A comprehensive resource for induced pluripotent stem cells from patients with primary tauopathies

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies

A PDA-based dietary self-monitoring intervention to reduce sodium intake in an in-center hemodialysis patient

Objective: The purpose of the BalanceWise-hemodialysis study is to determine the efficacy of a dietary intervention to reduce dietary sodium intake in patients receiving maintenance, in-center hemodialysis (HD). Personal digital assistant (PDA)-based dietary self-monitoring is paired with behavioral counseling. The purpose of this report is to present a case study of one participant's progression through the intervention. Methods: The PDA was individually programmed with the nutritional requirements of the participant. With 25 minutes of personalized instruction, the participant was able to enter his meals into the PDA using BalanceLog® software. Nutritional counseling was provided based on dietary sodium intake reports generated by BalanceLog®. Results: At initiation of the study the participant required 4 HD treatments per week. The participant entered 342 meals over 16 weeks (≥3 meals per day). BalanceLog® revealed that the participant consumed restaurant/fast food on a regular basis, and consumed significant amounts of corned beef as well as canned foods high in sodium. The study dietitian worked with the participant and his wife to identify food alternatives lower in sodium. Baseline sodium consumption was 4,692 mg, and decreased at a rate of 192 mg/week on average. After 11 weeks of intervention, interdialytic weight gains were reduced sufficiently to permit the participant to reduce HD treatments from 4 to 3 per week. Because of a low serum albumin at baseline (2.9 g/dL) the study dietitian encouraged the participant to increase his intake of high quality protein. Serum albumin level at 16 weeks was unchanged (2.9 g/dL). Because of intense pruritis and a high baseline serum phosphorus (6.5 mg/dL) BalanceLog® electronic logs were reviewed to identify sources of dietary phosphorus and counsel the participant regarding food alternatives. At 16 weeks the participant's serum phosphorus fell to 5.5 mg/dL. Conclusions: Self-monitoring rates were excellent. In a HD patient who was willing to self-monitor his dietary intake, BalanceLog® allowed the dietitian to target problematic foods and provide counseling that appeared to be effective in reducing sodium intake, reducing interdialytic weight gain, and alleviating hyperphosphatemia and hyperkalemia. Additional research is needed to evaluate the efficacy of the intervention. © 2008 Sevick et al, publisher and licensee Dove Medical Press Ltd

Long non-coding RNA SNHG8 drives stress granule formation in tauopathies

Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in the MAPT gene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream of MAPT mutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts \u3e200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying a MAPT p.P301L, IVS10 + 16, or p.R406W mutation and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of the MAPT mutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the three MAPT mutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs, SNHG8 was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer\u27s disease brains. We show that SNHG8 interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tau in vitro is sufficient to reduce SNHG8 expression and induce stress granule formation. Rescuing SNHG8 expression leads to reduced stress granule formation and reduced TIA1 levels in immortalized cells and in MAPT mutant neurons, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies

Decreasing the minimum length criterion for an episode of hypomania: evaluation using self-reported data from patients with bipolar disorder

Brief hypomania lasting less than 4 days may impair functioning and help to detect bipolarity. This study analyzed brief hypomania that occurred in patients with bipolar disorder who were diagnosed according to the DSM-IV criteria. Daily self-reported mood ratings were obtained from 393 patients (247 bipolar I and 146 bipolar II) for 6 months (75,284 days of data, mean 191.6 days). Episodes of hypomania were calculated using a 4, 3, 2, and single day length criterion. Brief hypomania occurred frequently. With a decrease in the minimum criterion from 4 days to 2 days, there were almost twice as many patients with an episode of hypomania (102 vs. 190), and more than twice as many episodes (305 vs. 863). Single days of hypomania were experienced by 271 (69%) of the sample. With a 2-day episode length, 33% of all hypomania remained outside of an episode. There was no significant difference in the percent of hypomanic days outside of an episode between patients with bipolar I and II disorders. There were no significant differences in the demographic characteristics of patients who met the 4-day minimum as compared with those who only experienced episodes of hypomania using a shortened length criterion. Decreasing the minimum length criterion for an episode of hypomania will cause a large increase in the number of patients who experience an episode and in the aggregate number of episodes, but will not distinguish subgroups within a sample who meet the DSM-IV criteria for bipolar disorder. Frequency may be an important dimensional aspect of brief hypomania. Clinicians should regularly probe for brief hypomania

The role of passion in exercise addiction, exercise volume, and exercise intensity in long-term exercisers

Recent studies have shown a relationship between the risk for exercise addiction (REA) and passion. This research examined whether levels of REA, volume of exercise (in weekly hours), and self-reported exercise intensities yield differences in obsessive passion and harmonious passion among individuals with long history of exercise. Respondents (n = 360) completed the Exercise Addiction Inventory, Passion Scale, and Borg Scale (assessing their usual exercise intensity), and reported their volume of exercise (hours per week). Regression analysis demonstrated that exercise intensity, obsessive passion, and harmonious passion were significant predictors (r2 = .381, p < .001) of the REA scores with obsessive passion being the strongest predictor (r2 = .318). Exercisers classified as at REA reported higher obsessive passion, harmonious passion, and exercise intensity (p ≤ .001) than those classified as symptomatic, who in turn scored higher on these measures (p ≤ .006) than asymptomatic exercisers. Participants reporting greater volumes of exercise also scored higher on obsessive passion, harmonious passion (p < .001), exercise intensity (p = .032), and REA scores (p = .042) than individuals who exercised less. Finally, women exercising between low and high intensities exhibited greater obsessive passion, as well as harmonious passion (p ≤ .005) than men reporting similar exercise intensities. These findings support the recently reported relationship between passion and REA. They also expand the current knowledge by demonstrating that obsessive passion and harmonious passion are greater in the individuals who exercise at higher volumes and with higher intensities

Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic PAH

Our systematic analysis of anion channels and transporters in idiopathic pulmonary arterial hypertension (IPAH) showed marked upregulation of the Cl- channel TMEM16A gene.We hypothesised that TMEM16A overexpression might represent a novel vicious circle in the molecular pathways causing PAH.We investigated healthy donor lungs (n=40) and recipient lungs with IPAH (n=38) for the expression of anion channel and transporter genes in small pulmonary arteries and pulmonary arterial smooth muscle cells (PASMC). In IPAH, TMEM16A was strongly upregulated and patch-clamp recordings confirmed an increased Cl- current in PASMC (n=9-10). These cells were depolarised and could be repolarized by TMEM16A inhibitors or knock-down experiments (n=6-10). Inhibition/knock-down of TMEM16A reduced proliferation of IPAH-PASMC (n=6). Conversely, overexpression of TMEM16A in healthy donor PASMC produced an IPAH-like phenotype. Chronic application of benzbromarone in two independent animal models significantly decreased right ventricular pressure and reversed remodelling of established PH.Our findings suggest that increased TMEM16A expression and activity comprise an important pathologic mechanism underlying vasoconstriction and remodelling of pulmonary arteries in PAH. Inhibition of TMEM16A represents a novel therapeutic approach to achieve reverse remodelling in PAH

Rare germline copy number variants (CNVs) and breast cancer risk.

Funder: CIHRGermline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance

Association between solar insolation and a history of suicide attempts in bipolar I disorder

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p <0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.Peer reviewe

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice