Lowering β-Amyloid Levels Rescues Learning and Memory in a Down Syndrome Mouse Model

β-amyloid levels are elevated in Down syndrome (DS) patients throughout life and are believed to cause Alzheimer's disease (AD) in adult members of this population. However, it is not known if β-amyloid contributes to intellectual disability in younger individuals. We used a γ-secretase inhibitor to lower β-amyloid levels in young mice that model DS. This treatment corrected learning deficits characteristic of these mice, suggesting that β-amyloid-lowering therapies might improve cognitive function in young DS patients

Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae

It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining ≥5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Controlling factors for the spatial variability of soil magnetic susceptibility across England and Wales

We review the nature and importance of soil factors implicated in the formation of secondary ferrimagnetic minerals in soils and palaeosols worldwide. The findings are examined with respect to temperate regions through a comprehensive analysis of over 5000 samples of surface soil from England and Wales taken from a 5 × 5 km grid. Over 30 soil and environmental attributes are considered for each sample as proxies for soil forming factors. Measurements of low field magnetic susceptibility (mass specific) and frequency dependent susceptibility (mass specific and percentage) on each sample provide estimates of the concentration and grain size of ferrimagnetic minerals. Maps of soil magnetism across England and Wales show non-random distributions and clusters. One subset of data is clearly linked to contamination from atmospheric pollution, and excluded from subsequent analyses. The concentration of ferrimagnetic minerals in the non-polluted set is broadly proportional to the concentration of minerals falling into the viscous superparamagnetic domain size range (~ 15–25 nm). This set shows clusters of high magnetic concentrations particularly over specific parent materials such as schists and slates, mudstones and limesto

Single Rapamycin Administration Induces Prolonged Downward Shift in Defended Body Weight in Rats

Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy

DAPT raises APP-CTF levels and lowers Aβ levels in brains of 4-month-old Ts65Dn mice.

<p>Four-month-old Ts65Dn mice and wild type colony mate controls were treated with vehicle or DAPT (100 mg/kg/day) for 4 days. (A) Representative western blots of APP, CTFs and β-actin from control (ctrl) and Ts65Dn (Ts) mice. (B) Left panel, quantification of APP (Students t-test, mean±s.e.m.,unpaired, two-tailed, n = 8 per group). Ctrl+Vehicle vs. Ts+Vehicle, p = 0.0003; Ctrl+DAPT vs. Ts+DAPT, p = 0.0002; Ctrl+Vehicle vs. Ts+DAPT, p = 0.0001; Ctrl+DAPT vs. Ts+Vehicle, p = 0.0006. Right panel, combined (C99, C89 and C83) CTFs (all means differ significantly, n = 8, 1-way ANOVA, p = 0.0002; significant differences between individual pairs of mean calculated by Students t-test, mean±s.e.m., unpaired, two-tailed). (C) Aβ40 and Aβ42 quantification from control and Ts65Dn mice. Left panel, Aβ40 (Students t-test, mean±s.e.m., unpaired, two-tailed, n = 6 per group); Ctrl+Vehicle vs. Ts+Vehicle, p = 0.0173; Ctrl+Vehicle vs. Ctrl+DAPT, p = 0.0043; Ctrl+DAPT vs. Ts+Vehicle, p = 0.0079; Ts+Vehicle vs. Ts+DAPT, p = 0.0082. Right panel, Aβ42 (Students t-test, mean±s.e.m., unpaired, two-tailed, n = 6 per group); Ctrl+Vehicle vs. Ts+Vehicle, p = 0.0169; Ctrl+DAPT vs. Ts+Vehicle, p = 0.0003; Ts+Vehicle vs. Ts+DAPT, p = 0.0052.</p

DAPT reverses cognitive deficits in 4-month-old Ts65Dn mice in the Morris water maze.

<p>DAPT was administered to Ts65Dn and control mice (100 mg/kg/day) two days prior to, and throughout, the maze testing. (A) Hidden platform test, latency to reach platform during training. (B) Probe trial on day 12, number of platform crossings. (C) Visible platform test, latency to reach platform. (D) Thigmotaxis. Statistical Analysis: n = 6 for all groups (A–D). (A) 2-way ANOVA with repeated measures revealed a main effect of genotype F1,20 = 11.31, p = 0.003 & Day F10,200 = 4.90, p = 3.00E-06 and an interaction between genotype and DAPT F1,20 = 7.73, p = 0.012. Post-hoc planned comparison test between Ts65Dn+vehicle and all 3 other groups (Ts65Dn+vehicle vs. Ts65Dn+DAPT p = 0.02, Ts65Dn+vehicle vs. control+vehicle p = 0.0003, Ts65Dn+vehicle vs. control+DAPT p = 0.008, n = 6 in all groups for all figures). (B) 2-way ANOVA for number of target platform crossings revealed an interaction between genotype and DAPT F1,20 = 8.46, p = 0.009. Post-hoc planned comparison test revealed a significant difference between Ts65Dn+vehicle vs. Ts65Dn+DAPT p = 0.01 and between Ts65Dn+vehicle vs. control+vehicle p = 0.007. No significant differences were observed for number of crossings of the analogous, virtual opposite platform location (not shown). (C) 2-way ANOVA with repeated measures revealed significant effects of genotype, F1,20 = 9.91, p = 0.005 and day, F10,200 = 21.42, p = 0.001, as well as a significant interaction between genotype and DAPT, F1,20 = 5.43, p = 0.03. Post-hoc planned comparison test revealed significant differences between Ts65Dn+vehicle vs. all 3 other groups (vs. Ts65Dn+DAPT p = 0.04, vs. control+vehicle p = 0.003, and vs. control+DAPT p = 0.005). (D) 2-way ANOVA with repeated measures revealed main effects of genotype, F1,20 = 5.13, p = 0.03 & day F10,200 = 21.94, p<1.00E-06 with an interaction between genotype and DAPT, F1,20 = 5.43, p = 0.03. Post-hoc planned comparison test revealed only a significant difference between Ts65Dn+vehicle vs. control+vehicle p = 0.004.</p

A short pre-conception bout of predation risk affects both children and grandchildren

Abstract Traumatic events that affect physiology and behavior in the current generation may also impact future generations. We demonstrate that an ecologically realistic degree of predation risk prior to conception causes lasting changes in the first filial (F1) and second filial (F2) generations. We exposed male and female mice to a live rat (predator stress) or control (non-predator) condition for 5 min. Ten days later, stressed males and females were bred together as were control males and females. Adult F1 offspring from preconception-stressed parents responded to a mild stressor with more anxiety-like behavior and hyperarousal than offspring from control parents. Exposing these F1 offspring to the mild stressor increased neuronal activity (cFOS) in the hippocampus and altered glucocorticoid system function peripherally (plasma corticosterone levels). Even without the mild stressor, F1 offspring from preconception-stressed parents still exhibited more anxiety-like behaviors than controls. Cross-fostering studies confirmed that preconception stress, not maternal social environment, determined offspring behavioral phenotype. The effects of preconception parental stress were also unexpectedly persistent and produced similar behavioral phenotypes in the F2 offspring. Our data illustrate that a surprisingly small amount of preconception predator stress alters the brain, physiology, and behavior of future generations. A better understanding of the ‘long shadow’ cast by fearful events is critical for understanding the adaptive costs and benefits of transgenerational plasticity. It also suggests the intriguing possibility that similar risk-induced changes are the rule rather than the exception in free-living organisms, and that such multigenerational impacts are as ubiquitous as they are cryptic