Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the FUS gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies

Yawning, fatigue and cortisol: expanding the Thompson Cortisol Hypothesis.

Yawning and its involvement in neurological disorders has become the new scientific conundrum. Cortisol levels are known to rise during stress and fatigue; yawning may occur when we are under stress or tired. However, the link between yawning, fatigue, and cortisol has not been fully understood. Expansion of the Thompson Cortisol Hypothesis proposes that the stress hormone, cortisol, is responsible for yawning and fatigue especially in people with incomplete innervation such as multiple sclerosis. This informs our understanding of the functional importance of the brain stem region of the brain in regulating stress and fatigue

Hurricane Florence and suicide mortality in North Carolina: A controlled interrupted time-series analysis

Background Natural disasters are associated with increased mental health disorders and suicidal ideation; however, associations with suicide deaths are not well understood. We explored how Hurricane Florence, which made landfall in September 2018, may have impacted suicide deaths in North Carolina (NC). Methods We used publicly available NC death records data to estimate associations between Hurricane Florence and monthly suicide death rates using a controlled, interrupted time series analysis. Hurricane exposure was determined by using county-level support designations from the Federal Emergency Management Agency. We examined effect modification by sex, age group, and race/ethnicity. Results 8363 suicide deaths occurred between January 2014 and December 2019. The overall suicide death rate in NC between 2014 and 2019 was 15.53 per 100 000 person-years (95% CI 15.20 to 15.87). Post-Hurricane, there was a small, immediate increase in the suicide death rate among exposed counties (0.89/100 000 PY; 95% CI -2.69 to 4.48). Comparing exposed and unexposed counties, there was no sustained post-Hurricane Florence change in suicide death rate trends (0.02/100 000 PY per month; 95% CI -0.33 to 0.38). Relative to 2018, NC experienced a statewide decline in suicides in 2019. An immediate increase in suicide deaths in Hurricane-affected counties versus Hurricane-unaffected counties was observed among women, people under age 65 and non-Hispanic black individuals, but there was no sustained change in the months after Hurricane Florence. Conclusions Although results did not indicate a strong post-Hurricane Florence impact on suicide rates, subgroup analysis suggests differential impacts of Hurricane Florence on several groups, warranting future follow-up

Multiwavelength Observations of Supersonic Plasma Blob Triggered by Reconnection Generated Velocity Pulse in AR10808

Using multi-wavelength observations of Solar and Heliospheric Observatory (SoHO)/Michelson Doppler Imager (MDI), Transition Region and Coronal Explorer (TRACE) 171 \AA, and H$\alpha$ from Culgoora Solar Observatory at Narrabri, Australia, we present a unique observational signature of a propagating supersonic plasma blob before an M6.2 class solar flare in AR10808 on 9th September 2005. The blob was observed between 05:27 UT to 05:32 UT with almost a constant shape for the first 2-3 minutes, and thereafter it quickly vanished in the corona. The observed lower bound speed of the blob is estimated as $\sim$215 km s$^{-1}$ in its dynamical phase. The evidence of the blob with almost similar shape and velocity concurrent in H$\alpha$ and TRACE 171 \AA\ supports its formation by multi-temperature plasma. The energy release by a recurrent 3-D reconnection process via the separator dome below the magnetic null point, between the emerging flux and pre-existing field lines in the lower solar atmosphere, is found to be the driver of a radial velocity pulse outwards that accelerates this plasma blob in the solar atmosphere. In support of identification of the possible driver of the observed eruption, we solve the two-dimensional ideal magnetohydrodynamic equations numerically to simulate the observed supersonic plasma blob. The numerical modelling closely match the observed velocity, evolution of multi-temperature plasma, and quick vanishing of the blob found in the observations. Under typical coronal conditions, such blobs may also carry an energy flux of 7.0$\times10^{6}$ ergs cm$^{-2}$ s$^{-1}$ to re-balance the coronal losses above active regions.Comment: Solar Physics; 22 Pages; 8 Figure

Innovations in suicide prevention research (INSPIRE): a protocol for a population-based case–control study

