Dihydropyrimidine-thiones and clioquinol synergize to target beta-amyloid cellular pathologies through a metal-dependent mechanism

The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer’s disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity. Cotreatment ameliorated Aβ toxicity by reducing Aβ levels and restoring functional vesicle trafficking. Notably, these low doses significantly reduced deleterious off-target effects caused by CQ on mitochondria at higher concentrations. Both single and combinatorial treatments also reduced death of neurons expressing Aβ in a nematode, indicating that DHPM-thiones target a conserved protective mechanism. Furthermore, this conserved activity suggests that expression of the Aβ peptide causes similar cellular pathologies from yeast to neurons. Our identification of a new cytoprotective scaffold that requires metal-binding underscores the critical role of metal phenomenology in mediating Aβ toxicity. Additionally, our findings demonstrate the valuable potential of synergistic compounds to enhance on-target activities, while mitigating deleterious off-target effects. The identification and prosecution of synergistic compounds could prove useful for developing AD therapeutics where combination therapies may be required to antagonize diverse pathologies.D.F.T was funded by NRSA Fellowship NIH 5F32NS061419. D.F.T. and S.L. were supported by WIBR funds in support of research on Regenerative Disease, the Picower/JPB Foundation, and the Edward N. and Della L. Thome Foundation. G.A.C. and S.L. were funded by a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award. L.E.B., R.T., and S.E.S. were funded by NIH GM086180, NIH GM067041, and NIH GM111625. (5F32NS061419 - NRSA Fellowship NIH; WIBR funds in support of research on Regenerative Disease; Picower/JPB Foundation; Edward N. and Della L. Thome Foundation; Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award; GM086180 - NIH; NIH GM067041 - NIH; NIH GM111625 - NIH)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705239/Accepted manuscrip

Alumina and Synthesis Intermediates Derived from Diethylkaluminum Amide, Benzaldehyde and Water

The reaction of diethylaluminum amide [Et2AINH2] with benzaldehyde in toluene produces a solution of ethylaluminoxane polymer [EtAlO] and hydrobenzamide [PhCH=NCH(Ph)N=CHPh]. Alumina then is precipitated by the addition of water. Transition aluminas that may be useful in heterogeneous catalyst applications are obtained after calcining. Details of the chemistry of solution intermediates according to 1H NMR and the properties of the alumina product according to surface area analyses and powder x-ray diffraction are described

Low-Density Granulocytes Are a Novel Immunopathological Feature in Both Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

Objective: To investigate whether low-density granulocytes (LDGs) are an immunophenotypic feature of patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD). Methods: Blood samples were collected from 20 patients with NMOSD and 17 patients with MS, as well as from 15 patients with Systemic Lupus Erythematosus (SLE) and 23 Healthy Donors (HD). We isolated peripheral blood mononuclear cells (PBMCs) with density gradient separation and stained the cells with antibodies against CD14, CD15, CD16, and CD45, and analyzed the cells by flow cytometry or imaging flow cytometry. We defined LDGs as CD14-CD15(high) and calculated their share in total PBMC leukocytes (CD45+) as well as the share of CD16(hi) LDGs. Clinical data on disease course, medication, and antibody status were obtained. Results: LDGs were significantly more common in MS and NMOSD than in HDs, comparable to SLE samples (median values HD 0.2%, MS 0.9%, NMOSD 2.1%, SLE 4.3%). 0/23 of the HDs, but 17/20 NMOSD and 11/17 MS samples as well as 13/15 SLE samples had at least 0.7 % LDGs. NMOSD patients without continuous immunosuppressive treatment had significantly more LDGs compared to their treated counterparts. LDG nuclear morphology ranged from segmented to rounded, suggesting a heterogeneity within the group. Conclusion: LDGs are a feature of the immunophenotype in some patients with MS and NMOSD

Evolution of Protoneutron Stars

We study the thermal and chemical evolution during the Kelvin-Helmholtz phase of the birth of a neutron star, employing neutrino opacities that are consistently calculated with the underlying equation of state (EOS). Expressions for the diffusion coefficients appropriate for general relativistic neutrino transport in the equilibrium diffusion approximation are derived. The diffusion coefficients are evaluated using a field-theoretical finite temperature EOS that includes the possible presence of hyperons. The variation of the diffusion coefficients is studied as a function of EOS and compositional parameters. We present results from numerical simulations of protoneutron star cooling for internal stellar properties as well as emitted neutrino energies and luminosities. We discuss the influence of the initial stellar model, the total mass, the underlying EOS, and the addition of hyperons on the evolution of the protoneutron star and upon the expected signal in terrestrial detectors.Comment: 67 pages, 25 figure

