batswana was not captured by public databases. Uncaptured variants were significantly enriched (p = 2.2 × 10-16) for coding variants with minor allele frequencies between 1% and 5% and included predicted-damaging non-synonymous variants. Among variants found in public databases, corresponding allele frequencies varied widely, with Botswana having significantly higher allele frequencies among rare (<1%) pathogenic and damaging variants. Batswana clustered with other Southern African populations, but distinctly from 1000 Genomes African populations, and had limited evidence for admixture with extra-continental ancestries. We also observed a surprising lack of genetic substructure in Botswana, despite multiple tribal ethnicities and language groups, alongside a higher degree of relatedness than purported founder populations from the 1000 Genomes project. Our observations reveal a complex, but distinct, ancestral history and genomic architecture among Batswana and suggest that disease mapping within similar Southern African populations will require a deeper repository of genetic variation and allelic dependencies than presently exists.

Practical Approaches for Whole-Genome Sequence Analysis of Heart- and Blood-Related Traits.

Whole-genome sequencing (WGS) allows for a comprehensive view of the sequence of the human genome. We present and apply integrated methodologic steps for interrogating WGS data to characterize the genetic architecture of 10 heart- and blood-related traits in a sample of 1,860 African Americans. In order to evaluate the contribution of regulatory and non-protein coding regions of the genome, we conducted aggregate tests of rare variation across the entire genomic landscape using a sliding window, complemented by an annotation-based assessment of the genome using predefined regulatory elements and within the first intron of all genes. These tests were performed treating all variants equally as well as with individual variants weighted by a measure of predicted functional consequence. Significant findings were assessed in 1,705 individuals of European ancestry. After these steps, we identified and replicated components of the genomic landscape significantly associated with heart- and blood-related traits. For two traits, lipoprotein(a) levels and neutrophil count, aggregate tests of low-frequency and rare variation were significantly associated across multiple motifs. For a third trait, cardiac troponin T, investigation of regulatory domains identified a locus on chromosome 9. These practical approaches for WGS analysis led to the identification of informative genomic regions and also showed that defined non-coding regions, such as first introns of genes and regulatory domains, are associated with important risk factor phenotypes. This study illustrates the tractable nature of WGS data and outlines an approach for characterizing the genetic architecture of complex traits.

A hybrid computational strategy to address WGS variant analysis in >5000 samples.

BACKGROUND: The decreasing costs of sequencing are driving the need for cost effective and real time variant calling of whole genome sequencing data. The scale of these projects are far beyond the capacity of typical computing resources available with most research labs. Other infrastructures like the cloud AWS environment and supercomputers also have limitations due to which large scale joint variant calling becomes infeasible, and infrastructure specific variant calling strategies either fail to scale up to large datasets or abandon joint calling strategies. RESULTS: We present a high throughput framework including multiple variant callers for single nucleotide variant (SNV) calling, which leverages hybrid computing infrastructure consisting of cloud AWS, supercomputers and local high performance computing infrastructures. We present a novel binning approach for large scale joint variant calling and imputation which can scale up to over 10,000 samples while producing SNV callsets with high sensitivity and specificity. As a proof of principle, we present results of analysis on Cohorts for Heart And Aging Research in Genomic Epidemiology (CHARGE) WGS freeze 3 dataset in which joint calling, imputation and phasing of over 5300 whole genome samples was produced in under 6 weeks using four state-of-the-art callers. The callers used were SNPTools, GATK-HaplotypeCaller, GATK-UnifiedGenotyper and GotCloud. We used Amazon AWS, a 4000-core in-house cluster at Baylor College of Medicine, IBM power PC Blue BioU at Rice and Rhea at Oak Ridge National Laboratory (ORNL) for the computation. AWS was used for joint calling of 180 TB of BAM files, and ORNL and Rice supercomputers were used for the imputation and phasing step. All other steps were carried out on the local compute cluster. The entire operation used 5.2 million core hours and only transferred a total of 6 TB of data across the platforms. CONCLUSIONS: Even with increasing sizes of whole genome datasets, ensemble joint calling of SNVs for low coverage data can be accomplished in a scalable, cost effective and fast manner by using heterogeneous computing platforms without compromising on the quality of variants.

