Accidental Father-to-Son HIV-1 Transmission During the Seroconversion Period

A 4-year-old child born to an HIV-1 seronegative mother was diagnosed with HIV-1, the main risk factor being transmission from the child's father who was seroconverting at the time of the child's birth. In the context of a forensic investigation, we aimed to identify the source of infection of the child and date of the transmission event. Samples were collected from the father and child at two time points about 4 years after the child's birth. Partial segments of three HIV-1 genes (gag, pol, and env) were sequenced and maximum likelihood (ML) and Bayesian methods were used to determine direction and estimate date of transmission. Neutralizing antibodies were determined using a single cycle assay. Bayesian trees displayed a paraphyletic-monophyletic topology in all three genomic regions, with the father's host label at the root, which is consistent with father-to-son transmission. ML trees found similar topologies in gag and pol and a monophyletic-monophyletic topology in env. Analysis of the time of the most recent common ancestor of each HIV-1 gene population indicated that the child was infected shortly after the father. Consistent with the infection history, both father and son developed broad and potent HIV-specific neutralizing antibody responses. In conclusion, the direction of transmission implicated the father as the source of transmission. Transmission occurred during the seroconversion period when the father was unaware of the infection and was likely accidental. This case shows how genetic, phylogenetic, and serological data can contribute for the forensic investigation of HIV transmission.info:eu-repo/semantics/publishedVersio

A novel haemoglobin variant mimicking cyanotic congenital heart disease

Screening for critical congenital heart defects in newborn babies can aid in early recognition, with the prospect of improved outcome. However, as this universal newborn screening is implemented, there will be an increasing number of false-positive results. In order to avoid multiple investigations and uncertainty, an haemoglobin (Hb) variant must be included in the differential diagnosis in otherwise well newborns with low oxygen saturation by pulse oximetry. We describe a novel fetal Hb variant (heterozygous γ-globin gene (HBG1) mutation in exon 2 c.202G>A (p.Val68Met)) identified in a newborn with positive pulse oximetry screening for congenital heart disease.info:eu-repo/semantics/publishedVersio

Confounding from Cryptic Relatedness in Case-Control Association Studies

Case-control association studies are widely used in the search for genetic variants that contribute to human diseases. It has long been known that such studies may suffer from high rates of false positives if there is unrecognized population structure. It is perhaps less widely appreciated that so-called “cryptic relatedness” (i.e., kinship among the cases or controls that is not known to the investigator) might also potentially inflate the false positive rate. Until now there has been little work to assess how serious this problem is likely to be in practice. In this paper, we develop a formal model of cryptic relatedness, and study its impact on association studies. We provide simple expressions that predict the extent of confounding due to cryptic relatedness. Surprisingly, these expressions are functions of directly observable parameters. Our analytical results show that, for well-designed studies in outbred populations, the degree of confounding due to cryptic relatedness will usually be negligible. However, in contrast, studies where there is a sampling bias toward collecting relatives may indeed suffer from excessive rates of false positives. Furthermore, cryptic relatedness may be a serious concern in founder populations that have grown rapidly and recently from a small size. As an example, we analyze the impact of excess relatedness among cases for six phenotypes measured in the Hutterite population

Coverage and Characteristics of the Affymetrix GeneChip Human Mapping 100K SNP Set

Improvements in technology have made it possible to conduct genome-wide association mapping at costs within reach of academic investigators, and experiments are currently being conducted with a variety of high-throughput platforms. To provide an appropriate context for interpreting results of such studies, we summarize here results of an investigation of one of the first of these technologies to be publicly available, the Affymetrix GeneChip Human Mapping 100K set of single nucleotide polymorphisms (SNPs). In a systematic analysis of the pattern and distribution of SNPs in the Mapping 100K set, we find that SNPs in this set are undersampled from coding regions (both nonsynonymous and synonymous) and oversampled from regions outside genes, relative to SNPs in the overall HapMap database. In addition, we utilize a novel multilocus linkage disequilibrium (LD) coefficient based on information content (analogous to the information content scores commonly used for linkage mapping) that is equivalent to the familiar measure r (2) in the special case of two loci. Using this approach, we are able to summarize for any subset of markers, such as the Affymetrix Mapping 100K set, the information available for association mapping in that subset, relative to the information available in the full set of markers included in the HapMap, and highlight circumstances in which this multilocus measure of LD provides substantial additional insight about the haplotype structure in a region over pairwise measures of LD

Human Extracellular-Matrix Functionalization of 3D hiPSC-Based Cardiac Tissues Improves Cardiomyocyte Maturation

