Electrospun gelatin/hyaluronic acid nanofibers as a platform for uric acid delivery to neural tissue.

Uric acid (UA) is an antioxidant that has been reported to be a neuroprotective compound for injuries and diseases, and specifically, diseases of the central nervous system. However, uric acid is highly insoluble in aqueous solutions, and high levels in the serum lead to gout, which limits its use in humans. Here, we develop a novel drug delivery platform that will release uric acid in a sustained manner for application to neural tissue.

Valacyclovir and Acyclovir Are Substrates of the Guanine Deaminase Cytosolic PSD-95 Interactor (Cypin).

Valacyclovir, enzymatically hydrolyzed in the body to acyclovir, is a guanine-based nucleoside analog commonly prescribed as an antiviral therapy. Previous reports suggest that guanosine analogs bind to guanine deaminase; however, it is unclear whether they act as inhibitors or substrates. Data from our laboratory suggest that inhibition of guanine deaminase by small molecules attenuates spinal cord injury-induced neuropathic pain.

RIPK3 promotes neuronal survival by suppressing excitatory neurotransmission during CNS viral infection.

While recent work has identified roles for immune mediators in the regulation of neural activity, the capacity for cell intrinsic innate immune signaling within neurons to influence neurotransmission remains poorly understood. However, the existing evidence linking immune signaling with neuronal function suggests that modulation of neurotransmission may serve previously undefined roles in host protection during infection of the central nervous system. Here, we identify a specialized function for RIPK3, a kinase traditionally associated with necroptotic cell death, in preserving neuronal survival during neurotropic flavivirus infection through the suppression of excitatory neurotransmission.

Overexpression of α-Klotho isoforms promotes distinct Effects on BDNF-Induced Alterations in Dendritic Morphology.

α-Klotho (α-Kl) is a modulator of aging, neuroprotection, and cognition. Transcription of the Klotho gene produces two splice variants-a membrane protein (mKl), which can be cleaved and released into the extracellular milieu, and a truncated secreted form (sKl). Despite mounting evidence supporting a role for α-Kl in brain function, the specific roles of α-Kl isoforms in neuronal development remain elusive.

Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury-Induced Mechanical Pain.

Cypin (cytosolic postsynaptic density protein 95 interactor) is the primary guanine deaminase in the central nervous system (CNS), promoting the metabolism of guanine to xanthine, an important reaction in the purine salvage pathway. Activation of the purine salvage pathway leads to the production of uric acid (UA). UA has paradoxical effects, specifically in the context of CNS injury as it confers neuroprotection, but it also promotes pain.

Stretch-Induced Injury Affects Cortical Neuronal Networks in a Time- and Severity-Dependent Manner.

Traumatic brain injury (TBI) is the leading cause of accident-related death and disability in the world and can lead to long-term neuropsychiatric symptoms, such as a decline in cognitive function and neurodegeneration. TBI includes primary and secondary injury, with head trauma and deformation of the brain caused by the physical force of the impact as primary injury, and cellular and molecular cascades that lead to cell death as secondary injury. Currently, there is no treatment for TBI-induced cell damage and neural circuit dysfunction in the brain, and thus, it is important to understand the underlying cellular mechanisms that lead to cell damage.

Time-dependent homeostatic mechanisms underlie brain-derived neurotrophic factor action on neural circuitry.

Plasticity and homeostatic mechanisms allow neural networks to maintain proper function while responding to physiological challenges. Despite previous work investigating morphological and synaptic effects of brain-derived neurotrophic factor (BDNF), the most prevalent growth factor in the central nervous system, how exposure to BDNF manifests at the network level remains unknown. Here we report that BDNF treatment affects rodent hippocampal network dynamics during development and recovery from glutamate-induced excitotoxicity in culture.

Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion.

The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model.

Cross-species transcriptomic analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion.

Recent advances in the genetics of schizophrenia (SCZ) have identified rare variants that confer high disease risk, including a 1.6 Mb deletion at chromosome 3q29 with a staggeringly large effect size (O.R.

Correction: Schiliro, C.; Firestein, B.L. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. 2021, , 1056.

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Cypin binds to tubulin heterodimers and microtubule protofilaments and regulates microtubule spacing in developing hippocampal neurons.

Cytosolic PSD-95 interactor (cypin) is a multifunctional, guanine deaminase that plays a major role in shaping the morphology of the dendritic arbor of hippocampal and cortical neurons. Cypin catalyzes the Zn-dependent deamination of guanine to xanthine, which is then metabolized to uric acid by xanthine oxidase. Cypin binds to tubulin heterodimers via its carboxyl terminal region (amino acids (aa) 350-454), which contains a collapsin response mediator protein (CRMP) homology domain (aa 350-403).

Glutamate Receptors Mediate Changes to Dendritic Mitochondria in Neurons Grown on Stiff Substrates.

The stiffness of brain tissue changes during development and disease. These changes can affect neuronal morphology, specifically dendritic arborization. We previously reported that N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors regulate dendrite number and branching in a manner that is dependent on substrate stiffness.