Comprehensive and accurate genome analysis at scale using DRAGEN accelerated algorithms.

Research and medical genomics require comprehensive and scalable solutions to drive the discovery of novel disease targets, evolutionary drivers, and genetic markers with clinical significance. This necessitates a framework to identify all types of variants independent of their size (e.g., SNV/SV) or location (e.g., repeats). Here we present DRAGEN that utilizes novel methods based on multigenomes, hardware acceleration, and machine learning based variant detection to provide novel insights into individual genomes with ~30min computation time (from raw reads to variant detection). DRAGEN outperforms all other state-of-the-art methods in speed and accuracy across all variant types (SNV, indel, STR, SV, CNV) and further incorporates specialized methods to obtain key insights in medically relevant genes (e.g., HLA, SMN, GBA). We showcase DRAGEN across 3,202 genomes and demonstrate its scalability, accuracy, and innovations to further advance the integration of comprehensive genomics for research and medical applications.

Alginate-Based Cryogels for Combined Chemo/Photothermal Antibacterial Therapy and Rapid Hemostasis.

As novel wound dressings, cryogels with rapid hemostatic property and good sterilization effect are urgently desirable for wound healing. To reduce the use of antibiotics, antibacterial photothermal therapy with broad-spectrum bactericidal capacity and non-obvious bacterial resistance has been widely researched. However, photothermal agents usually suffer from poor hemostatic ability. In this research, sodium alginate (SA) and epigallocatechin gallate (EGCG) were non-covalently cross-linked in suit by ferric ions to obtain SA/EGCG/Fe (SEF) cryogels after lyophilization as an antibacterial wound dressing. Next, its photothermal performance was intensively assessed. Moreover, its hemostasis and bactericidal effect were evaluated. First, it displayed extraordinary photothermal ability owing to the formation of Fe3+/EGCG-based metal phenolic networks (MPNs) inside the SEF cryogel. Furthermore, in vitro and in vivo assays illustrated that it exhibits rapid hemostatic capacity owing to its high porosity and MPN-mediated cell adhesion capacity. In conclusion, the SEF cryogel manifests satisfactory hemostatic and bactericidal properties. Therefore, it is a promising wound-dressing candidate for clinical applications.

Growth of Scenedesmus obliquus on anaerobic soybean wastewater using different wasted organics for high biomass production and nutrients recycling.

The microalgae culture in mixing sewage with different characteristics may significantly improve biomass production and nutrients recycling efficiency. In this study, three waste organic wastewater including molasses, alcohol and glycerol wastewater were mixed with anaerobic soybean wastewater as mediums for microalgae culture. The optimal mixture of molasses, alcohol and glycerol wastewater was at an initial carbon-nitrogen ratio of 7:1, 5:1 and 10:1, improving biomass production by 60.4%, 31.3% and 68.7%, respectively. The removal efficiencies of organics, ammonia nitrogen and phosphorus at optimal mixture were 54.8-62.4%, 79.5-99.1% and 49.3-61.5%, and the removal rates increased by 340-630%, 27.5-66.3% and 36.3-70.2% compared to the blank culture. In addition, the culture in mixed wastewater increased lipids contrast by 0.7-1.3 times, while achieving higher saturation in fatty acids. The results suggested that microalgae culture using mixed wastewater was a strategy for high biomass production and nutrients recycling efficiency.

Disparities in detection of suspected child abuse.

