Zika virus encephalitis causes transient reduction of functional cortical connectivity.

Significance: Determining the long-term cognitive impact of infections is clinically challenging. Using functional cortical connectivity, we demonstrate that interhemispheric cortical connectivity is decreased in individuals with acute Zika virus (ZIKV) encephalitis. This correlates with decreased presynaptic terminals in the somatosensory cortex.

N-acylbenzimidazoles as selective Acylators of the catalytic cystein of the coronavirus 3CL protease.

The 3CL protease (3CL, M) plays a key role in the replication of the SARS-CoV-2 and was validated as therapeutic target by the development and approval of specific antiviral drugs (nirmatrelvir, ensitrelvir), inhibitors of this protease. Moreover, its high conservation within the coronavirus family renders it an attractive therapeutic target for the development of anti-coronavirus compounds with broad spectrum activity to control COVID-19 and future coronavirus diseases. Here we report on the design, synthesis and structure-activity relationships of a new series of small covalent reversible inhibitors of the SARS-CoV-2 3CL.

Attention-Based CNN-BiLSTM for Sleep State Classification of Spatiotemporal Wide-Field Calcium Imaging Data.

Background: Wide-field calcium imaging (WFCI) with genetically encoded calcium indicators allows for spatiotemporal recordings of neuronal activity in mice. When applied to the study of sleep, WFCI data are manually scored into the sleep states of wakefulness, non-REM (NREM) and REM by use of adjunct EEG and EMG recordings. However, this process is time-consuming, invasive and often suffers from low inter- and intra-rater reliability.

Capillary electrokinetic chromatography for chiral separation of potential SARS-CoV-2 3CL protease inhibitors.

In this work, a capillary electrophoresis method was developed as a quality control tool to determine the enantiomeric purity of a series of five chiral compounds evaluated as potential severe acute respiratory syndrome coronavirus 2 3CL protease inhibitors. The first cyclodextrin tested, that is, highly sulfated-β-cyclodextrin, at 6% (m/v) in a 25 mM phosphate buffer, using a capillary dynamically coated with polyethylene oxide, at an applied voltage of 15 kV and a temperature of 25°C, was found to successfully separate the five derivatives. The limits of detection and quantification were calculated together with the greenness score of the method in order to evaluate the method in terms of analytical and environmental performance.

Myeloid cell activation during Zika virus encephalitis predicts recovery of functional cortical connectivity.

Neurologic complications of Zika virus (ZIKV) infection across the lifespan have been described during outbreaks in Southeast Asia, South America, and Central America since 2016. In the adult CNS ZIKV tropism for neurons is tightly linked to its effects, with neuronal loss within the hippocampus during acute infection and protracted synapse loss during recovery, which is associated with cognitive deficits. The effects of ZIKV on cortical networks have not been evaluated.

Mecp2 deletion results in profound alterations of developmental and adult functional connectivity.

As a regressive neurodevelopmental disorder with a well-established genetic cause, Rett syndrome and its Mecp2 loss-of-function mouse model provide an excellent opportunity to define potentially translatable functional signatures of disease progression, as well as offer insight into the role of Mecp2 in functional circuit development. Thus, we applied widefield optical fluorescence imaging to assess mesoscale calcium functional connectivity (FC) in the Mecp2 cortex both at postnatal day (P)35 in development and during the disease-related decline. We found that FC between numerous cortical regions was disrupted in Mecp2 mutant males both in juvenile development and early adulthood.

Open-source statistical and data processing tools for wide-field optical imaging data in mice.

Significance: Wide-field optical imaging (WOI) can produce concurrent hemodynamic and cell-specific calcium recordings across the entire cerebral cortex in animal models. There have been multiple studies using WOI to image mouse models with various environmental or genetic manipulations to understand various diseases. Despite the utility of pursuing mouse WOI alongside human functional magnetic resonance imaging (fMRI), and the multitude of analysis toolboxes in the fMRI literature, there is not an available open-source, user-friendly data processing and statistical analysis toolbox for WOI data.

Novel dithiocarbamates selectively inhibit 3CL protease of SARS-CoV-2 and other coronaviruses.

Since end of 2019, the global and unprecedented outbreak caused by the coronavirus SARS-CoV-2 led to dramatic numbers of infections and deaths worldwide. SARS-CoV-2 produces two large viral polyproteins which are cleaved by two cysteine proteases encoded by the virus, the 3CL protease (3CL) and the papain-like protease, to generate non-structural proteins essential for the virus life cycle. Both proteases are recognized as promising drug targets for the development of anti-coronavirus chemotherapy.

Transient disruption of functional connectivity and depression of neural fluctuations in a mouse model of acute septic encephalopathy.

Septic encephalopathy leads to major and costly burdens for a large percentage of admitted hospital patients. Elderly patients are at an increased risk, especially those with dementia. Current treatments are aimed at sedation to combat mental status changes and are not aimed at the underlying cause of encephalopathy.

SIRT1 mediates hypoxic postconditioning- and resveratrol-induced protection against functional connectivity deficits after subarachnoid hemorrhage.

