Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo

2020-06-24/25 DAILY UNM GLOBAL HEALTH COVID-19 BRIEFING

Executive Summary: NM Highlights: Governor update. NM schools reopening. Parents split on allowing kids play sports. Santa Fe streets closure. Paid leave for ABQ businesses. 207 cases and 5 deaths. International Highlights: 9% HCW positive in Italy. Australian lessons. Economics, Workforce, Supply Chain, PPE: Plan for return to normalcy. Mask cleaning. Epidemiology Highlights: US years of life lost high. Fever and cough most prevalent symptoms. Hypertension and diabetes most prevalent comorbidities. Hypertension, diabetes and respiratory disease most prevalent in fatal cases. Practice Guidelines: Brazilian guidelines on thromboembolic complications in COVID-19. Novel design of door handle to touch with a forearm. Drugs, Vaccines, Therapies, Clinical Trials: Potential dexamethasone shortage. Arbidol potentially effective. Pixatimod promising. In-silico repurposing. 51 new COVID-19 trials. Other Science: Transmission prior to symptoms. Solar inactivation of coronaviruses. Risk factors for severity. Laboratory tests associated with outcomes

2020-05-22 DAILY UNM GLOBAL HEALTH COVID-19 BRIEFING

Executive Summary: NM Highlights: 12 positive cases at NMSU. Short-term rentals restrictions. Dine-in reopening. US Highlights: Models to forecast COVID-19 deaths. Places of worship reopening. Contact tracing at University of Alabama. International Highlights: More deaths among poor. Mortality data in Italy. High death toll in Brazil. Global vaccines fall behind. Italy cases drop. Vaccines to go through India. Epidemiology Highlights: Children not pandemic drivers. Healthcare Policy Recommendations: Burnout of HCWs. NYC surgeons’ response. Foggy glasses tips. Practice Guidelines: Recommendations are provided on surgical strategies during COVID-19, management of hypertension, anesthesia practice, avoiding drug-induced cardiovascular impairments, arrhythmia management, elective surgery reboot, nutritional management, stroke care, neurointerventional surgery, blood management. Testing: Unregulated tests identified. Interpreting test results. Drugs, Vaccines, Therapies, Clinical Trials: Vaccine trials results. Vaccine moves to trials. Monoclonal antibody identified. Hydroxychloroquine no benefit. Adjuvant corticosteroid therapy. Old drugs may benefit. Vaccines inducing antibodies. Other Science: Mortality and CKD/liver disease. Transmission in pregnancy. Pathophysiology insights. Readmission characteristics. Sodium and severity. Simulated sunlight disinfects

2020-06-22/23 DAILY UNM GLOBAL HEALTH COVID-19 BRIEFING

Executive Summary: NM Highlights: Balloon Fiesta postponed. Robot to sanitize ABQ International Sunport. NMSU plan for fall 2020. NM public schools reopening plan. Fewer hospitalizations for COVID-19. NM case update. US Highlights: Visa restrictions. International Highlights: Second wave in South Korea. Epidemiology: Lockdown can suppress COVID-19. Case fatality rate associated with incidence. Predictors of ICU care and ventilators. Anxiety and depression from COVID-19. Asymptomatic patients as source of infection. Heterogeneous populations affect herd immunity. Healthcare Policy Recommendations: New FDA guidance on clinical trials conduct. Practice Guidelines: The guidelines are provided on COVID-19 diagnostics (Infectious Diseases Society of America), respiratory support for COVID-19 patients and optimizing mental care delivery during COVID-19 pandemic. Drugs, Vaccines, Therapies, Clinical Trials: Antithrombotic therapy systematic review. Drug repurposing. 58 new trials. Other Science: Safety of antihypertensives (ACEs and ARBs). Low testosterone linked to escalation of care. Neurological findings and hypercoagulability

Epigenome-wide association data implicates DNA methylation-mediated genetic risk in psoriasis

Abstract Background Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status. Methods We utilized the genome-wide methylation data of psoriatic skin (PP, N = 114) and unaffected control skin (NN, N = 62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility. Results We identified 129 SNP-CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P < 0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106, the TSS1500 promoter region of DMBX1 and the body of SIK3. Conclusions This study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis

2020-05-11 DAILY UNM GLOBAL HEALTH COVID-19 BRIEFING

Executive Summary: NM case counts. Navajo Nation documentary. Medicaid reimbursement increase. Excess NYC mortality. German R0\u3e1. Chile COVID-19 certificates. High female incidence in Quebec. Swab 3D printing. Evidence lacking school reopening. Cloth mask review. WHO 2nd wave warning. Higher mortality in minorities. Environmental transmission controls. Behavior change. Correctional environment guidelines. Wuhan hospital transformation. Maximizing GI training. Threat and conformity. Recommendations on managing COVID-19 (first Italian SARS patients), and obesity and metabolic syndrome. Guidelines for neurologists. Ethics of off-label drugs use. Abbott antibody test approval. CRISPR test FDA approval. Viral sample inactivation. HCQ+azithromycin no benefit. Public-Private partnership for clinical trials. Drug repurposing. Cancer patient considerations. 35 new COVID-19 trials. Hyperinflammatory shock in children. Symptom app