BACKGROUND: Child abuse is a significant cause of injury and death among children, but accurate identification is often challenging. This study aims to assess whether racial disparities exist in the identification of child abuse. METHODS: The 2010-2014 and 2016-2017 National Trauma Data Bank was queried for trauma patients ages 1-17. Using ICD-9CM and ICD-10CM codes, children with injuries consistent with child abuse were identified and analyzed by race. RESULTS: Between 2010-2014 and 2016-2017, 798,353 patients were included in NTDB. Suspected child abuse victims (SCA) accounted for 7903 (1%) patients. Of these, 51% were White, 33% Black, 1% Asian, 0.3% Native Hawaiian/Other Pacific Islander, 2% American Indian, and 12% other race. Black patients were disproportionately overrepresented, composing 12% of the US population, but 33% of SCA patients (p < 0.001). Although White SCA patients were more severely injured (ISS 16-24: 20% vs 16%, p < 0.01) and had higher in-hospital mortality (9% vs. 6%, p = 0.01), Black SCA patients were hospitalized longer (7.2 ± 31.4 vs. 6.2 ± 9.9 days, p < 0.01) despite controlling for ISS (1-15: 4. 5.7 ± 35.7 vs. 4.2 ± 6.2 days, p < 0.01). In multivariate regression, Black children continued to have longer lengths of stay despite controlling for ISS and insurance type. CONCLUSIONS: Utilizing a nationally representative dataset, Black children were disproportionately identified as potential victims of abuse. They were also subjected to longer hospitalizations, despite milder injuries. Further studies are needed to better understand the etiology of the observed trends and whether they reflect potential underlying unconscious or conscious biases of mandated reporters. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: III.

Research progress on the effects of nanoparticles on gas hydrate formation.

Gas hydrate has great application potential in gas separation, energy storage, seawater desalination, etc. However, the intensity of mass and heat transfer is not enough to meet the needs of efficient hydrate synthesis. Nanoparticles, different from other liquid chemical additives, are considered as effective additives to promote hydrate formation due to their rich specific surface area and excellent thermal conductivity. This work summarizes the effect of the nanoparticles on the thermodynamics and kinetics of hydrate formation. And also, this work probes into the mechanism of the effect of the nanoparticles on the formation of hydrate as well as provides some suggestions for future research. It is found that it's difficult for nanoparticles to effectively promote the formation of the gas hydrate without the use of surfactants, because the adhesion characteristics of the nanoparticles make them easily agglomerate or even agglomerate in solution. In addition, at present, the research on the influence of nanoparticles on the formation and decomposition of natural gas hydrate is still very fragmented, and the micro mechanism of the influence is not clear, which requires more systematic and specific research in the future. At the same time, the development of nanoparticles that can promote the formation of natural gas hydrate should also become the focus of future research.

Alginate-based aerogels as wound dressings for efficient bacterial capture and enhanced antibacterial photodynamic therapy.

The development of novel wound dressings, such as aerogels, with rapid hemostasis and bactericidal capacities for pre-hospital care is necessary. To prevent the occurrence of bacterial resistance, antibacterial photodynamic therapy (aPDT) with broad-spectrum antibacterial ability and negligible bacterial resistance has been intensively studied. However, photosensitizers often suffer from poor water solubility, short singlet oxygen (1O2) half-life and restricted 1O2 diffusion distance. Herein, sodium alginate was covalently modified by photosensitizers and phenylboronic acid, and cross-linked by Ca(II) ions to generate SA@TPAPP@PBA aerogel after lyophilization as an antibacterial photodynamic wound dressing. Afterwards, its photodynamic and bacterial capture activities were intensively evaluated. Furthermore, its hemostasis and bactericidal efficiency against Staphylococcus aureus were assessed via in vitro and in vivo assays. First, chemical immobilization of photosensitizers led to an enhancement of its solubility. Moreover, it showed an excellent hemostasis capacity. Due to the formation of reversible covalent bonds between phenylboronic acid and diol groups on bacterial cell surface, the aerogel could capture S. aureus tightly and dramatically enhance aPDT. To sum up, the prepared aerogel illustrated excellent hemostasis capacity and antibacterial ability against S. aureus. Therefore, they have great potential to be utilized as wound dressing in clinical trials.

Allele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci.

To assess the impact of genetic variation in regulatory loci on human health, we constructed a high-resolution map of allelic imbalances in DNA methylation, histone marks, and gene transcription in 71 epigenomes from 36 distinct cell and tissue types from 13 donors. Deep whole-genome bisulfite sequencing of 49 methylomes revealed sequence-dependent CpG methylation imbalances at thousands of heterozygous regulatory loci. Such loci are enriched for stochastic switching, which is defined as random transitions between fully methylated and unmethylated states of DNA. The methylation imbalances at thousands of loci are explainable by different relative frequencies of the methylated and unmethylated states for the two alleles. Further analyses provided a unifying model that links sequence-dependent allelic imbalances of the epigenome, stochastic switching at gene regulatory loci, and disease-associated genetic variation.