The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity.

Cytotoxic neuronal swelling and glutamate excitotoxicity are two hallmarks of ischemic stroke. However, the underlying molecular mechanisms are not well understood. Here, it is reported that SWELL1, the essential subunit of the volume-regulated anion channel (VRAC), plays a dual role in ischemic injury by promoting neuronal swelling and glutamate excitotoxicity.

KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3.

Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is , whose mutations cause KAT6A syndrome, with ID as a common clinical feature. However, the underlying molecular mechanism remains unknown.

Possible association of keratoconus progression with gender-affirming hormone therapy: A case report.

Purpose: To present a case of keratoconus progression following gender-affirming hormone therapy.

Observations: A 28-year-old male-to-female transgender patient with potential past ocular history of subclinical keratoconus presented with subacute worsening myopia of both eyes (OU), 4 months after initiation of gender-affirming hormone therapy. A diagnosis of keratoconus was established based on slit-lamp exam and computerized corneal tomography.

ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain.

Following peripheral nerve injury, extracellular adenosine 5'-triphosphate (ATP)-mediated purinergic signaling is crucial for spinal cord microglia activation and neuropathic pain. However, the mechanisms of ATP release remain poorly understood. Here, we show that volume-regulated anion channel (VRAC) is an ATP-releasing channel and is activated by inflammatory mediator sphingosine-1-phosphate (S1P) in microglia.

ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain.

Following peripheral nerve injury, extracellular ATP-mediated purinergic signaling is crucial for spinal cord microglia activation and neuropathic pain. However, the mechanisms of ATP release remain poorly understood. Here, we show that volume-regulated anion channel (VRAC) is an ATP-releasing channel and is activated by inflammatory mediator sphingosine-1-phosphate (S1P) in microglia.

Ventral tegmental area astrocytes modulate cocaine reward by tonically releasing GABA.

Addictive drugs increase ventral tegmental area (VTA) dopamine (DA) neuron activity through distinct cellular mechanisms, one of which involves disinhibition of DA neurons by inhibiting local GABA neurons. How drugs regulate VTA GABA neuron activity and drive addictive behaviors remains poorly understood. Here, we show that astrocytes control VTA GABA neuron activity in cocaine reward via tonic inhibition in mice.

Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC.

Desensitization is a common property of membrane receptors, including ion channels. The newly identified proton-activated chloride (PAC) channel plays an important role in regulating the pH and size of organelles in the endocytic pathway, and is also involved in acid-induced cell death. However, how the PAC channel desensitizes is largely unknown.

Sensational astrocytes: Mechanotransduction in adult brain function.

Sensing the mechanical microenvironment is an essential aspect of all life, yet its mechanism remains poorly understood. In this issue of Neuron, Chi et al. reveal the role of astrocyte mechanosensitive Piezo1 channel in adult neurogenesis and cognitive function.

Genetic activation of glucokinase in a minority of pancreatic beta cells causes hypoglycemia in mice.

Aims: Glucokinase (GK) is expressed in the glucose-sensing cells of the islets of Langerhans and plays a critical role in glucose homeostasis. Here, we tested the hypothesis that genetic activation of GK in a small subset of β-cells is sufficient to change the glucose set-point of the whole islet.

Material And Methods: Mouse models of cell-type specific GK deficiency (GKKO) and genetic enzyme activation (GKKI) in a subset of β-cells were obtained by crossing the αGSU (gonadotropin alpha subunit)-Cre transgene with the appropriate GK mutant alleles.

Molecular determinants of pH sensing in the proton-activated chloride channel.

In response to acidic pH, the widely expressed proton-activated chloride (PAC) channel opens and conducts anions across cellular membranes. By doing so, PAC plays an important role in both cellular physiology (endosome acidification) and diseases associated with tissue acidosis (acid-induced cell death). Despite the available structural information, how proton binding in the extracellular domain (ECD) leads to PAC channel opening remains largely unknown.

Characterization of an Anti-CD5 Directed CAR T-Cell against T-Cell Malignancies.

T-cell malignancies often result in poor prognosis and outcome for patients. Immunotherapy has recently emerged as a revolutionary treatment against cancer, and the success seen in CD19 CAR clinical trials may extend to T cell diseases. However, a shared antigen pool coupled with the impact of T-cell depletion incurred by targeting T cell disease remain concepts to be clinically explored with caution.

Targeting Two Antigens Associated with B-ALL with CD19-CD123 Compound Car T Cell Therapy.

The recent FDA approval of the first CAR immunotherapy marks a watershed moment in the advancement toward a cure for cancer. CD19 CAR treatment for B cell acute lymphocytic leukemia has achieved unprecedented remission rates. However, despite success in treating previously relapsed and refractory patients, CD19 CAR faces similar challenges as traditional chemotherapy, in that malignancy can adapt and overcome treatment.

Two pair-rule responsive enhancers regulate wingless transcription in the Drosophila blastoderm embryo.

Background: While many developmentally relevant enhancers act in a modular fashion, there is growing evidence for nonadditive interactions between distinct cis-regulatory enhancers. We investigated if nonautonomous enhancer interactions underlie transcription regulation of the Drosophila segment polarity gene, wingless.