The work here presented was funded by Fundacao para a Ciencia e Tecnologia (FCT) projects NETDIAMOND (SAICTPAC/0047/2015), financially supported by FEEI-Lisboa2020 and FCT/POCI-01-0145-FEDER-016385, and MetaCardio (PTDC/BTM-SAL/32566/2017); iNOVA4-Health -UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by FCT/Ministerio da Ciencia, Tecnologia e Ensino Superior, through national funds is acknowledged; Funding from INTERFACE Programme, through the Innovation, Technology and Circular Economy Fund (FITEC), is gratefully acknowledged; and EU-funded projects BRAV3 (H2020, ID:874827) and ERAatUC (ref. 669088). HVA, AFL, and DS were financed by FCT Grants SFRH/BPD/120595/2016 and PD/BD/139078/2018 and PD/BD/106051/2015, respectively.Human induced pluripotent stem cells (hiPSC) possess significant therapeutic potential due to their high self-renewal capability and potential to differentiate into specialized cells such as cardiomyocytes. However, generated hiPSC-derived cardiomyocytes (hiPSC-CM) are still immature, with phenotypic and functional features resembling the fetal rather than their adult counterparts, which limits their application in cell-based therapies, in vitro cardiac disease modeling, and drug cardiotoxicity screening. Recent discoveries have demonstrated the potential of the extracellular matrix (ECM) as a critical regulator in development, homeostasis, and injury of the cardiac microenvironment. Within this context, this work aimed to assess the impact of human cardiac ECM in the phenotype and maturation features of hiPSC-CM. Human ECM was isolated from myocardium tissue through a physical decellularization approach. The cardiac tissue decellularization process reduced DNA content significantly while maintaining ECM composition in terms of sulfated glycosaminoglycans (s-GAG) and collagen content. These ECM particles were successfully incorporated in three-dimensional (3D) hiPSC-CM aggregates (CM+ECM) with no impact on viability and metabolic activity throughout 20 days in 3D culture conditions. Also, CM+ECM aggregates displayed organized and longer sarcomeres, with improved calcium handling when compared to hiPSC-CM aggregates. This study shows that human cardiac ECM functionalization of hiPSC-based cardiac tissues improves cardiomyocyte maturation. The knowledge generated herein provides essential insights to streamline the application of ECM in the development of hiPSC-based therapies targeting cardiac diseases.publishersversionpublishe

A Comparative Proteomic Analysis of Praziquantel-Susceptible and Praziquantel-Resistant Schistosoma mansoni Reveals Distinct Response Between Male and Female Animals

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Parameter Estimation and Quantitative Parametric Linkage Analysis with GENEHUNTER-QMOD

Objective: We present a parametric method for linkage analysis of quantitative phenotypes. The method provides a test for linkage as well as an estimate of different phenotype parameters. We have implemented our new method in the program GENEHUNTER-QMOD and evaluated its properties by performing simulations. Methods: The phenotype is modeled as a normally distributed variable, with a separate distribution for each genotype. Parameter estimates are obtained by maximizing the LOD score over the normal distribution parameters with a gradient-based optimization called PGRAD method. Results: The PGRAD method has lower power to detect linkage than the variance components analysis (VCA) in case of a normal distribution and small pedigrees. However, it outperforms the VCA and Haseman-Elston regression for extended pedigrees, nonrandomly ascertained data and non-normally distributed phenotypes. Here, the higher power even goes along with conservativeness, while the VCA has an inflated type I error. Parameter estimation tends to underestimate residual variances but performs better for expectation values of the phenotype distributions. Conclusion: With GENEHUNTER-QMOD, a powerful new tool is provided to explicitly model quantitative phenotypes in the context of linkage analysis. It is freely available at http://www.helmholtz-muenchen.de/genepi/downloads. Copyright (C) 2012 S. Karger AG, Base

Purifying Selection in Deeply Conserved Human Enhancers Is More Consistent than in Coding Sequences

(c) 2014 De Silva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Combined Linkage and Association Analyses of the 124-bp Allele of Marker D2S2944 with Anxiety, Depression, Neuroticism and Major Depression

A central issue in psychiatric genetics is whether positive findings replicate. Zubenko et al. (2002b, Mol. Psychiatry 7:460-467) reported an association of the 124-bp allele of D2S2944 with recurrent early-onset major depression for females. We tested for association of this allele to continuous measures of anxiety, depression and neuroticism in a Dutch sample of 347 males and 448 females, and to DSM-IV major depression in a subsample of 210 males and 295 females. The association of the 124-bp allele to depression in females was not replicated, but there were significant associations (not significant after correction for multiple testing) with anxiety and anxious depression in males. However, the association occurred in the absence of evidence for linkage in this region on chromosome 2. © 2006 Springer Science+Business Media, Inc