Cortical Acetylcholine Response to Deep Brain Stimulation of the Basal Forebrain in Mice.

Deep brain stimulation (DBS) using electrical stimulation of neuronal tissue in the basal forebrain to enhance release of the neurotransmitter acetylcholine is under consideration to improve executive function in patients with dementia. While some small studies indicate a positive response in the clinical setting, the relationship between DBS and acetylcholine pharmacokinetics is incompletely understood. We examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain.

Cortical Acetylcholine Response to Deep Brain Stimulation of the Basal Forebrain.

Background: Deep brain stimulation (DBS), the direct electrical stimulation of neuronal tissue in the basal forebrain to enhance release of the neurotransmitter acetylcholine, is under consideration as a method to improve executive function in patients with dementia. While some small studies indicate a positive response in the clinical setting, the relationship between DBS and acetylcholine pharmacokinetics is incompletely understood.

Objective: We examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain.

Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.

Mitochondrial function is tightly linked to morphology, and fragmentation of dendritic mitochondria during noxious conditions suggests loss of function. In the normoxic cortex, spreading depolarization (SD) is a phenomenon underlying migraine aura. It is unknown whether mitochondria structure is affected by normoxic SD.

Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.

Mitochondrial function is tightly linked to their morphology, and fragmentation of dendritic mitochondria during noxious conditions suggests loss of function. In the normoxic cortex, spreading depolarization (SD) is a phenomenon underlying migraine aura. It is unknown whether mitochondria structure is affected by normoxic SD.

Plasticity of perisynaptic astroglia during ischemia-induced spreading depolarization.

High astroglial capacity for glutamate and potassium clearance aids in recovering spreading depolarization (SD)-evoked disturbance of ion homeostasis during stroke. Since perisynaptic astroglia cannot be imaged with diffraction-limited light microscopy, nothing is known about the impact of SD on the ultrastructure of a tripartite synapse. We used serial section electron microscopy to assess astroglial synaptic coverage in the sensorimotor cortex of urethane-anesthetized male and female mice during and after SD evoked by transient bilateral common carotid artery occlusion.

Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling.

In ischemic stroke and post-traumatic brain injury (TBI), blood-brain barrier disruption leads to leaking plasma amino acids (AA) into cerebral parenchyma. Bleeding in hemorrhagic stroke and TBI also release plasma AA. Although excitotoxic AA were extensively studied, little is known about non-excitatory AA during hypoxic injury.

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention.

Background: When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD).

Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization.

Background: Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury.

Origin Sample Prediction and Spatial Modeling of Antimicrobial Resistance in Metagenomic Sequencing Data.

The steady elaboration of the Metagenomic and Metadesign of Subways and Urban Biomes (MetaSUB) international consortium project raises important new questions about the origin, variation, and antimicrobial resistance of the collected samples. CAMDA (Critical Assessment of Massive Data Analysis, http://camda.info/) forum organizes annual challenges where different bioinformatics and statistical approaches are tested on samples collected around the world for bacterial classification and prediction of geographical origin.

Misannotated Multi-Nucleotide Variants in Public Cancer Genomics Datasets Lead to Inaccurate Mutation Calls with Significant Implications.

Although next-generation sequencing is widely used in cancer to profile tumors and detect variants, most somatic variant callers used in these pipelines identify variants at the lowest possible granularity, single-nucleotide variants (SNV). As a result, multiple adjacent SNVs are called individually instead of as a multi-nucleotide variants (MNV). With this approach, the amino acid change from the individual SNV within a codon could be different from the amino acid change based on the MNV that results from combining SNV, leading to incorrect conclusions about the downstream effects of the variants.

Modeling performance of sample collection sites using whole exome sequencing metrics.

Although next-generation sequencing assays are routinely carried out using samples from cancer trials, the sequencing data are not always of the required quality. There is a need to evaluate the performance of tissue collection sites and provide feedback about the quality of next-generation sequencing data. This study used a modeling approach based on whole exome sequencing quality control (QC) metrics to evaluate the relative performance of sites participating in the Bristol Myers Squibb Immuno-Oncology clinical trials sample collection.

Rapid Neuronal Ultrastructure Disruption and Recovery during Spreading Depolarization-Induced Cytotoxic Edema.

