Rhythmicity of intestinal IgA responses confers oscillatory commensal microbiota mutualism.

Interactions between the mammalian host and commensal microbiota are enforced through a range of immune responses that confer metabolic benefits and promote tissue health and homeostasis. Immunoglobulin A (IgA) responses directly determine the composition of commensal species that colonize the intestinal tract but require substantial metabolic resources to fuel antibody production by tissue-resident plasma cells. Here, we demonstrate that IgA responses are subject to diurnal regulation over the course of a circadian day. Specifically, the magnitude of IgA secretion, as well as the transcriptome of intestinal IgA+ plasma cells, was found to exhibit rhythmicity. Oscillatory IgA responses were found to be entrained by time of feeding and were also found to be in part coordinated by the plasma cell-intrinsic circadian clock via deletion of the master clock gene Arntl. Moreover, reciprocal interactions between the host and microbiota dictated oscillatory dynamics among the commensal microbial community and its associated transcriptional and metabolic activity in an IgA-dependent manner. Together, our findings suggest that circadian networks comprising intestinal IgA, diet, and the microbiota converge to align circadian biology in the intestinal tract and to ensure host-microbial mutualism.

Do Concentration or Activity of Selenoproteins Change in Acute Stroke Patients? A Systematic Review and Meta-Analyses.

INTRODUCTION: Stroke is characterized by deleterious oxidative stress. Selenoprotein enzymes are essential endogenous antioxidants, and detailed insight into their role after stroke could define new therapeutic treatments. This systematic review aimed to elucidate how blood selenoprotein concentration and activity change in the acute phase of stroke. METHODS: We searched PubMed, EMBASE, and Medline databases for studies measuring serial blood selenoprotein concentration or activity in acute stroke patients or in stroke patients compared to non-stroke controls. Meta-analyses of studies stratified by the type of stroke, blood compartment, and type of selenoprotein measurement were conducted. RESULTS: Eighteen studies and data from 941 stroke patients and 708 non-stroke controls were included in this review. Glutathione peroxidase (GPx) was the only identified selenoprotein, and its activity was most frequently measured. Results from 12 studies and 693 patients showed that compared to non-stroke controls in acute ischaemic stroke patients, the GPx activity increased in haemolysate (standardized mean difference [SMD]: 0.27, 95% CI: 0.07-0.47) but decreased in plasma (mean difference [MD]: -1.08 U/L, 95% CI: -1.94 to -0.22) and serum (SMD: -0.54, 95% CI: -0.91 to -0.17). From 4 identified studies in 106 acute haemorrhagic stroke patients, the GPx activity decreased in haemolysate (SMD: -0.40, 95% CI: -0.68 to -0.13) and remained unchanged in plasma (MD: -0.10 U/L, 95% CI: -0.81 to 0.61) and serum (MD: -5.00 U/mL, 95% CI: -36.17 to 26.17) compared to non-stroke controls. Results from studies assessing the GPx activity in the haemolysate compartment were inconsistent and characterized by high heterogeneity. CONCLUSIONS: Our results suggest a reduction of the blood GPx activity in acute ischaemic stroke patients, a lack of evidence regarding a role for GPx in haemorrhagic stroke patients, and insufficient evidence for other selenoproteins.

The effects of digital cognitive behavioral therapy for insomnia on cognitive function: a randomized controlled trial.

STUDY OBJECTIVES: We sought to examine the impact of digital cognitive behavioral therapy (dCBT) for insomnia on both self-reported cognitive impairment and objective cognitive performance. METHODS: The Defining the Impact of Sleep improvement on Cognitive Outcomes (DISCO) trial was an online, two-arm, single-blind, randomized clinical trial of dCBT versus wait-list control. Participants were aged 25 years and older, met DSM-5 diagnostic criteria for insomnia disorder, and reported difficulties with concentration or memory. Assessments were carried out online at baseline, and 10 and 24 weeks post-randomization. The primary outcome measure was self-reported cognitive impairment, assessed with the British Columbia Cognitive Complaints Inventory (BC-CCI). Secondary outcomes included tests of cognitive performance, insomnia symptoms, cognitive failures, fatigue, sleepiness, depression, and anxiety. RESULTS: Four hundred and ten participants with insomnia were recruited and assigned to dCBT (N = 205) or wait-list control (N = 205). At 10 weeks post-randomization the estimated adjusted mean difference for the BC-CCI was -3.03 (95% CI: -3.60, -2.47; p < 0.0001, d = -0.86), indicating that participants in the dCBT group reported less cognitive impairment than the control group. These effects were maintained at 24 weeks (d = -0.96) and were mediated, in part, via reductions in insomnia severity and increased sleep efficiency. Treatment effects in favor of dCBT, at both 10 and 24 weeks, were found for insomnia severity, sleep efficiency, cognitive failures, fatigue, sleepiness, depression, and anxiety. We found no between-group differences in objective tests of cognitive performance. CONCLUSIONS: Our study shows that dCBT robustly decreases self-reported cognitive impairment at post-treatment and these effects are maintained at 6 months.

Cortical contributions to anticipatory postural adjustments in the trunk.

