Genetic Variants Within the Erythroid Transcription Factor, KLF1, and Reduction of the Expression of Lutheran and Other Blood Group Antigens: Review of the In(Lu) Phenotype

Erythroid-specific Krüppel-like factor 1, or KLF1, is an integral transcriptional activator for erythropoiesis. Genetic variants within KLF1 can result in a range of erythropoietic clinical phenotypes from benign to significant. The In(Lu) phenotype refers to changes in the quantitative expression of blood group–associated red cell surface molecules due to KLF1 variants which are otherwise clinically benign. These clinically benign KLF1 variants are associated with a reduced expression of 1 or more red cell membrane proteins/carbohydrates that carry blood group antigens for the LU (Lutheran), IN (Indian), P1PK, LW (Landsteiner-Wiener), KN (Knops), OK, RAPH, and I blood group systems. This is of significance during routine serologic blood typing when expression falls below the test sensitivity and therefore impacts on the ability to accurately detect the presence of affected blood group antigens. This is of clinical importance because the transfusion requirements for individuals with the In(Lu) phenotype differ from those of individuals that have a true Lunull phenotype. With this review, we summarize the current body of knowledge with regard to the In(Lu) phenotype and associated KLF1 variants. Our review also highlights discordant reports and provides insights for future research and management strategies. Serological heterogeneity in blood group expression of In(Lu) individuals has been shown, but studies are limited by the low prevalence of the phenotype and therefore the small numbers of samples. They are further limited by availability and inconsistent application of serological reagents and varying test algorithms. With the advent of genome sequence-based testing, an increasing list of In(Lu)-associated KLF1 variants is being revealed. The spectrum of effects on blood group expression due to these variants warrants further attention, and a consistent methodological approach of studies in larger cohorts is required. We propose that a recently reported testing framework of standardized serological studies, flow cytometry, and variant analysis be adopted; and that the international databases be curated to document KLF1 variability and the resultant In(Lu) red cell blood group expression. This will provide better classification of KLF1 variants affecting blood group expression and allow for phenotype prediction from genotype, accurate typing of In(Lu) individuals, and better transfusion management of related challenging transfusion scenarios

Pre-operative immune cell numbers and ratios are associated with peri-operative adverse outcomes in transfused patients

Background and objectivesTransfusion-related immune modulation (TRIM) and associated adverse outcomes during major surgery are increasingly important to patients and health services internationally. A panel of pre-operative blood tests is an essential part of the pre-operative anaesthetic assessment. This panel of blood tests commonly considers numbers of immune cells (i.e., lymphocytes, monocytes, and neutrophils and cell ratios) that may be used as biomarkers to evaluate and potentially predict post-operative adverse outcomes.DesignThis retrospective data collection from eight hospital databases, within the Royal Brisbane and Women's Hospital, considered only patients who received blood transfusion during surgery (2016–2018) (n = 2,121). The association between pre-operative immune cell numbers and ratios and adverse outcomes were assessed. Adverse outcomes were coded using the International Classification of Diseases-10 (ICD-10) coding which specifically considered transfusion-related immune modulation. Results were adjusted for confounding factors.ResultsAfter adjustment, decreased pre-operative lymphocyte numbers and increased neutrophil/lymphocyte ratio (NLR) were associated with increased odds of developing infection; decreased NLR with decreased odds of developing adverse renal outcomes; and decreased lymphocyte numbers with decreased odds of developing adverse cardiovascular outcomes. Monocyte numbers, neutrophil numbers, and the lymphocyte/monocyte ratio (LMR) were not associated with increased adverse outcomes after adjustment.ConclusionPre-operative lymphocyte numbers and NLR are associated with adverse outcomes during peri-operative transfusion. Future assessment of peri-operative immune modulation should include the assessment of immune cell function and numbers

Pandemic H1N1 Influenza A Viruses Are Resistant to the Antiviral Activities of Innate Immune Proteins of the Collectin and Pentraxin Superfamilies

Abstract Acquired immune responses elicited to recent strains of seasonal H1N1 influenza viruses provide limited protection against emerging A(H1N1) pandemic viruses. Accordingly, pre-existing or rapidly induced innate immune defenses are of critical importance in limiting early infection. Respiratory secretions contain proteins of the innate immune system, including members of the collectin and pentraxin superfamilies. These mediate potent antiviral activity and act as an initial barrier to influenza infection. In this study, we have examined the sensitivity of H1N1 viruses, including pandemic virus strains, for their sensitivity to collectins (surfactant protein [SP]-D and mannose-binding lectin [MBL]) and to the pentraxin PTX3. Human SP-D and MBL inhibited virus-induced hemagglutinating activity, blocked the enzymatic activity of the viral neuraminidase, and neutralized the ability of H1N1 viruses to infect human respiratory epithelial cells in a manner that correlated with the degree of glycosylation in the globular head of the hemagglutinin. Recent seasonal H1N1 viruses expressed three to four N-glycosylation sequons on the head of hemagglutinin and were very sensitive to inhibition by SP-D or MBL, whereas A(H1N1) pandemic viruses expressed a single N-glycosylation sequon and were resistant to either collectin. Of interest, both seasonal and pandemic H1N1 viruses were resistant to PTX3. Thus, unlike recent seasonal H1N1 strains of influenza virus, A(H1N1) pandemic viruses are resistant to the antiviral activities of innate immune proteins of the collectin superfamily

