Using public control genotype data to increase power and decrease cost of case–control genetic association studies

Genome-wide association (GWA) studies are a powerful approach for identifying novel genetic risk factors associated with human disease. A GWA study typically requires the inclusion of thousands of samples to have sufficient statistical power to detect single nucleotide polymorphisms (SNPs) that are associated with only modest increases in risk of disease given the heavy burden of a multiple test correction that is necessary to maintain valid statistical tests. Low statistical power and the high financial cost of performing a GWA study remains prohibitive for many scientific investigators anxious to perform such a study using their own samples. A number of remedies have been suggested to increase statistical power and decrease cost, including the utilization of free publicly available genotype data and multi-stage genotyping designs. Herein, we compare the statistical power and relative costs of alternative association study designs that use cases and screened controls to study designs that are based only on, or additionally include, free public control genotype data. We describe a novel replication-based two-stage study design, which uses free public control genotype data in the first stage and follow-up genotype data on case-matched controls in the second stage, that preserves many of the advantages inherent when using only an epidemiologically matched set of controls. Specifically, we show that our proposed two-stage design can substantially increase statistical power and decrease cost of performing a GWA study while controlling the type I error rate that can be inflated when using public controls due to differences in ancestry and batch genotype effects

pH-regulated nonelectrogenic anion transport by phenylthiosemicarbazones

Gated ion transport across biological membrane is an intrinsic process regulated by protein channels. Synthetic anion carriers (anionophores) have potential applications in biological research, however, previous reported examples are mostly nonspecific, capable of mediating both electrogenic and electroneutral (non-electrogenic) transport processes. Here, we show the transmembrane Cl? transport studies of synthetic phenylthiosemicarbazones mimicking the function of acid-sensing (proton-gated) ion channels. These anionophores have remarkable pH-switchable transport properties with up to 640-fold increase in transport efficacy on going from pH 7.2 to 4.0. This “gated” process is triggered by protonation of the imino nitrogen and concomitant conformational change of the anion binding thiourea moiety from anti to syn. By using a combination of two cationophore-coupled transport assays, with either monensin or valinomycin, we have elucidated the fundamental transport mechanism of phenylthiosemicarbazones which is shown to be non-electrogenic, inseparable H+/Cl? cotransport. This study demonstrates the first examples of pH-switchable non-electrogenic anion transporter

Engineering Robust Metallic Zero-Mode States in Olympicene Graphene Nanoribbons

Metallic graphene nanoribbons (GNRs) represent a critical component in the toolbox of low-dimensional functional materials technolo-gy serving as 1D interconnects capable of both electronic and quantum information transport. The structural constraints imposed by on-surface bottom-up GNR synthesis protocols along with the limited control over orientation and sequence of asymmetric monomer building blocks during the radical step-growth polymerization has plagued the design and assembly of metallic GNRs. Here we report the regioregular synthesis of GNRs hosting robust metallic states by embedding a symmetric zero-mode superlattice along the backbone of a GNR. Tight-binding electronic structure models predict a strong nearest-neighbor electron hopping interaction between adjacent zero-mode states resulting in a dispersive metallic band. First principles DFT-LDA calculations confirm this prediction and the robust, metallic zero-mode band of olympicene GNRs (oGNRs) is experimentally corroborated by scanning tunneling spectroscopy.Comment: 8 pages, 4 figure

The androgen receptor CAG and GGN repeat polymorphisms and prostate cancer susceptibility in African-American men: results from the Flint Men’s Health Study

Repeat lengths of the CAG and GGN micro-satellites in exon 1 of the androgen receptor (AR) gene have been hypothesized to be associated with prostate cancer risk. In vitro studies have showed an inverse association between AR CAG and GGN repeat length and activity levels of the AR product. It is known that men of African descent have a higher incidence of and greater mortality from prostate cancer than men of Caucasian or Asian descent and, on average, a smaller number of repeats at AR CAG and GGN. Consistent with these findings, studies have also found increased AR protein expression levels in benign prostatic hyperplasia and prostatic diseased tissues from men of African descent. Despite these findings, limited studies have been conducted to evaluate the association between repeat lengths at AR CAG and prostate cancer risk in African Americans. Our study is the first such study to examine whether repeat length of the AR GGN repeat is associated with prostate cancer risk in African Americans. We found no evidence for an association between AR CAG or GGN repeat lengths and prostate cancer risk in a population-based sample of African Americans

Electronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats

Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal crosstalk from the neighboring electrodes. Local return electrodes within each pixel limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 55 μm. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated the computational modeling of the field confinement in such an optically-controlled circuit by in-vitro and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40 μm pixels matches the pixel pitch, while with 20 μm pixels, it reaches the 28 μm limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration

Genome-wide linkage scan for prostate cancer susceptibility genes in men with aggressive disease: significant evidence for linkage at chromosome 15q12