KEY POINTS: Increases in activity of trunk muscles that occur prior to, or concurrent with, a voluntary limb movement are termed anticipatory postural adjustments (APAs). APAs are important for maintaining postural stability in response to perturbations but the neural mechanisms underlying APAs remain unclear. Our results showed that corticospinal excitability of erector spinae (ES) muscle increased at 40 ms prior to rapid shoulder flexion, with a reduction in intracortical inhibition and no change in spinal excitability. Changes in corticospinal excitability were observed in ES, with similar excitability profiles between standing and lying positions, but were not observed in rectus abdominis. We suggest that the neural control of postural adjustments involves changes at a cortical level, which in part are due to reduced inhibition. ABSTRACT: Voluntary limb movements are associated with increases in trunk muscle activity, some of which occur within a time window considered too fast to be induced by sensory feedback; these increases are termed anticipatory postural adjustments (APAs). Although it is known that the function of APAs is to maintain postural stability in response to perturbations, excitability of the corticospinal projections to the trunk muscles during the APAs remains unclear. Thirty-four healthy subjects performed rapid shoulder flexion in response to a visual cue in standing and lying positions. Transcranial magnetic stimulation (TMS) was delivered over the trunk motor cortex to examine motor evoked potentials (MEPs) in erector spinae (ES) and in rectus abdominis (RA) muscles at several time points prior to the rise in electromyographic activity (EMG) of anterior deltoid (AD) muscle. TMS was also used to assess short-interval intracortical inhibition (SICI) and cervicomedullary MEPs (CMEPs) in ES in the standing position. MEPs in ES were larger at time points closer to the rise in AD EMG in both standing and lying positions, whereas MEPs in RA did not differ over the time course examined. Notably, SICI was reduced at time points closer to the rise in AD EMG, with no change in CMEPs. Our results demonstrate that increasing excitability of corticospinal projections to the trunk muscles prior to a voluntary limb movement is likely to be cortical in origin and is muscle specific.

Effects of digital Cognitive Behavioural Therapy for Insomnia on cognitive function: study protocol for a randomised controlled trial.

BACKGROUND: The daytime effects of insomnia pose a significant burden to patients and drive treatment seeking. In addition to subjective deficits, meta-analytic data show that patients experience reliable objective impairments across several cognitive domains. While Cognitive Behavioural Therapy for Insomnia (CBT-I) is an effective and scalable treatment, we know little about its impact upon cognitive function. Trials of CBT-I have typically used proxy measures for cognitive functioning, such as fatigue or work performance scales, and no study has assessed self-reported impairment in cognitive function as a primary outcome. Moreover, only a small number of studies have assessed objective cognitive performance, pre-to-post CBT-I, with mixed results. This study specifically aims to (1) investigate the impact of CBT-I on cognitive functioning, assessed through both self-reported impairment and objective performance measures, and (2) examine whether change in sleep mediates this impact. METHODS/DESIGN: We propose a randomised controlled trial of 404 community participants meeting criteria for Insomnia Disorder. In the DISCO trial (D efining the I mpact of improved S leep on CO gnitive function (DISCO)) participants will be randomised to digital automated CBT-I delivered by a web and/or mobile platform (in addition to treatment as usual (TAU)) or to a wait-list control (in addition to TAU). Online assessments will take place at 0 (baseline), 10 (post-treatment), and 24 (follow-up) weeks. At week 25, all participants allocated to the wait-list group will be offered digital CBT-I, at which point the controlled element of the trial will be complete. The primary outcome is self-reported cognitive impairment at post-treatment (10 weeks). Secondary outcomes include objective cognitive performance, insomnia severity, sleepiness, fatigue, and self-reported cognitive failures and emotional distress. All main analyses will be carried out on completion of follow-up assessments and will be based on the intention-to-treat principle. Further analyses will determine to what extent observed changes in self-reported cognitive impairment and objective cognitive performance are mediated by changes in sleep. The trial is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) based at Oxford University Hospitals NHS Trust and University of Oxford, and by the NIHR Oxford Health BRC. DISCUSSION: This study will be the first large-scale examination of the impact of digital CBT-I on self-reported cognitive impairment and objective cognitive performance. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN89237370 . Registered on 17 October 2016.

Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease.

In Parkinson's disease, misfolded α-synuclein accumulates, often in a ubiquitinated form, in neuronal inclusions termed Lewy bodies. An important outstanding question is whether ubiquitination in Lewy bodies is directly relevant to α-synuclein trafficking or turnover and Parkinson's pathogenesis. By comparative analysis in human postmortem brains, we found that ubiquitin immunoreactivity in Lewy bodies is largely due to K63-linked ubiquitin chains and markedly reduced in the substantia nigra compared with the neocortex. The ubiquitin staining in cells with Lewy bodies inversely correlated with the content and pathological localization of the deubiquitinase Usp8. Usp8 interacted and partly colocalized with α-synuclein in endosomal membranes and, both in cells and after purification, it deubiquitinated K63-linked chains on α-synuclein. Knockdown of Usp8 in the Drosophila eye reduced α-synuclein levels and α-synuclein-induced eye toxicity. Accordingly, in human cells, Usp8 knockdown increased the lysosomal degradation of α-synuclein. In the dopaminergic neurons of the Drosophila model, unlike knockdown of other deubiquitinases, Usp8 protected from α-synuclein-induced locomotor deficits and cell loss. These findings strongly suggest that removal of K63-linked ubiquitin chains on α-synuclein by Usp8 is a critical mechanism that reduces its lysosomal degradation in dopaminergic neurons and may contribute to α-synuclein accumulation in Lewy body disease.