2020-05-14 DAILY UNM GLOBAL HEALTH COVID-19 BRIEFING

Executive Summary: NM restrictions loosen. NM case count. Navajo Nation case count. 9 state parks open. Sunport revenue loss. Trump projects vaccine delivery. Wisconsin court case. Smokers quit. Ireland reopening. Danish schools open. Philippine typhoon evacuation. PPE-induced pressure injuries and facial dermatoses. U.S. mask stockpile. PPE for surgeons. Intubation time with aerosol box. Consumer spending with social restrictions. Suicide increase expected. Undetected virus homeless. Chinese infection control. 5% Spain infected. Sanitizing booth. Healthcare worker infection routes. Kawasaki disease France. CDC Kawaski guidance. Italian deaths characterized. CDC reopening school guidance. COVID-19 and epistemology. Monitoring misleading claims. UN mental health policy brief. CDC vaccination schedules. Guidelines on managing endoscopy units. COVID-19 lab testing (for lab professionals). Cancer surgery triage. Operating room practices. Orthodontic treatment. 3D printed NP swabs effective. Salt-water irrigation reduces duration. Corticosteroids ineffectual. Vaccines require biomanufacturing infrastructure. French pharm giant promises fair vaccine distribution. 26 new trials registered. LDH, lymphocytes and hs-CRP predict mortality. Fibrinogen higher in SARS. Insulin resistance. Glycemic monitoring. Hemostasis abnormalities. New phobia scale. OR global consensus. Inpatient cognitive assessments are challenging. Loud speech increases transmission. Monkeys present similarly. Human-to-dog transmission. Cat transmission

Simplified Models for LHC New Physics Searches

This document proposes a collection of simplified models relevant to the design of new-physics searches at the LHC and the characterization of their results. Both ATLAS and CMS have already presented some results in terms of simplified models, and we encourage them to continue and expand this effort, which supplements both signature-based results and benchmark model interpretations. A simplified model is defined by an effective Lagrangian describing the interactions of a small number of new particles. Simplified models can equally well be described by a small number of masses and cross-sections. These parameters are directly related to collider physics observables, making simplified models a particularly effective framework for evaluating searches and a useful starting point for characterizing positive signals of new physics. This document serves as an official summary of the results from the "Topologies for Early LHC Searches" workshop, held at SLAC in September of 2010, the purpose of which was to develop a set of representative models that can be used to cover all relevant phase space in experimental searches. Particular emphasis is placed on searches relevant for the first ~50-500 pb-1 of data and those motivated by supersymmetric models. This note largely summarizes material posted at http://lhcnewphysics.org/, which includes simplified model definitions, Monte Carlo material, and supporting contacts within the theory community. We also comment on future developments that may be useful as more data is gathered and analyzed by the experiments.Comment: 40 pages, 2 figures. This document is the official summary of results from "Topologies for Early LHC Searches" workshop (SLAC, September 2010). Supplementary material can be found at http://lhcnewphysics.or

Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes

Abstract Background Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 μm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus (Type II DM). We investigated the role of hypothalamic inflammation in PM2.5-mediated diabetes development. Methods KKay mice, a genetically susceptible model of Type II DM, were assigned to either concentrated PM2.5 or filtered air (FA) for 4–8 weeks via a versatile aerosol concentrator and exposure system, or administered intra-cerebroventricular with either IKKβ inhibitor (IMD-0354) or TNFα antibody (infliximab) for 4–5 weeks simultaneously with PM2.5 exposure. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen, visceral adipose tissue and hypothalamus were collected to measure inflammatory cells using flow cytometry. Standard immunohistochemical methods and quantitative PCR were used to assess targets of interest. Results PM2.5 exposure led to hyperglycemia and insulin resistance, which was accompanied by increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKβ inhibitor [IMD-0354, n = 8 for each group)], but not TNFα blockade with infliximab [(n = 6 for each group], improved glucose tolerance, insulin sensitivity, rectified energy homeostasis (O2 consumption, CO2 production, respiratory exchange ratio and heat generation) and reduced peripheral inflammation in response to PM2.5. Conclusions Central inhibition of IKKβ prevents PM2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.http://deepblue.lib.umich.edu/bitstream/2027.42/109486/1/12989_2014_Article_53.pd