Epidemiological and twin studies have consistently demonstrated a strong genetic component to prostate cancer (PCa) susceptibility. To date, numerous linkage studies have been performed to identify chromosomal regions containing PCa susceptibility genes. Unfortunately, results from these studies have failed to form any obvious consensus regarding which regions are most likely to contain genes that may contribute to PCa predisposition. One plausible explanation for the difficulty in mapping susceptibility loci is the existence of considerable heterogeneity in the phenotype of PCa, with significant variation in clinical stage and grade of disease even among family members. To address this issue, we performed a genome-wide linkage scan on 71 informative families with two or more men with aggressive PCa. When only men with aggressive PCa were coded as affected, statistically significant evidence for linkage at chromosome 15q12 was detected (LOD=3.49; genome-wide p =0.005). Furthermore, the evidence for linkage increased when analyses were restricted to Caucasian–American pedigrees ( n =65; LOD=4.05) and pedigrees with two confirmed aggressive cases ( n =42, LOD=4.76). Interestingly, a 1-LOD support interval about our peak at 15q12 overlaps a region of suggestive linkage, 15q11, identified by a recent linkage study on 1,233 PCa families by the International Consortium for Prostate Cancer Genetics. Using a more rigid definition of PCa in linkage studies will result in a severe reduction in sample sizes available for study, but may ultimately prove to increase statistical power to detect susceptibility genes for this multigenic trait.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47600/1/439_2006_Article_149.pd

NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells

NOTCH signaling is required for the arterial specification and formation of hematopoietic stem cells (HSCs) and lympho-myeloid progenitors in the embryonic aorta-gonad-mesonephros region and extraembryonic vasculature from a distinct lineage of vascular endothelial cells with hemogenic potential. However, the role of NOTCH signaling in hemogenic endothelium (HE) specification from human pluripotent stem cell (hPSC) has not been studied. Here, using a chemically defined hPSC differentiation system combined with the use of DLL1-Fc and DAPT to manipulate NOTCH, we discover that NOTCH activation in hPSC-derived immature HE progenitors leads to formation of CD144+CD43−CD73−DLL4+Runx1 + 23-GFP+ arterial-type HE, which requires NOTCH signaling to undergo endothelial-to-hematopoietic transition and produce definitive lympho-myeloid and erythroid cells. These findings demonstrate that NOTCH-mediated arterialization of HE is an essential prerequisite for establishing definitive lympho-myeloid program and suggest that exploring molecular pathways that lead to arterial specification may aid in vitro approaches to enhance definitive hematopoiesis from hPSCs

Pathogenic TNF-α drives peripheral nerve inflammation in an Aire-deficient model of autoimmunity

Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g., Guillain Barré Syndrome and chronic inflammatory demyelinating polyneuropathy), immune cells are proinflammatory and promote autoimmune demyelination. An understanding of immune cell phenotypes that distinguish these conditions may, therefore, reveal new therapeutic targets for switching immune cells from an inflammatory role to a reparative state. In an autoimmune regulator (Aire)-deficient mouse model of inflammatory neuropathy, we used single-cell RNA sequencing of sciatic nerves to discover a transcriptionally heterogeneous cellular landscape, including multiple myeloid, innate lymphoid, and lymphoid cell types. Analysis of cell-cell ligand-receptor interactions uncovered a macrophage-mediated tumor necrosis factor-α (TNF-α) signaling axis that is induced by interferon-γ and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-α signaling is associated with metabolic reprogramming of macrophages and polarization of macrophages from a reparative state in injury to a pathogenic, inflammatory state in autoimmunity. Autocrine TNF-α signaling induced macrophage expression of multiple genes (Clec4e, Marcksl1, Cxcl1, and Cxcl10) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-α/TNF-α signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-α axis may be effectively targeted to resolve inflammatory neuropathies

The Human Melanoma Proteome Atlas—Complementing the melanoma transcriptome

The MM500 meta‐study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass‐spectrometry‐based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well‐annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein‐coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease

Promoting Latinx health equity through community-engaged policy and practice reforms in North Carolina

IntroductionThe Latinx Advocacy Team & Interdisciplinary Network for COVID-19 (LATIN-19) is a unique multi-sector coalition formed early in the COVID-19 pandemic to address the multi-level health inequities faced by Latinx communities in North Carolina.MethodsWe utilized the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework to conduct a directed content analysis of 58 LATIN-19 meeting minutes from April 2020 through October 2021. Application of the NIMHD Research Framework facilitated a comprehensive assessment of complex and multidimensional barriers and interventions contributing to Latinx health while centering on community voices and perspectives.ResultsCommunity interventions focused on reducing language barriers and increasing community-level access to social supports while policy interventions focused on increasing services to slow the spread of COVID-19.DiscussionOur study adds to the literature by identifying community-based strategies to ensure the power of communities is accounted for in policy reforms that affect Latinx health outcomes across the U.S. Multisector coalitions, such as LATIN-19, can enable the improved understanding of underlying barriers and embed community priorities into policy solutions to address health inequities