Liver X receptor-dependent inhibition of microglial nitric oxide synthase 2

Background The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis. Methods The effect of LXR activation on microglia and central nervous system (CNS) inflammation was studied using a synthetic LXR agonist in cultured microglia, a microglial cell line and experimental allergic encephalomyelitis (EAE), an animal model of CNS inflammation. Results LXR activation inhibited nitric oxide synthase 2, inducible (Nos2) expression and nitric oxide production in lipopolysaccharide (LPS)-stimulated microglia. Inhibition of microglial activation in response to interferon-γ was less reliable. In LPS-stimulated cells, LXR activation did not inhibit nuclear translocation of NF-kappaB1 p50. Instead, LXR-dependent Nos2 repression was associated with inhibition of histone 4 acetylation and inhibition of NF-kappaB1 p50 binding at the Nos2 promoter. Histone acetylation and NF-kappaB1 p50 binding were mechanistically linked, and histone deacetylase (HDAC) activity appeared to be important for LXR-dependent transcriptional repression of Nos2. Analysis of CNS gene expression in animals undergoing EAE showed that the expressions of Lxr and LXR-dependent genes were downregulated during CNS inflammation. Nevertheless, administration of LXR agonist GW3965 during the effector phase of EAE delayed the onset of clinical disease and reversed the diminished expression of LXR-dependent reverse cholesterol transport genes. However, the CNS expressions of Nos2 and other inflammatory genes were not significantly inhibited by LXR activation in EAE, and clinical disease severity was comparable to vehicle controls at later time points in LXR agonist treated animals. Conclusions LXR can be targeted to modulate microglial activation. LXR-dependent repression of inflammatory genes may be stimulus-dependent and impaired by HDAC inhibition. Endogenous LXR activity does not appear to modulate CNS inflammation, but LXR activity can be partially restored in the CNS by administration of exogenous LXR agonist with an impact on clinical disease severity at early, but not late, time points in EAE

A Poly(cobaloxime)/Carbon Nanotube Electrode: Freestanding Buckypaper with Polymer-Enhanced H2-Evolution Performance.

A freestanding H2-evolution electrode consisting of a copolymer-embedded cobaloxime integrated into a multiwall carbon nanotube matrix by π-π interactions is reported. This electrode is straightforward to assemble and displays high activity towards hydrogen evolution in near-neutral pH solution under inert and aerobic conditions, with a cobalt-based turnover number (TON(Co)) of up to 420. An analogous electrode with a monomeric cobaloxime showed less activity with a TON(Co) of only 80. These results suggest that, in addition to the high surface area of the porous network of the buckypaper, the polymeric scaffold provides a stabilizing environment to the catalyst, leading to further enhancement in catalytic performance. We have therefore established that the use of a multifunctional copolymeric architecture is a viable strategy to enhance the performance of molecular electrocatalysts.We acknowledge support by the Christian Doppler Research Association (Austrian Federal Ministry of Science, Research and Economy and National Foundation for Research, Technology and Development), the OMV Group, the EPSRC, the BBSRC (Grant BB/K010220/1) and the Woolf Fisher Trust in New Zealand and the Cambridge Trusts. We also thank the National EPSRC XPS User’s Service (NEXUS) at Newcastle University, UK.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/anie.20151137

Supramolecular electrode assemblies for bioelectrochemistry

For more than three decades, the field of bioelectrochemistry has provided novel insights into the catalytic mechanisms of enzymes, the principles that govern biological electron transfer, and has elucidated the basic principles for bioelectrocatalytic systems. Progress in biochemistry, bionanotechnology, and our ever increasing ability to control the chemistry and structure of electrode surfaces has enabled the study of ever more complex systems with bioelectrochemistry. This feature article highlights developments over the last decade, where supramolecular approaches have been employed to develop electrode assemblies that increase enzyme loading on the electrode or create more biocompatible environments for membrane enzymes. Two approaches are particularly highlighted: the use of layer-by-layer assembly, and the modification of electrodes with planar lipid membranes

Enhancing Cognition in Older Persons with Depression or Anxiety with a Combination of Mindfulness-Based Stress Reduction (MBSR) and Transcranial Direct Current Stimulation (tDCS): Results of a Pilot Randomized Clinical Trial.

OBJECTIVES: Individuals with subjective memory complaints and symptoms of depression and/or anxiety are at high risk for further cognitive decline, and possible progression to dementia. Low-burden interventions to help slow or prevent cognitive decline in this high-risk group are needed. The objective of this study is to assess the feasibility of combining Mindfulness-Based Stress Reduction (MBSR) with transcranial direct current stimulation (tDCS) to increase putative benefits of MBSR for cognitive function and everyday mindfulness in depressed or anxious older adults with subjective cognitive decline. METHODS: We conducted a two-site pilot double-blind randomized sham-controlled trial, combining active MBSR with either active or sham tDCS. The intervention included weekly in-class group sessions at the local university hospital and daily at-home practice. Anodal tDCS was applied for 30 min during MBSR meditative practice, both in-class and at-home. RESULTS: Twenty-six individuals with subjective cognitive complaints and symptoms of depression and/or anxiety were randomized to active (n = 12) or sham tDCS (n = 14). The combination of MBSR and tDCS was safe and well tolerated, though at-home adherence and in-class attendance were variable. While they were not statistically significant, the largest effect sizes for active vs. sham tDCS were for everyday mindfulness (d = 0.6) and social functioning (d = 0.9) (F (1,21) = 3.68, p = 0.07 and F (1,21) = 3.9, p = 0.06, respectively). CONCLUSIONS: Our findings suggest that it is feasible and safe to combine tDCS with MBSR in older depressed and anxious adults, including during remote, at-home use. Furthermore, tDCS may enhance MBSR via transferring its meditative learning and practice into increases in everyday mindfulness. Future studies need to improve adherence to MBSR with tDCS. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03653351 and NCT03680664). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12671-021-01764-9

Broad repetitive transcranial magnetic stimulation (rTMS) of the precuneus in Alzheimers disease: A rationale and study design.