Functional connectivity (FC) is a sensitive metric that provides a readout of whole cortex coordinate neural activity in a mouse model. We examine the impact of experimental SAH modeled through endovascular perforation, and the effectiveness of subsequent treatment on FC, through three key questions: 1) Does the endovascular perforation model of SAH induce deficits in FC; 2) Does exposure to hypoxic conditioning provide protection against these FC deficits and, if so, is this neurovascular protection SIRT1-mediated; and 3) does treatment with the SIRT1 activator resveratrol alone provide protection against these FC deficits? Cranial windows were adhered on skull-intact mice that were then subjected to either sham or SAH surgery and either left untreated or treated with hypoxic post-conditioning (with or without EX527) or resveratrol for 3 days. Mice were imaged 3 days post-SAH/sham surgery, temporally aligned with the onset of major SAH sequela in mice.

Automated sleep state classification of wide-field calcium imaging data via multiplex visibility graphs and deep learning.

Background: Wide-field calcium imaging (WFCI) allows for monitoring of cortex-wide neural dynamics in mice. When applied to the study of sleep, WFCI data are manually scored into the sleep states of wakefulness, non-REM (NREM) and REM by use of adjunct EEG and EMG recordings. However, this process is time-consuming and often suffers from low inter- and intra-rater reliability and invasiveness.

NMR Spectroscopy of the Main Protease of SARS-CoV-2 and Fragment-Based Screening Identify Three Protein Hotspots and an Antiviral Fragment.

The main protease (3CLp) of the SARS-CoV-2, the causative agent for the COVID-19 pandemic, is one of the main targets for drug development. To be active, 3CLp relies on a complex interplay between dimerization, active site flexibility, and allosteric regulation. The deciphering of these mechanisms is a crucial step to enable the search for inhibitors.

A Multivariate Functional Connectivity Approach to Mapping Brain Networks and Imputing Neural Activity in Mice.

Temporal correlation analysis of spontaneous brain activity (e.g., Pearson "functional connectivity," FC) has provided insights into the functional organization of the human brain.

Functional Connectivity of the Developing Mouse Cortex.

Cross-sectional studies have established a variety of structural, synaptic, and cell physiological changes corresponding to critical periods in cortical development. However, the emergence of functional connectivity (FC) in development has not been fully characterized, and hemodynamic-based measures are vulnerable to any neurovascular coupling changes occurring in parallel. We therefore used optical fluorescence imaging to trace longitudinal calcium FC in the awake, resting-state mouse cortex at 5 developmental timepoints beginning at postnatal day 15 (P15) and ending in early adulthood at P60.

Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration.

Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood.

Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway.

Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump α2-Na/K ATPase cause familial hemiplegic migraine, but the mechanisms by which α2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we show that mice in which α2-Na/K ATPase is conditionally deleted in astrocytes display episodic paralysis.

Separability of calcium slow waves and functional connectivity during wake, sleep, and anesthesia.

Modulation of brain state, e.g., by anesthesia, alters the correlation structure of spontaneous activity, especially in the delta band.

Maternal Fluoxetine Exposure Alters Cortical Hemodynamic and Calcium Response of Offspring to Somatosensory Stimuli.

Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model.

Regulation of LC3 lipidation by the autophagy-specific class III phosphatidylinositol-3 kinase complex.

Autophagy is a conserved eukaryotic pathway critical for cellular adaptation to changes in nutrition levels and stress. The class III phosphatidylinositol (PI)3-kinase complexes I and II (PI3KC3-C1 and -C2) are essential for autophagosome initiation and maturation, respectively, from highly curved vesicles. We used a cell-free reaction that reproduces a key autophagy initiation step, LC3 lipidation, as a biochemical readout to probe the role of autophagy-related gene (ATG)14, a PI3KC3-C1-specific subunit implicated in targeting the complex to autophagy initiation sites.

ESM-CT: a precise method for localization of DBS electrodes in CT images.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus produces variable effects in Parkinson disease. Variation may result from different electrode positions relative to target. Thus, precise electrode localization is crucial when investigating DBS effects.

Unintended Side Effects of Transformation Are Very Rare in .

Received wisdom in the field of fungal biology holds that the process of editing a genome by transformation and homologous recombination is inherently mutagenic. However, that belief is based on circumstantial evidence. We provide the first direct measurement of the effects of transformation on a fungal genome by sequencing the genomes of 29 transformants and 30 untransformed controls with high coverage.

Functional connectivity structure of cortical calcium dynamics in anesthetized and awake mice.

The interplay between hemodynamic-based markers of cortical activity (e.g. fMRI and optical intrinsic signal imaging), which are an indirect and relatively slow report of neural activity, and underlying synaptic electrical and metabolic activity through neurovascular coupling is a topic of ongoing research and debate.

Biopolymer Molecular Weight Can Modulate the Wound Healing Efficacy of Multivalent Sonic Hedgehog-Hyaluronic Acid Conjugates.

There is a clinical need for new therapeutics to improve healing of chronic impaired wounds. Thus, we investigated how biopolymer conjugation could be used to improve the wound healing performance of a key growth factor for tissue regeneration: Sonic hedgehog (Shh). We generated two multivalent Shh conjugates (mvShh) using hyaluronic acid with two different MWs, which exhibited equivalent potency and proteolytic protection in vitro.

MTORC1-mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy.

NRBF2/Atg38 has been identified as the fifth subunit of the macroautophagic/autophagic class III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps15 and PIK3C3/Vps34. However, its functional mechanism and regulation are not fully understood. Here, we report that NRBF2 is a fine tuning regulator of PtdIns3K controlled by phosphorylation.