Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in specific and relevant biological pathways, allowing regulators of human erythropoiesis and modifiers of blood diseases to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits

Gene Signatures of T-Cell Activation Can Serve as Predictors of Functionality for SARS-CoV-2-Specific T-Cell Receptors

The importance of T cells in controlling SARS-CoV-2 infections has been demonstrated widely, but insights into the quality of these responses are still limited due to technical challenges. Indeed, understanding the functionality of the T-cell receptor (TCR) repertoire of a polyclonal antigen-specific population still requires the tedious work of T-cell cloning or TCR re-expression and subsequent characterization. In this work, we show that it is possible to discriminate highly functional and bystander TCRs based on gene signatures of T-cell activation induced by recent peptide stimulation. SARS-CoV-2-specific TCRs previously identified by cytokine release after peptide restimulation and subsequent single-cell RNA sequencing were re-expressed via CRISPR-Cas9-mediated gene editing into a Jurkat-based reporter cell line system suitable for high-throughput screening. We could observe differences in SARS-CoV-2 epitope recognition as well as a wide range of functional avidities. By correlating these in vitro TCR engineered functional data with the transcriptomic profiles of the corresponding TCR-expressing parental T cells, we could validate that gene signatures of recent T-cell activation accurately identify and predict truly SARS-CoV-2-specific TCRs. In summary, this work paves the way for alternative approaches useful for the functional analysis of global antigen-specific TCR repertoires with largely improved throughput

Divergent Views on the Future of Automotive Retailing

A.T. KearneyOffice for the Study of Automotive Transportationhttp://deepblue.lib.umich.edu/bitstream/2027.42/156402/1/Divergent of Views on the future of Automotive Retailing.pd

Two-Year Follow-Up on Chemosensory Dysfunction and Adaptive Immune Response after Infection with SARS-CoV-2 in a Cohort of 44 Healthcare Workers

Persistent chemosensory dysfunction (PCD) is a common symptom of long-COVID. Chemosensory dysfunction (CD) as well as SARS-CoV-2-specific antibody levels and CD8+ T-cell immunity were investigated in a cohort of 44 healthcare workers up to a median of 721 days after a positive PCR test. CD was assessed using questionnaires and psychophysical screening tests. After 721 days, 11 of 44 (25%) participants reported PCD, with five describing an impaired quality of life. One participant reported hyperosmia (increased sense of smell). The risk of PCD at 721 days was higher for participants reporting qualitative changes (parosmia (altered smell), dysgeusia (altered taste), or phantosmia (hallucination of smell)) during initial infection than in those with isolated quantitative losses during the first COVID-19 infection (62.5% vs. 7.1%). The main recovery rate occurred within the first 100 days and did not continue until follow-up at 2 years. No correlation was found between antibody levels and CD, but we observed a trend of a higher percentage of T-cell responders in participants with CD. In conclusion, a significant proportion of patients suffer from PCD and impaired quality of life 2 years after initial infection. Qualitative changes in smell or taste during COVID-19 pose a higher risk for PCD

Accommodation Downsizing

OverviewAging in place policies are a common response of governments to population aging (See “Aging in Place”). Typically, this involves increasing aged care services delivered to the home and home modifications to improve accessibility, thereby reducing (or postponing) transitions to more costly institutional aged care (See “Home Modifications”). This aligns with the desire of many older people to remain in their family homes for as long as possible (Venti and Wise 1990; Olsberg and Winters 2005; Croucher 2008; Judd et al. 2010; Porteus 2011; Fernald 2014; James 2016a). However, contradictory factors to “staying put” include the unsuitability/inaccessibility of the design of conventional housing stock; the increasing maintenance burden accompanying declining ability or sudden shocks of illness, disability, relationship breakdown, and partner’s death; claims of underutilization of housing by older people; and potential for reducing housing equity to support nonhousing consumption due to reduced post retirement income (See “Home Equity Conversions”). These constitute the main arguments for older people downsizing their accommodation to continue aging in place. However, downsizing among older people is not as prevalent or straightforward as this implies