Detecting spatial regimes in ecosystems

Research on early warning indicators has generally focused on assessing temporal transitions with limited application of these methods to detecting spatial regimes. Traditional spatial boundary detection procedures that result in ecoregion maps are typically based on ecological potential (i.e. potential vegetation), and often fail to account for ongoing changes due to stressors such as land use change and climate change and their effects on plant and animal communities. We use Fisher information, an information theory-based method, on both terrestrial and aquatic animal data (U.S. Breeding Bird Survey and marine zooplankton) to identify ecological boundaries, and compare our results to traditional early warning indicators, conventional ecoregion maps and multivariate analyses such as nMDS and cluster analysis. We successfully detected spatial regimes and transitions in both terrestrial and aquatic systems using Fisher information. Furthermore, Fisher information provided explicit spatial information about community change that is absent from other multivariate approaches. Our results suggest that defining spatial regimes based on animal communities may better reflect ecological reality than do traditional ecoregion maps, especially in our current era of rapid and unpredictable ecological change

CCR5 Haplotypes and Mother-to-Child HIV Transmission in Malawi

CCR5 and CCR2 gene polymorphisms (SNPs) have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Delta32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein.We investigated the association between infant CCR2/CCR5 diplotype and HIV mother to child transmission (MTCT) in Malawi. Blood samples from infants (n = 552) of HIV positive women who received nevirapine were genotyped using a post-PCR multiplex ligase detection reaction and haplotypes were identified based on 8 CCR2/CCR5 SNPs and the open reading frame 32 base pair deletion. Following verification of Hardy-Weinberg equilibrium, log linear regression was performed to examine the association between mutations and MTCT. Overall, protection against MTCT was weakly associated with two CCR5 SNPs, -2459G (Risk ratio [RR], 0.78; confidence interval [CI], 0.54-1.12), and the linked CCR5 -2135T (RR, 0.78; CI, 0.54-1.13). No child carried the CCR5 Delta32 SNP. Maternal Viral Load (MVL) was found to be an effect measure modifier. Among mothers with low MVL, statistically significant protection against MTCT was observed for -2459G (RR, 0.50; CI, 0.27-0.91), and -2135T (RR, 0.51; CI, 0.28-0.92). Statistically significant protection was not found at high MVL.Results from this study suggest that CCR5 SNPs -2459G and -2135T associated with reduced receptor expression protect against MTCT of HIV at low MVLs, whereas high MVLs may over-ride differences in coreceptor availability

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Shifting the Paradigm: The Putative Mitochondrial Protein ABCB6 Resides in the Lysosomes of Cells and in the Plasma Membrane of Erythrocytes

ABCB6, a member of the adenosine triphosphate–binding cassette (ABC) transporter family, has been proposed to be responsible for the mitochondrial uptake of porphyrins. Here we show that ABCB6 is a glycoprotein present in the membrane of mature erythrocytes and in exosomes released from reticulocytes during the final steps of erythroid maturation. Consistent with its presence in exosomes, endogenous ABCB6 is localized to the endo/lysosomal compartment, and is absent from the mitochondria of cells. Knock-down studies demonstrate that ABCB6 function is not required for de novo heme biosynthesis in differentiating K562 cells, excluding this ABC transporter as a key regulator of porphyrin synthesis. We confirm the mitochondrial localization of ABCB7, ABCB8 and ABCB10, suggesting that only three ABC transporters should be classified as mitochondrial proteins. Taken together, our results challenge the current paradigm linking the expression and function of ABCB6 to mitochondria

SNAPSHOT USA 2019 : a coordinated national camera trap survey of the United States

This article is protected by copyright. All rights reserved.With the accelerating pace of global change, it is imperative that we obtain rapid inventories of the status and distribution of wildlife for ecological inferences and conservation planning. To address this challenge, we launched the SNAPSHOT USA project, a collaborative survey of terrestrial wildlife populations using camera traps across the United States. For our first annual survey, we compiled data across all 50 states during a 14-week period (17 August - 24 November of 2019). We sampled wildlife at 1509 camera trap sites from 110 camera trap arrays covering 12 different ecoregions across four development zones. This effort resulted in 166,036 unique detections of 83 species of mammals and 17 species of birds. All images were processed through the Smithsonian's eMammal camera trap data repository and included an expert review phase to ensure taxonomic accuracy of data, resulting in each picture being reviewed at least twice. The results represent a timely and standardized camera trap survey of the USA. All of the 2019 survey data are made available herein. We are currently repeating surveys in fall 2020, opening up the opportunity to other institutions and cooperators to expand coverage of all the urban-wild gradients and ecophysiographic regions of the country. Future data will be available as the database is updated at eMammal.si.edu/snapshot-usa, as well as future data paper submissions. These data will be useful for local and macroecological research including the examination of community assembly, effects of environmental and anthropogenic landscape variables, effects of fragmentation and extinction debt dynamics, as well as species-specific population dynamics and conservation action plans. There are no copyright restrictions; please cite this paper when using the data for publication.Publisher PDFPeer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe