A catalog of common, intermediate and well‐documented (CIWD) HLA‐A, ‐B, ‐C, ‐DRB1, ‐DRB3, ‐DRB4, ‐DRB5, ‐DQB1 and ‐DPB1 alleles has been compiled from over 8 million individuals using data from 20 ...unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two‐field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well‐documented (≥5 occurrences) or not‐CIWD. Overall 26% of alleles in IPD‐IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two‐field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well‐documented alleles. Full‐field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.
At the DKMS Life Science Lab, Next Generation Sequencing (NGS) has been used for ultra-high-volume high-resolution genotyping of HLA loci for the last three and a half years. Here, we report on our ...experiences in genotyping the HLA, CCR5, ABO, RHD and KIR genes using a direct amplicon sequencing approach on Illumina MiSeq and HiSeq 2500 instruments.
Between January 2013 and June 2016, 2,714,110 samples largely from German, Polish and UK-based potential stem cell donors have been processed. 98.9% of all alleles for the targeted HLA loci (HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1) were typed at high resolution or better. Initially a simple three-step workflow based on nanofluidic chips in conjunction with 4-primer amplicon tagging was used. Over time, we found that this setup results in PCR artefacts such as primer dimers and PCR-mediated recombination, which may necessitate repeat typing. Split workflows for low- and high-DNA-concentration samples helped alleviate these problems and reduced average per-locus repeat rates from 3.1 to 1.3%. Further optimisations of the workflow included the use of phosphorothioate oligos to reduce primer degradation and primer dimer formation, and employing statistical models to predict read yield from initial template DNA concentration to avoid intermediate quantification of PCR products. Finally, despite the populations typed at DKMS Life Science Lab being relatively homogenous genetically, an analysis of 1.4 million donors processed between January 2015 and May 2016 led to the discovery of 1,919 distinct novel HLA alleles.
Amplicon-based NGS HLA genotyping workflows have become the workhorse in high-volume tissue typing of registry donors. The optimisation of workflow practices over multiple years has led to insights and solutions that improve the efficiency and robustness of short amplicon based genotyping workflows.
•One of the largest population studies on the impact of CCR5Δ32 on COVID-19.•CCR5Δ32 does not determine risk of contracting SARS-CoV-2, nor its disease course.•Further research on implications of ...CCR5Δ32 for immune responses is warranted.
To determine the impact of the 32 bp deletion (CCR5Δ32) in the coding region of the C-C chemokine receptor 5 (CCR5) on the risk of contracting SARS-CoV-2 and severe COVID-19.
Cross-sectional study among stem cell donors registered with DKMS in Germany. Genetic information was linked to self-reported COVID-19 outcome data. Multivariable regression models were fitted to determine the risk of contracting SARS-CoV-2, severe respiratory tract infection (RTI) and respiratory hospitalization.
CCR5 information was available for 110 544 donors who were tested at least once for SARS-CoV-2; 5536 reported SARS-CoV-2 infection. For 4758 donors, the COVID-19 disease course was fully evaluable; 498 reported no symptoms, 1227 described symptoms of severe respiratory tract infection, of whom 164 required respiratory hospitalization. The distribution of CCR5Δ32 genotypes (homozygous wild-type vs CCR5Δ32 present) did not differ significantly between individuals with or without SARS-CoV-2 infection (odds ratio (OR) 0.96, 95% CI 0.89-1.03, P = 0.21) nor between individuals with or without symptomatic infection (OR 1.13, 95% CI 0.88-1.45, P = 0.32), severe RTI (OR 1.03, 95% CI 0.88-1.22, P = 0.68) or respiratory hospitalization (OR 1.16, 95% CI 0.79-1.69, P = 0.45).
Our data implicate that CCR5Δ32 mutations do not determine the risk of SARS-CoV-2 infections nor the disease course.
We registered the study with the German Center for Infection Research (https://dzif.clinicalsite.org/de/cat/2099/trial/4361).
Deprotonation of a Hydridoborate Anion Landmann, Johannes; Keppner, Fabian; Hofmann, Daniel B. ...
Angewandte Chemie International Edition,
March 1, 2017, Volume:
56, Issue:
10
Journal Article
Peer reviewed
The first deprotonation of a borohydride anion was achieved by treatment of BH(CN)3− with strong non‐nucleophilic bases, which resulted in the formation of alkali‐metal salts of the tricyanoborate ...dianion B(CN)32− in up to 97 % yield and 99.5 % purity. BH(CN)3− is less acidic than (Me3Si)2NH but a stronger acid than iPr2NH. Less sterically hindered, more nucleophilic bases such as PhLi and MeLi mostly attack a CN group under formation of imine dianions RC(N)B(CN)32−, which can be hydrolyzed to ketones of the RC(O)B(CN)3− type. The boron‐centered nucleophile B(CN)32− reacts with CO2 and CN+ reagents to give salts of the B(CN)3CO22− dianion and the tetracyanoborate anion B(CN)4−, respectively, in excellent yields.
Attack at boron: In the first deprotonation of a hydridoborate anion, the readily accessible BH(CN)3− anion reacts with strong non‐nucleophilic bases to yield the boron‐centered nucleophile B(CN)32− in high yield and purity. The B(CN)32− dianion reacts with CN+ sources to give the tetracyanoborate anion and with CO2 to yield the carboxylic acid derivative B(CN)3CO22−, which is a promising starting material for cyanoborate chemistry and materials science.
Despite over 41 million registered potential volunteer stem cell donors worldwide, many patients in need of a transplant do not find an HLA‐matched unrelated donor or cord blood units, with the ...respective odds differing significantly between various populations. In this study, we analysed data of 2205 unsuccessful real‐life donor searches sent to the DKMS Registry to identify populations in which further donor recruitment would be associated with particularly large patient benefits. For that purpose, we estimated haplotype frequencies of 67 donor populations at various sample sizes and entered them into two different mathematical models. These models assessed patient benefits from population‐specific donor recruitment, operationalised by the number of originally unsuccessful searches that may become successful due to new donors. Consistently, across the different mathematical models and sample sizes, we obtained several countries from East and Southeast Asia (Thailand, Vietnam, China, and the Philippines) and the population of Asians in the USA as countries/populations where donor recruitment activities would be particularly beneficial for patients. We also identified various countries in Southeast and Central Europe as possible target regions for donor recruitment with above‐average patient benefits. The results presented are registry‐specific in the sense that they were obtained by optimising unsuccessful searches that had been sent to the DKMS Registry. Therefore, it would be desirable to apply the presented methods to a global data set that includes all unsuccessful stem cell donor searches worldwide and uses population‐specific haplotype frequencies based on all donors available in the WMDA Search & Match Service.
HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the
HLA
genotype on the ...severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of
in silico
predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the
HLA
genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the
HLA
genotype.
Numerous monitoring efforts are underway to improve understanding of ocean acidification and its impacts on coastal environments, but there is a need to develop a coordinated approach that ...facilitates spatial and temporal comparisons of drivers and responses on a regional scale. Toward that goal, the California Current Acidification Network (C-CAN) held a series of workshops to develop a set of core principles for facilitating integration of ocean acidification monitoring efforts on the US West Coast. The recommended core principles include: (1) monitoring measurements should facilitate determination of aragonite saturation state (Ωarag) as the common currency of comparison, allowing a complete description of the inorganic carbon system; (2) maximum uncertainty of ±0.2 in the calculation of Ωaragis required to adequately link changes in ocean chemistry to changes in ecosystem function; (3) inclusion of a variety of monitoring platforms and levels of effort in the network will insure collection of high-frequency temporal data at fixed locations as well as spatial mapping across locations; (4) physical and chemical oceanographic monitoring should be linked with biological monitoring; and (5) the monitoring network should share data and make it accessible to a broad audience.
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The challenge of heat exchanger network retrofit is often addressed using deterministic algorithms. However, the complexity of the retrofit problems, combined with multi-period ...operation, makes it very difficult to find any feasible solution. In contrast, stochastic algorithms are more likely to find feasible solutions in complex solution spaces. This work presents a customized evolutionary based optimization algorithm to address this challenge. The algorithm has two levels, whereby, a genetic algorithm optimizes the topology of the heat exchanger network on the top level. Based on the resulting topology, a differential evolution algorithm optimizes the heat loads of the heat exchangers in each operating period. The following bullet points highlight the customization of the algorithm:•The advantage of using both algorithms: the genetic algorithm is used for the topology optimization (discrete variables) and the differential evolution for the heat load optimization (continuous variables).•Penalizing and preserving strategies are used for constraint handling•The evaluation of the genetic algorithm is parallelized, meaning the differential evolution algorithm is performed on each chromosome parallel on multiple cores.
The guidelines for the implementation and reporting of HLA nomenclature for the World Marrow Donor Association have served as a reliable standard for communication of HLA data in the hematopoietic ...cell transplantation process. Wider use of next‐generation sequencing made a special provision of the guidelines increasingly pertinent: how to communicate novel HLA alleles. Novel alleles need to be recognized by the WHO Nomenclature Committee for Factors of the HLA system to obtain official allele designations. Until then they have to be handled according to the specific rules. Leaving the actual rules basically unchanged we give some advice on how to communicate novel alleles to best facilitate the search process for cases where novel alleles are identified on donor or patient side.
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