46 research outputs found
The Crisis in America's Housing: Confronting Myths and Promoting a Balanced Housing Policy
This report debunks three common myths about housing policies. Myth 1: Subsidized housing is unnecessary. Myth 2: Federal government housing subsidies go disproportionately to low-income renters in urban areas. Myth 3: Homeownership is the best housing option for everyone.
Meijer\u27s Makers
This Innovation Portfolio is the result of a semester long project that examined the role of a regional campus in its community: more specifically, examining how the GVSU Meijer Campus can best integrate into and support its community. The Meijer Campus was originally designed to engage adult learners of the Holland business community. Our team sought out how to reinvigorate the campus through innovating based on this original goal. During the winter of 2017, our team undertook a series of steps to better understand the needs of the Holland community, considering how to design the Meijer Campus to fit those needs. Interviews with stakeholders and secondary research led us to common insights that were then composed into innovations and later prototypes. The final prototype was the Meijer Makerâs Design Lab, a gymnasium for the mind
High resolution mapping and positional cloning of ENU-induced mutations in the Rw region of mouse chromosome 5
<p>Abstract</p> <p>Background</p> <p>Forward genetic screens in mice provide an unbiased means to identify genes and other functional genetic elements in the genome. Previously, a large scale ENU mutagenesis screen was conducted to query the functional content of a ~50 Mb region of the mouse genome on proximal Chr 5. The majority of phenotypic mutants recovered were embryonic lethals.</p> <p>Results</p> <p>We report the high resolution genetic mapping, complementation analyses, and positional cloning of mutations in the target region. The collection of identified alleles include several with known or presumed functions for which no mutant models have been reported (<it>Tbc1d14</it>, <it>Nol14</it>, <it>Tyms</it>, <it>Cad</it>, <it>Fbxl5</it>, <it>Haus3</it>), and mutations in genes we or others previously reported (<it>Tapt1</it>, <it>Rest</it>, <it>Ugdh</it>, <it>Paxip1</it>, <it>Hmx1, Otoe, Nsun7</it>). We also confirmed the causative nature of a homeotic mutation with a targeted allele, mapped a lethal mutation to a large gene desert, and localized a spermiogenesis mutation to a region in which no annotated genes have coding mutations. The mutation in <it>Tbc1d14 </it>provides the first implication of a critical developmental role for RAB-GAP-mediated protein transport in early embryogenesis.</p> <p>Conclusion</p> <p>This collection of alleles contributes to the goal of assigning biological functions to all known genes, as well as identifying novel functional elements that would be missed by reverse genetic approaches.</p
COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study
Background:
The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms.
Methods:
International, prospective observational study of 60â109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms.
Results:
âTypicalâ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (â€â18 years: 69, 48, 23; 85%), older adults (â„â70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each Pâ<â0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country.
Interpretation:
This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men
Abnormal interactions between perifollicular mast cells and CD8+ T-cells may contribute to the pathogenesis of alopecia areata
Alopecia areata (AA) is a CD8+ T-cell dependent autoimmune disease of the hair follicle (HF) in which the collapse of HF immune privilege (IP) plays a key role. Mast cells (MCs) are crucial immunomodulatory cells implicated in the regulation of T cell-dependent immunity, IP, and hair growth. Therefore, we explored the role of MCs in AA pathogenesis, focusing on MC interactions with CD8+ T-cells in vivo, in both human and mouse skin with AA lesions. Quantitative (immuno-)histomorphometry revealed that the number, degranulation and proliferation of perifollicular MCs are significantly increased in human AA lesions compared to healthy or non-lesional control skin, most prominently in subacute AA. In AA patients, perifollicular MCs showed decreased TGFÎČ1 and IL-10 but increased tryptase immunoreactivity, suggesting that MCs switch from an immuno-inhibitory to a pro-inflammatory phenotype. This concept was supported by a decreased number of IL-10+ and PD-L1+ MCs, while OX40L+, CD30L+, 4-1BBL+ or ICAM-1+ MCs were increased in AA. Lesional AA-HFs also displayed significantly more peri- and intrafollicular- CD8+ T-cells as well as more physical MC/CD8+ T-cell contacts than healthy or non-lesional human control skin. During the interaction with CD8+ T-cells, AA MCs prominently expressed MHC class I and OX40L, and sometimes 4-1BBL or ICAM-1, suggesting that MC may present autoantigens to CD8+ T-cells and/or co-stimulatory signals. Abnormal MC numbers, activities, and interactions with CD8+ T-cells were also seen in the grafted C3H/HeJ mouse model of AA and in a new humanized mouse model for AA. These phenomenological in vivo data suggest the novel AA pathobiology concept that perifollicular MCs are skewed towards pro-inflammatory activities that facilitate cross-talk with CD8+ T-cells in this disease, thus contributing to triggering HF-IP collapse in AA. If confirmed, MCs and their CD8+ T-cell interactions could become a promising new therapeutic target in the future management of AA