Background Suicide deaths have been increasing for the past 20 years in the USA resulting in 45 979 deaths in 2020, a 29% increase since 1999. Lack of data linkage between entities with potential to implement large suicide prevention initiatives (health insurers, health institutions and corrections) is a barrier to developing an integrated framework for suicide prevention. Objectives Data linkage between death records and several large administrative datasets to (1) estimate associations between risk factors and suicide outcomes, (2) develop predictive algorithms and (3) establish long-term data linkage workflow to ensure ongoing suicide surveillance. Methods We will combine six data sources from North Carolina, the 10th most populous state in the USA, from 2006 onward, including death certificate records, violent deaths reporting system, large private health insurance claims data, Medicaid claims data, University of North Carolina electronic health records and data on justice involved individuals released from incarceration. We will determine the incidence of death from suicide, suicide attempts and ideation in the four subpopulations to establish benchmarks. We will use a nested case–control design with incidence density-matched population-based controls to (1) identify short-term and long-term risk factors associated with suicide attempts and mortality and (2) develop machine learning-based predictive algorithms to identify individuals at risk of suicide deaths. Discussion We will address gaps from prior studies by establishing an in-depth linked suicide surveillance system integrating multiple large, comprehensive databases that permit establishment of benchmarks, identification of predictors, evaluation of prevention efforts and establishment of long-term surveillance workflow protocols

Comparative Analysis of Calcineurin Inhibitor-Based Methotrexate and Mycophenolate Mofetil-Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P <.001) and grade III to IV acute GVHD (RR, 1.93; P =.006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P =.008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results

Toward a 21st-century health care system: Recommendations for health care reform

The coverage, cost, and quality problems of the U.S. health care system are evident. Sustainable health care reform must go beyond financing expanded access to care to substantially changing the organization and delivery of care. The FRESH-Thinking Project (www.fresh-thinking.org) held a series of workshops during which physicians, health policy experts, health insurance executives, business leaders, hospital administrators, economists, and others who represent diverse perspectives came together. This group agreed that the following 8 recommendations are fundamental to successful reform: 1. Replace the current fee-for-service payment system with a payment system that encourages and rewards innovation in the efficient delivery of quality care. The new payment system should invest in the development of outcome measures to guide payment. 2. Establish a securely funded, independent agency to sponsor and evaluate research on the comparative effectiveness of drugs, devices, and other medical interventions. 3. Simplify and rationalize federal and state laws and regulations to facilitate organizational innovation, support care coordination, and streamline financial and administrative functions. 4. Develop a health information technology infrastructure with national standards of interoperability to promote data exchange. 5. Create a national health database with the participation of all payers, delivery systems, and others who own health care data. Agree on methods to make de-identified information from this database on clinical interventions, patient outcomes, and costs available to researchers. 6. Identify revenue sources, including a cap on the tax exclusion of employer-based health insurance, to subsidize health care coverage with the goal of insuring all Americans. 7. Create state or regional insurance exchanges to pool risk, so that Americans without access to employer-based or other group insurance could obtain a standard benefits package through these exchanges. Employers should also be allowed to participate in these exchanges for their employees' coverage. 8. Create a health coverage board with broad stakeholder representation to determine and periodically update the affordable standard benefit package available through state or regional insurance exchanges

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion

Search for jet extinction in the inclusive jet-pT spectrum from proton-proton collisions at s=8 TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.The first search at the LHC for the extinction of QCD jet production is presented, using data collected with the CMS detector corresponding to an integrated luminosity of 10.7  fb−1 of proton-proton collisions at a center-of-mass energy of 8 TeV. The extinction model studied in this analysis is motivated by the search for signatures of strong gravity at the TeV scale (terascale gravity) and assumes the existence of string couplings in the strong-coupling limit. In this limit, the string model predicts the suppression of all high-transverse-momentum standard model processes, including jet production, beyond a certain energy scale. To test this prediction, the measured transverse-momentum spectrum is compared to the theoretical prediction of the standard model. No significant deficit of events is found at high transverse momentum. A 95% confidence level lower limit of 3.3 TeV is set on the extinction mass scale