Notes

GlcNAc-Asn (GNA) can be a biomarker for NGLY1 insufficiency.
Furthermore, the active site of CafB crystals grown under zinc-limiting conditions has a novel conformation in which the solvent-exposed catalytic cysteine (C116) is flipped out of the metal coordination sphere, facilitating release of the zinc ion. Taken together, our results suggest that A. fumigatus use sophisticated activity-inhibiting strategies to enhance its survival during infection.Mavoglurant binds to same allosteric site on metabotropic glutamate receptor 5 (mGluR5) as [11C]-ABP688, a radioligand. This open-label, single-center pilot study estimates extent of occupancy of mGluR5 receptors following single oral doses of mavoglurant, using [11C]-ABP688 positron emission tomography (PET) imaging, in six healthy males aged 20-40 years. This study comprised three periods and six subjects were divided into two cohorts. On Day 1 (Period 1), baseline clinical data and safety samples were obtained along with PET scan. During Period 2 (1-7 days after Period 1), cohort 1 and 2 received mavoglurant 25 mg and 100 mg, respectively. During Period 3 (7 days after Period 2), cohort 1 and 2 received mavoglurant 200 mg and 400 mg, respectively. Mavoglurant showed the highest distribution volumes in the cingulate region with lower uptake in cerebellum and white matter, possibly because myelinated axonal sheets maybe devoid of mGlu5 receptors. Maximum concentrations of mavoglurant were observed around 2-3.25 h post-dose. Mavoglurant passed the blood-brain barrier and induced dose- and exposure-dependent displacement of [11C]-ABP688 from the mGluR5 receptors, 3-4 h post-administration (27%, 59%, 74%, 85% receptor occupancy for mavoglurant 25 mg, 100 mg, 200 mg, 400 mg dose, respectively). WM-1119 molecular weight There were no severe adverse effects or clinically significant changes in safety parameters. This is the first human receptor occupancy study completed with Mavoglurant. It served to guide the dosing of mavoglurant in the past and currently ongoing clinical studies. Furthermore, it confirms the utility of [11C]-ABP688 as a unique tool to study drug-induced occupancy of mGlu5 receptors in the living human brain.Mounting evidence shows that brain functions and cognitive states are dynamically changing even in the resting state rather than remaining at a single constant state. Due to the relatively small changes in BOLD (blood-oxygen-level-dependent) signals across tasks, it is difficult to detect the change of cognitive status without requiring prior knowledge of the experimental design. To address this challenge, we present a dynamic graph learning approach to generate an ensemble of subject-specific dynamic graph embeddings, which allows us to use brain networks to disentangle cognitive events more accurately than using raw BOLD signals. The backbone of our method is essentially a representation learning process for projecting BOLD signals into a latent vertex-temporal domain with the greater biological underpinning of brain activities. Specifically, the learned representation domain is jointly formed by (1) a set of harmonic waves that govern the topology of whole-brain functional connectivities and (2) a set of Fourier bases that characterize the temporal dynamics of functional changes. In this regard, our dynamic graph embeddings provide a new methodology to investigate how these self-organized functional fluctuation patterns oscillate along with the evolving cognitive status. We have evaluated our proposed method on both simulated data and working memory task-based fMRI datasets, where our dynamic graph embeddings achieve higher accuracy in detecting multiple cognitive states than other state-of-the-art methods.
Age-related changes in brain structure may constitute the starting point for cerebral function alteration. Physical activity (PA) demonstrated favorable associations with total brain volume, but its relationship with cortical thickness (CT) remains unclear. We investigated the cross-sectional associations between PA level and CT in community-dwelling people aged 70 years and older.

A total of 403 older adults aged 74.8 ± 4.0 years (mean ± SD) who underwent a baseline magnetic resonance imaging examination and who had data on PA and confounders were included. PA was assessed with a questionnaire. Participants were categorized according to PA levels. Multiple linear regressions were used to compare the brain CT (mm) of the inactive group (no PA at all) with 6 active groups (growing PA levels) in 34 regions of interest.

Compared with inactive persons, people who achieved PA at a level of 1500-1999 metabolic equivalent task-min/week (i.e., about 6-7 h of brisk walking for exercise and those who achieved it p to fulfil remaining knowledge gaps in this field.In teleost fish, radial glial cells (RGCs) are progenitor cells for neurons and the major cell type synthesizing neuroestrogens. We hypothesized that chemical exposure impairs mitochondrial bioenergetics of RGCs, which then may lead to downstream consequences for neuroestrogen production. Here we provide proof of concept that mitochondria of RGCs can be perturbed by fungicides. We isolated RGCs from a mixed sex population of goldfish (Carassius auratus) and measured metabolic capacity of primary cells to a model mitotoxin fluazinam, a broad-spectrum fungicide that inhibits mitochondria electron transport chain (or ETC) Complex I. Using immunocytochemistry and real-time PCR, we demonstrate that the goldfish primary cell cultures are highly enriched for glia after multiple passages. Cytotoxicity assays revealed that glia treated with >25 μM fluazinam for 24 and 48-h showed reduced viability. As such, metabolic assays were conducted with non-cytotoxic concentrations (0.25-12.5 μM). Fluazinam did not affect oxygen consumption rates of RGCs at 24 h, but after 48 h, oligomycin induced ATP-linked respiration was decreased by both 6.25 and 12.5 μM fluazinam. Moreover, concentrations as low as 0.25 μM disrupted the mitochondrial membrane potential of RGCs, reflecting strong uncoupling effects of the fungicide on mitochondria. Here we provide proof of concept that mitochondrial bioenergetics of teleostean RGCs can be responsive to agrochemicals. Additional studies are required to address low-dose exposures in vivo and to determine if metabolic disruption impairs neuroendocrine functions of RGCs. We propose this mechanism constitutes a novel aspect of neuroendocrine disruption, significant because dysregulation of neuron-glia communication is expected to contribute to neuroendocrine disruption.
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