Abnormal interactions between perifollicular mast cells and CD8+ T-cells may contribute to the pathogenesis of alopecia areata
Alopecia areata (AA) is a CD8+ T-cell dependent autoimmune disease of the hair follicle (HF) in which the collapse of HF immune privilege (IP) plays a key role. Mast cells (MCs) are crucial immunomodulatory cells implicated in the regulation of T cell-dependent immunity, IP, and hair growth. Therefore, we explored the role of MCs in AA pathogenesis, focusing on MC interactions with CD8+ T-cells in vivo, in both human and mouse skin with AA lesions. Quantitative (immuno-)histomorphometry revealed that the number, degranulation and proliferation of perifollicular MCs are significantly increased in human AA lesions compared to healthy or non-lesional control skin, most prominently in subacute AA. In AA patients, perifollicular MCs showed decreased TGFÎČ1 and IL-10 but increased tryptase immunoreactivity, suggesting that MCs switch from an immuno-inhibitory to a pro-inflammatory phenotype. This concept was supported by a decreased number of IL-10+ and PD-L1+ MCs, while OX40L+, CD30L+, 4-1BBL+ or ICAM-1+ MCs were increased in AA. Lesional AA-HFs also displayed significantly more peri- and intrafollicular- CD8+ T-cells as well as more physical MC/CD8+ T-cell contacts than healthy or non-lesional human control skin. During the interaction with CD8+ T-cells, AA MCs prominently expressed MHC class I and OX40L, and sometimes 4-1BBL or ICAM-1, suggesting that MC may present autoantigens to CD8+ T-cells and/or co-stimulatory signals. Abnormal MC numbers, activities, and interactions with CD8+ T-cells were also seen in the grafted C3H/HeJ mouse model of AA and in a new humanized mouse model for AA. These phenomenological in vivo data suggest the novel AA pathobiology concept that perifollicular MCs are skewed towards pro-inflammatory activities that facilitate cross-talk with CD8+ T-cells in this disease, thus contributing to triggering HF-IP collapse in AA. If confirmed, MCs and their CD8+ T-cell interactions could become a promising new therapeutic target in the future management of AA
Human AA lesions show increased density, proliferation and degranulation of perifollicular MCs.
<p>The immunohistochemical identification and evaluation of MCs by c-Kit (A,D), TB (B,E) or Ki-67/tryptase (C,F) revealed a strong increase of MC numbers in AA (DâF) compared to control healthy (AâC) skin. Red arrows indicate MCs. C-Kit/tryptase double-IF shows immature c-Kit+ MCs (stained in green) and mature c-Kit+/tryptase+ MCs in AA skin (stained in green and red) (G). See inserted panels in the bottom left of each Figure for higher magnification views of the area highlighted in the small boxes. Reference area for the quantitative analysis using (immuno-)histomorphometry for cell counting in the connective tissue sheath (CTS) and perifollicular dermis (PFD). CTS+PFD represents the total area including the space demarcated up to 200 ”m from the HF basement membrane (C,F). Fold change of MC density detected by c-Kit, TB and tryptase stainings (H). Black line indicates the control. Analysis derived from 69â81areas (HFs) of 11â17 AA patients and from 50â69 areas (HFs) of 5â7 healthy controls, ±SEM, *pâ€0.05, **pâ€0.01, ***pâ€0.001, Mann-Whitney-U-Test or Student t-test (for c-Kit, TB and tryptase compared to respective controls and for comparing bars between CTS and PFD), Kruskal-Wallis test (p<0.0001) followed by Dunn's test (for comparing c-Kit, TB and tryptase within CTS and PFD). Identification of MCs by Ki-67/tryptase IHC (I,J,M), Ki-67/tryptase IF (K), Ki-67/c-Kit IHC (L) and TB (N) showing non-degranulating, non proliferating MCs (blue arrows), degranulating, non-proliferating MCs (green arrows), non-degranulating MCs undergoing proliferation (red arrows) and proliferating degranulating MCs (orange arrows). Quantitative analysis of MC proliferation by Ki-67/tryptase IHC (O). Analysis derived from 81 areas (HFs) of 17 AA patients and 50 areas (HFs) of 7 healthy controls, ±SEM, Mann-Whitney-U-Test (ns). Quantitative analysis of MC degranulation by TB histochemistry and Ki-67/tryptase IHC (P). Black line indicates the control. Analysis derived from 69â81 areas (HFs) of 11â17 AA patients and 50â69 areas (HFs) of 5â7 healthy controls, ±SEM, *pâ€0.05, **pâ€0.05, ***pâ€0.001 Mann-Whitney-U-Test (compare to control), Mann-Whitney test (TB compare to tryptase) (ns). Scale bars: 100 ”m (AâG) and 20 ”m (IâN) Connective tissue sheath (CTS), hair shaft (HS), inner root sheath (IRS), outer root sheath (ORS), perifollicular dermis (PFD), toluidine blue (TB), sebaceous gland (SG).</p