Evaluating circadian dysfunction in mouse models of Alzheimer\u27s disease: Where do we stand?

Circadian dysfunction has been described in patients with symptomatic Alzheimer\u27s disease (AD), as well as in presymptomatic phases of the disease. Modeling this circadian dysfunction in mouse models would provide an optimal platform for understanding mechanisms and developing therapies. While numerous studies have examined behavioral circadian function, and in some cases clock gene oscillation, in mouse models of AD, the results are variable and inconsistent across models, ages, and conditions. Ultimately, circadian changes observed in APP/PS1 models are inconsistent across studies and do not always replicate circadian phenotypes observed in human AD. Other models, including the 3xTG mouse, tau transgenic lines, and the accelerated aging SAMP8 line, show circadian phenotypes more consistent with human AD, although the literature is either inconsistent or minimal. We summarize these data and provide some recommendations to improve and standardize future studies of circadian function in AD mouse models

A single-nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor alters the development of host immunity

The acquisition of malaria immunity is both remarkably slow and unpredictable. At present, we know little about the malaria parasite genes that influence the host\u27s ability to mount a protective immune response. Here, we show that a single-nucleotide polymorphism (SNP) resulting in a single amino acid change (S to F) in an ApiAP2 transcription factor in the rodent malaria parasit

Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer\u27s disease

A promising new therapeutic target for the treatment of Alzheimer\u27s disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary A

Evolution of Mass Outflow in Protostars

We have surveyed 84 Class 0, Class I, and flat-spectrum protostars in mid-infrared [Si II], [Fe II] and [S I] line emission, and 11 of these in far-infrared [O I] emission. We use the results to derive their mass outflow rates. Thereby we observe a strong correlation of mass outflow rates with bolometric luminosity, and with the inferred mass accretion rates of the central objects, which continues through the Class 0 range the trend observed in Class II young stellar objects. Along this trend from large to small mass-flow rates, the different classes of young stellar objects lie in the sequence Class 0 -- Class I/flat-spectrum -- Class II, indicating that the trend is an evolutionary sequence in which mass outflow and accretion rates decrease together with increasing age, while maintaining rough proportionality. The survey results include two which are key tests of magnetocentrifugal outflow-acceleration mechanisms: the distribution of the outflow/accretion branching ratio b, and limits on the distribution of outflow speeds. Neither rule out any of the three leading outflow-acceleration, angular-momentum-ejection mechanisms, but they provide some evidence that disk winds and accretion-powered stellar winds (APSWs) operate in many protostars. An upper edge observed in the branching-ratio distribution is consistent with the upper bound of b = 0.6 found in models of APSWs, and a large fraction (0.31) of the sample have branching ratio sufficiently small that only disk winds, launched on scales as large as several AU, have been demonstrated to account for them.Comment: Version submitted to ApJ: 36 pages, 3 tables, 8 figure

Does the peer-led Honest, Open, Proud program reduce stigma’s impact for everyone? An individual participant data meta-regression analysis

Purpose Many people with mental illness experience self-stigma and stigma-related stress and struggle with decisions whether to disclose their condition to others. The peer-led Honest, Open, Proud (HOP) group program supports them in their disclosure decisions. In randomized controlled trials, HOP has shown positive effects on self-stigma and stigma stress on average. This study examined individual predictors of HOP outcomes and tested the hypothesis that stigma stress reduction at the end of HOP mediates positive HOP effects at follow-up. Methods Six RCTs were included with data at baseline, post (after the HOP program) and at 3- or 4-week follow-up. Baseline variables were entered in meta-regression models to predict change in self-stigma, stigma stress, depressive symptoms and quality of life among HOP participants. Mediation models examined change in stigma stress (post) as a mediator of HOP effects on self-stigma, depressive symptoms, and quality of life at follow-up. Results More shame at baseline, and for some outcomes reduced empowerment, predicted reduced HOP effects on stigma stress, self-stigma, depressive symptoms, and quality of life. Younger age was related to greater improvements in stigma stress after the HOP program. Stigma stress reductions at the end of HOP mediated positive effects on self-stigma, depressive symptoms and quality of life at follow-up. Conclusion Participants who are initially less burdened by shame may benefit more from HOP. Stigma stress reduction could be a key mechanism of change that mediates effects on more distal outcomes. Implications for the further development of HOP are discussed

REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, includin

Finding substructures in protostellar disks in Ophiuchus

High-resolution, millimeter observations of disks at the protoplanetary stage reveal substructures such as gaps, rings, arcs, spirals, and cavities. While many protoplanetary disks host such substructures, only a few at the younger protostellar stage have shown similar features. We present a detailed search for early disk substructures in ALMA 1.3 and 0.87~mm observations of ten protostellar disks in the Ophiuchus star-forming region. Of this sample, four disks have identified substructure, two appear to be smooth disks, and four are considered ambiguous. The structured disks have wide Gaussian-like rings ($\sigma_R/R_{\mathrm{disk}}\sim0.26$) with low contrasts ($C<0.2$) above a smooth disk profile, in comparison to protoplanetary disks where rings tend to be narrow and have a wide variety of contrasts ($\sigma_R/R_{\mathrm{disk}}\sim0.08$ and $C$ ranges from $0-1$). The four protostellar disks with the identified substructures are among the brightest sources in the Ophiuchus sample, in agreement with trends observed for protoplanetary disks. These observations indicate that substructures in protostellar disks may be common in brighter disks. The presence of substructures at the earliest stages suggests an early start for dust grain growth and, subsequently, planet formation. The evolution of these protostellar substructures is hypothesized in two potential pathways: (1) the rings are the sites of early planet formation, and the later observed protoplanetary disk ring-gap pairs are secondary features, or (2) the rings evolve over the disk lifetime to become those observed at the protoplanetary disk stage.Comment: Accepted by ApJ, 22 pages, 10 figure

Dural lymphatics regulate clearance of extracellular tau from the CNS

BackgroundAlzheimer's disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid- (A) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD). The prion hypothesis suggests that after an initial trigger event, misfolded forms of tau are released into the extracellular space, where they spread through different brain regions, enter cells, and seeding previously normal forms. Thus understanding mechanisms regulating the clearance of extracellular tau from the CNS is important. The discovery of a true lymphatic system in the dura and its potential role in mediating A pathology prompted us to investigate its role in regulating extracellular tau clearance.MethodsTo study clearance of extracellular tau from the brain, we conjugated monomeric human tau with a near-infrared dye cypate, and injected this labeled tau in the parenchyma of both wild-type and K14-VEGFR3-Ig transgenic mice, which lack a functional CNS lymphatic system. Following injection we performed longitudinal imaging using fluorescence molecular tomography (FMT) and quantified fluorescence to calculate clearance of tau from the brain. To complement this, we also measured tau clearance to the periphery by measuring plasma tau in both groups of mice.ResultsOur results show that a significantly higher amount of tau is retained in the brains of K14-VEGFR3-Ig vs. wild type mice at 48 and 72h post-injection and its subsequent clearance to the periphery is delayed. We found that clearance of reference tracer human serum albumin (HSA) was also significantly delayed in the K14-VEGFR3-Ig mice.ConclusionsThe dural lymphatic system appears to play an important role in clearance of extracellular tau, since tau clearance is impaired in the absence of functional lymphatics. Based on our baseline characterization of extracellular tau clearance, future studies are warranted to look at the interaction between tau pathology and efficiency of lymphatic function.Peer reviewe