Mitigating the effects of omission errors on area and area change estimates

Information on Earth's land surface and change over time has never been easier to obtain, but making informed decisions to manage land well necessitates that this information is accurate and precise. In recent years, due largely to the inevitability of classification errors in remote sensing-based maps and the marked effects of these errors on subsequent area estimates, sample-based area estimates of land cover and land change have increased in importance and use. Area estimation of land cover and change by sampling is often made more efficient by a priori knowledge of the study area to be analyzed (e.g., stratification). Satellite data, obtained free of cost for virtually all of Earth's land surface, provide an excellent source for constructing landscape stratifications in the form of maps. Errors of omission, defined as sample units observed as land change but mapped as a stable class, may introduce considerable uncertainty in parameter estimates obtained from the sample data (e.g., area estimates of land change). The effects of omission errors are exacerbated in situations where the area of intact forest is large relative to the area of forest change, a common situation in countries that seek results-based payments for reductions in deforestation and associated carbon emissions. The presence of omission errors in such situations can preclude the acquisition of statistically valid evidence of a reduction in deforestation, and thus prevent payments. International donors and countries concerned with mitigating the effects of climate change are looking for guidance on how to reduce the effects of omission errors on area estimates of land change. This article presents the underlying reasons for the effects of omission errors on area estimates, case studies highlighting real-world examples of these effects, and proposes potential solutions. Practicable approaches to efficiently splitting large stable strata are presented that may reduce the effects of omission errors and immediately improve the quality of estimates. However, more research is needed before further recommendations can be provided on how to contain, mitigate and potentially eliminate the effects of omissions errors. © 2019 Elsevier Inc.This research was funded by support from the NASA Carbon Monitoring System ( NNX16AP26G ) and USGS/SilvaCarbon to Boston University (PI Pontus Olofsson). M.J. Sanz was supported by the Spanish Government through María de Maeztu excellence accreditation MDM-2017-0714

Inference with interference between units in an fMRI experiment of motor inhibition

An experimental unit is an opportunity to randomly apply or withhold a treatment. There is interference between units if the application of the treatment to one unit may also affect other units. In cognitive neuroscience, a common form of experiment presents a sequence of stimuli or requests for cognitive activity at random to each experimental subject and measures biological aspects of brain activity that follow these requests. Each subject is then many experimental units, and interference between units within an experimental subject is likely, in part because the stimuli follow one another quickly and in part because human subjects learn or become experienced or primed or bored as the experiment proceeds. We use a recent fMRI experiment concerned with the inhibition of motor activity to illustrate and further develop recently proposed methodology for inference in the presence of interference. A simulation evaluates the power of competing procedures.Comment: Published by Journal of the American Statistical Association at http://www.tandfonline.com/doi/full/10.1080/01621459.2012.655954 . R package cin (Causal Inference for Neuroscience) implementing the proposed method is freely available on CRAN at https://CRAN.R-project.org/package=ci

Generalized Vaidya Solutions

A large family of solutions, representing, in general, spherically symmetric Type II fluid, is presented, which includes most of the known solutions to the Einstein field equations, such as, the monopole-de Sitter-charged Vaidya ones.Comment: Gen. Relativ. Grav. 31 (1), 107-114 (1999

Differences in one-year health outcomes and resource utilization by definition of prolonged mechanical ventilation: a prospective cohort study

Abstract Introduction The outcomes of patients ventilated for longer than average are unclear, in part because of the lack of an accepted definition of prolonged mechanical ventilation (PMV). To better understand the implications of PMV provision, we compared one-year health outcomes between two common definitions of PMV as well as between PMV patients and those ventilated for shorter periods of time. Methods We conducted a secondary analysis of prospectively collected data from medical and surgical intensive care units at an academic tertiary care medical center. The study included 817 critically ill patients ventilated for ≥ 48 hours, 267 (33%) of whom received PMV based on receipt of a tracheostomy and ventilation for ≥ 96 hours. A total of 114 (14%) patients met the alternate definition of PMV by being ventilated for ≥ 21 days. Survival, functional status, and costs were measured at baseline and at 2, 6, and 12 months after discharge. Of one-year survivors, 71 (17%) were lost to follow up. Results PMV patients ventilated for ≥ 21 days had greater costs ($140,409 versus$143,389) and higher one-year mortality (58% versus 48%) than did PMV patients with tracheostomies who were ventilated for ≥ 96 hours. The majority of PMV deaths (58%) occurred after hospital discharge whereas 67% of PMV patients aged 65 years or older had died by one year. At one year PMV patients on average had limitations in two basic and five instrumental elements of functional status that exceeded both their pre-admission status and the one-year disability of those ventilated for < 96 hours. Costs per one-year survivor were $423,596,$266,105, and $165,075 for patients ventilated ≥ 21 days, ≥ 96 hours with a tracheostomy, and < 96 hours, respectively. Conclusion Contrasting definitions of PMV capture significantly different patient populations, with ≥ 21 days of ventilation specifying the most resource-intensive recipients of critical care. PMV patients, particularly the elderly, suffer from a significant burden of costly, chronic critical illness and are at high risk for death throughout the first year after intensive care