Results: We identified two wg enhancers active at the blastoderm stage: wg 3613u, located from -3.

Loss of results in dysregulation of in nephron progenitors.

We have previously demonstrated that loss of in nephron progenitors in a mouse model results in renal hypodysplasia and chronic kidney disease. Clinically, decreased congenital nephron endowment because of renal hypodysplasia is associated with an increased risk of hypertension and chronic kidney disease, and this is at least partly dependent on the self-renewal of nephron progenitors. Here, we present evidence for a novel molecular mechanism regulating the self-renewal of nephron progenitors and congenital nephron endowment by the highly conserved cluster.

Small non-coding RNA expression in mouse nephrogenic mesenchymal progenitors.

MicroRNAs (miRNAs) are small non-coding RNAs that are essential for the regulation of gene expression and play critical roles in human health and disease. Here we present comprehensive miRNA profiling data for mouse nephrogenic mesenchymal progenitors, a population of cells enriched for nephron progenitors that give rise to most cell-types of the nephron, the functional unit of the kidney. We describe a miRNA expression in nephrogenic mesenchymal progenitors, with 162 miRNAs differentially expressed in progenitors when compared to whole kidney.

Internet Gaming Disorder: An Emergent Health Issue for Men.

Internet gaming is a legitimate leisure activity worldwide; however, there are emerging concerns that vast numbers of gamers are becoming addicted. In 2013, the American Psychiatric Association (APA) classified Internet Gaming Disorder (IGD) as a condition warranting more clinical research ahead of formalizing it as a mental disorder. Proposed as a behavioral addiction, IGD shares many similarities in both physical and psychosocial manifestations with substance use disorder, including cerebral changes on functional magnetic resonance imaging (fMRI).

Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia.

Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously.

Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells.

Peripheral T-cell lymphomas (PTCLs) are a group of very aggressive non-Hodgkin's lymphomas (NHLs) with poor prognoses and account for a majority of T-cell malignancies. Overall, the standard of care for patients with T-cell malignancies is poorly established, and there is an urgent clinical need for a new approach. As demonstrated in B-cell malignancies, chimeric antigen receptor (CAR) immunotherapy provides great hope as a curative treatment regimen.

Implantation of a CyPass Supraciliary Stent Combined With Targeted iStent Trabecular Microbypass Stents in a Phakic Patient With Primary Open-angle Glaucoma.

Purpose: To report the first successful implantation of a CyPass supraciliary stent combined with 2 targeted iStent trabecular microbypass stents in a phakic primary open-angle glaucoma patient with markedly elevated intraocular pressures (IOP) on maximum tolerable medical therapy.

Methods: Case report.

Results: A 52-year-old phakic male patient with primary open-angle glaucoma with uncontrolled IOP in the right eye (OD) of 36 mm Hg on maximal topical pharmacotherapy.

X-ray Crystallographic Structure of a Giant Double-Walled Peptide Nanotube Formed by a Macrocyclic β-Sheet Containing Aβ.

This paper describes the supramolecular assembly of a macrocyclic β-sheet containing residues 16-22 of the β-amyloid peptide, Aβ. X-ray crystallography reveals that the macrocyclic β-sheet assembles to form double-walled nanotubes, with an inner diameter of 7 nm and outer diameter of 11 nm. The inner wall is composed of an extended network of hydrogen-bonded dimers.

Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies.

Peripheral T-cell lymphomas (PTCLS) comprise a diverse group of difficult to treat, very aggressive non-Hodgkin's lymphomas (NHLS) with poor prognoses and dismal patient outlook. Despite the fact that PTCLs comprise the majority of T-cell malignancies, the standard of care is poorly established. Chimeric antigen receptor (CAR) immunotherapy has shown in B-cell malignancies to be an effective curative option and this extends promise into treating T-cell malignancies.

Elucidation of the Teixobactin Pharmacophore.

This paper elucidates the teixobactin pharmacophore by comparing the arginine analogue of teixobactin Arg10-teixobactin to seven homologues with varying structure and stereochemistry. The roles of the guanidinium group at position 10, the stereochemistry of the macrolactone ring, and the "tail" comprising residues 1-5 are investigated. The guanidinium group is not necessary for activity; Lys10-teixobactin is more active than Arg10-teixobactin against Gram-positive bacteria in minimum inhibitory concentration (MIC) assays.

A fibril-like assembly of oligomers of a peptide derived from β-amyloid.

A macrocyclic β-sheet peptide containing two nonapeptide segments based on Aβ(15-23) (QKLVFFAED) forms fibril-like assemblies of oligomers in the solid state. The X-ray crystallographic structure of macrocyclic β-sheet peptide 3 was determined at 1.75 Å resolution.

The effect of chronic intracortical microstimulation on the electrode-tissue interface.

Objective: Somatosensation is critical for effective object manipulation, but current upper limb prostheses do not provide such feedback to the user. For individuals who require use of prosthetic limbs, this lack of feedback transforms a mundane task into one that requires extreme concentration and effort. Although vibrotactile motors and sensory substitution devices can be used to convey gross sensations, a direct neural interface is required to provide detailed and intuitive sensory feedback.