INTRODUCTION: Brain network dysfunction, particularly within the default mode network (DMN), is an increasingly apparent contributor to the clinical progression of Alzheimers disease (AD). Repetitive transcranial magnetic stimulation (rTMS) can target key DMN hubs, maintain signaling function, and delay or improve clinical outcomes in AD. Here, we present the rationale and design of a study using off-the-shelf equipment and the latest clinical evidence to expand on prior rTMS work and reduce participant burden in the process. METHODS: We will conduct a two-stage trial of large-coil rTMS targeting the precuneus (a key hub in the DMN affected by AD) in 54 participants with mild to moderate Alzheimers Clinical Syndrome focused primarily on determining tolerability and feasibility and secondarily focused on determining short-term efficacy for memory. The first stage will involve 5 to 10 participants receiving open-label active treatment to refine the protocol. The following second stage will consist of a 1:1 randomized, double-blind, sham-controlled clinical trial to study feasibility and tolerability while exploring target engagement and short-term efficacy for memory. Participants will undergo 16 total rTMS brain stimulation sessions over the course of 5 weeks. A full course of open-label active treatment will be offered as an extension to the sham group after unblinding. Outcomes will focus on completion rates and adverse events to demonstrate feasibility and tolerability. Further exploratory outcomes will include neuropsychological assessments, electroencephalography, neuroimaging, and blood biomarkers to demonstrate the feasibility of collection and explore preliminary changes in these measures. RESULTS: We anticipate this treatment is feasible and tolerable and may show evidence of target engagement and clinical improvement. DISCUSSION: Should we achieve expected positive outcomes in feasibility and tolerability, this will justify future work focusing on clear demonstrations of clinical efficacy and biomarker engagement, as well as enhancement of generalizability and scalability. HIGHLIGHTS: Induction-to-maintenance repetitive transcranial magnetic stimulation (rTMS) of the precuneus is a promising treatment for Alzheimers disease (AD), though recent methods require intensive personalization.We propose here a trial design of precuneus rTMS in mild-to-early-moderate AD dementia using exclusively off-the-shelf equipment and protocol modifications to reduce participant burden.Our two novel modifications from prior work are (1) using a larger rTMS coil, and (2) consolidating the induction phase of treatment.This trial focuses primarily on tolerability and feasibility while exploring clinical measures of efficacy and biomarkers of target engagement.Our trial is registered at ClinicalTrials.gov NCT06597942

Peripheral Alzheimer's Disease Biomarkers Are Related to Change in Subjective Memory in Older Women with Cardiovascular Risk Factors in a Trial of Yoga vs. Memory Training: Lien établi entre les biomarqueurs périphériques de la maladie d'Alzheimer et l'amélioration de la mémoire subjective chez les femmes âgées présentant des facteurs de risque cardiovasculaire dans le cadre d'un essai comparant le yoga à l'entraînement de la mémoire.

ObjectivesOlder women with cardiovascular risk factors and subjective memory complaints are at greater risk for Alzheimer's disease (AD). We examined the changes in AD peripheral biomarkers, including phosphorylated-tau (p-tau), Aβ40, Aβ42, and Aβ42/40 ratio, in a randomized controlled trial of Kundalini yoga (KY) versus memory enhancement training (MET) in aging women at risk for AD.MethodsWe recruited women (50+ years) with subjective memory complaints and high cardiovascular risk as defined by the ACC/AHA Guideline on the Assessment of Cardiovascular Risk. Participants were randomized into KY versus MET, each lasting for 12 weeks, with a 24-week follow-up. We obtained blood samples at baseline and week 24 and measured Aβ 40, Aβ 42, and p-Tau. Participants completed the Memory Functioning Questionnaire (MFQ) to assess subjective memory at baseline and follow-up.ResultsA total of 79 patients (KY = 40; MET = 39) were randomized, and biomarker data were available for 56 participants (KY = 24; MET = 32) at baseline and the 24-week follow-up. There were no group differences in AD biomarkers at baseline or at 24-week follow-up, and there were no significant changes in AD biomarkers from baseline to 24-week follow-up. Higher baseline levels of Aβ40 and Aβ42 were significantly associated with an improvement in subjective memory (MFQ Frequency of Forgetting and Seriousness of Forgetting) at follow-up. There was no significant association of the Aβ42/40 ratio and p-tau with changes in subjective memory.ConclusionsOur findings indicate that peripheral Aβ40 and Aβ42 levels are associated with improvement in memory self-awareness, particularly the reported frequency and perceived severity of forgetting. These levels may serve as potential biomarkers, reflecting underlying biological effects that could be utilized in future assessments. Further research is needed to determine how to successfully utilize peripheral biomarkers and subjective memory complaints to identify at-risk populations