Two major pathogenic events that cause acute brain damage during neurologic emergencies of stroke, head trauma, and cardiac arrest are spreading depolarizing waves and the associated brain edema that course across the cortex injuring brain cells. Virtually nothing is known about how spreading depolarization (SD)-induced cytotoxic edema evolves at the ultrastructural level immediately after insult and during recovery. In vivo 2-photon imaging followed by quantitative serial section electron microscopy was used to assess synaptic circuit integrity in the neocortex of urethane-anesthetized male and female mice during and after SD evoked by transient bilateral common carotid artery occlusion.

Obtaining Alumina from Kaolin Clay via Aluminum Chloride.

A method of alumina production based on hydrochloric acid processing of kaolin clays from the East Siberian deposits was studied. Hydrochloric acid leaching was carried out at 160 °C. The leaching solution was subjected to a two-stage crystallization of aluminum chloride hexahydrate (ACH).

Which Spreading Depolarizations Are Deleterious To Brain Tissue?

Spreading depolarizations (SDs) are profound disruptions of cellular homeostasis that slowly propagate through gray matter and present an extraordinary metabolic challenge to brain tissue. Recent work has shown that SDs occur commonly in human patients in the neurointensive care setting and have established a compelling case for their importance in the pathophysiology of acute brain injury. The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in September of 2018 included a discussion session focused on the question of "Which SDs are deleterious to brain tissue?" iCSD is attended by investigators studying various animal species including invertebrates, in vivo and in vitro preparations, diseases of acute brain injury and migraine, computational modeling, and clinical brain injury, among other topics.

Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small-Cell Lung Cancer.

Introduction: Tumor mutational burden (TMB) has emerged as a clinically relevant biomarker that may be associated with immune checkpoint inhibitor efficacy. Standardization of TMB measurement is essential for implementing diagnostic tools to guide treatment.

Objective: Here we describe the in-depth evaluation of bioinformatic TMB analysis by whole exome sequencing (WES) in formalin-fixed, paraffin-embedded samples from a phase III clinical trial.

Degradation of the extracellular matrix is part of the pathology of ulcerative colitis.

The scientific value of re-analyzing existing datasets is often proportional to the complexity of the data. Proteomics data are inherently complex and can be analyzed at many levels, including proteins, peptides, and post-translational modifications to verify and/or develop new hypotheses. In this paper, we present our re-analysis of a previously published study comparing colon biopsy samples from ulcerative colitis (UC) patients to non-affected controls.

Early identification of unusually clustered mutations and root causes in therapeutic antibody development.

This study reports findings of an unusual cluster of mutations spanning 22 bp (base pairs) in a monoclonal antibody expression vector. It was identified by two orthogonal methods: mass spectrometry on expressed protein and next-generation sequencing (NGS) on the plasmid DNA. While the initial NGS analysis confirmed the designed sequence modification, intact mass analysis detected an additional mass of the antibody molecule expressed in CHO cells.

Mutations and PD-1 Inhibitor Resistance in -Mutant Lung Adenocarcinoma.

is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that (KL) or (KP) comutations define distinct subgroups of -mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups.

Longitudinal two-photon imaging in somatosensory cortex of behaving mice reveals dendritic spine formation enhancement by subchronic administration of low-dose ketamine.

Ketamine, a well-known anesthetic, has recently attracted renewed attention as a fast-acting antidepressant. A single dose of ketamine induces rapid synaptogenesis, which may underlie its antidepressant effect. To test whether repeated exposure to ketamine triggers sustained synaptogenesis, we administered a sub-anesthetic dose of ketamine (10 mg/kg i.

Na channel variants in patients with painful and nonpainful peripheral neuropathy.

Objective: To examine the incidence of nonsynonymous missense variants in (Na1.7), (Na1.8), and (Na1.

CRISPR-DAV: CRISPR NGS data analysis and visualization pipeline.

Summary: The simplicity and precision of CRISPR/Cas9 system has brought in a new era of gene editing. Screening for desired clones with CRISPR-mediated genomic edits in a large number of samples is made possible by next generation sequencing (NGS) due to its multiplexing. Here we present CRISPR-DAV (CRISPR Data Analysis and Visualization) pipeline to analyze the CRISPR NGS data in a high throughput manner.