Förster resonance energy transfer efficiency of the vinculin tension sensor in cultured primary cortical neuronal growth cones.

: Interaction of neurons with their extracellular environment and the mechanical forces at focal adhesions and synaptic junctions play important roles in neuronal development. : To advance studies of mechanotransduction, we demonstrate the use of the vinculin tension sensor (VinTS) in primary cultures of cortical neurons. VinTS consists of TS module (TSMod), a Förster resonance energy transfer (FRET)-based tension sensor, inserted between vinculin's head and tail.

Carboxypeptidase E Independently Changes Microtubule Glutamylation, Dendritic Branching, and Neuronal Migration.

Neuronal migration and dendritogenesis are dependent on dynamic changes to the microtubule (MT) network. Among various factors that regulate MT dynamics and stability, post-translational modifications (PTMs) of MTs play a critical role in conferring specificity of regulatory protein binding to MTs. Thus, it is important to understand the regulation of PTMs during brain development as multiple developmental processes are dependent on MTs.

Deep brain stimulation: Challenges at the tissue-electrode interface and current solutions.

Deep brain stimulation (DBS) is used to treat the motor symptoms of Parkinson's disease patients by stimulating the subthalamic nucleus. However, optimization of DBS is still needed since the performance of the neural electrodes is limited by the body's response to the implant. This review discusses the issues with DBS, such as placement of electrodes, foreign body response, and electrode degradation.

Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation.

Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs.

Regional Neurodegeneration : The Protective Role of Neural Activity.

Traumatic brain injury is a devastating public health problem, the eighth leading cause of death across the world. To improve our understanding of how injury at the cellular scale affects neural circuit function, we developed a protocol to precisely injure individual neurons within an neural network. We used high speed calcium imaging to estimate alterations in neural activity and connectivity that occur followed targeted microtrauma.

Cytosolic PSD-95 interactor alters functional organization of neural circuits and AMPA receptor signaling independent of PSD-95 binding.

Cytosolic PSD-95 interactor (cypin) regulates many aspects of neuronal development and function, ranging from dendritogenesis to synaptic protein localization. While it is known that removal of postsynaptic density protein-95 (PSD-95) from the postsynaptic density decreases synaptic N-methyl-D-aspartate (NMDA) receptors and that cypin overexpression protects neurons from NMDA-induced toxicity, little is known about cypin's role in AMPA receptor clustering and function. Experimental work shows that cypin overexpression decreases PSD-95 levels in synaptosomes and the PSD, decreases PSD-95 clusters/μm, and increases mEPSC frequency.

CCP1, a Tubulin Deglutamylase, Increases Survival of Rodent Spinal Cord Neurons following Glutamate-Induced Excitotoxicity.

Microtubules (MTs) are cytoskeletal elements that provide structural support and act as roadways for intracellular transport in cells. MTs are also needed for neurons to extend and maintain long axons and dendrites that establish connectivity to transmit information through the nervous system. Therefore, in neurons, the ability to independently regulate cytoskeletal stability and MT-based transport in different cellular compartments is essential.

Cerebrospinal fluid replacement solutions promote neuroglia migratory behaviors and spinal explant outgrowth in microfluidic culture.

Disorders of the nervous system (NS) impact millions of adults, worldwide, as a consequence of traumatic injury, genetic illness, or chronic health conditions. Contemporary studies have begun to incorporate neuroglia into emerging NS therapies to harness the regenerative potential of glial-mediated synapses in the brain and spinal cord. However, the role of cerebrospinal fluid (CSF) that surrounds neuroglia and interfaces with their associated synapses remains only partially explored.

Uric acid released from poly(ε-caprolactone) fibers as a treatment platform for spinal cord injury.

Spinal cord injury (SCI) is characterized by a primary mechanical phase of injury, resulting in physical tissue damage, and a secondary pathological phase, characterized by biochemical processes contributing to inflammation, neuronal death, and axonal demyelination. Glutamate-induced excitotoxicity (GIE), in which excess glutamate is released into synapses and overstimulates glutamate receptors, is a major event in secondary SCI. GIE leads to mitochondrial damage and dysfunction, release of reactive oxygen species (ROS), DNA damage, and cell death.

Characterization hiPSC-derived neural progenitor cells and neurons to investigate the role of NOS1AP isoforms in human neuron dendritogenesis.

Abnormal dendritic arbor development has been implicated in a number of neurodevelopmental disorders, such as autism and Rett syndrome, and the neuropsychiatric disorder schizophrenia. Postmortem brain samples from subjects with schizophrenia show elevated levels of NOS1AP in the dorsolateral prefrontal cortex, a region of the brain associated with cognitive function. We previously reported that the long isoform of NOS1AP (NOS1AP-L), but not the short isoform (NOS1AP-S), negatively regulates dendrite branching in rat hippocampal neurons.

Colchicine to Weather the Cytokine Storm in Hospitalized Patients with COVID-19.

The repurposing of colchicine for the treatment of COVID-19 was suggested based in its immunomodulatory, anti-inflammatory, and anti-viral properties. We performed a single-center propensity score matched cohort study, including all consecutive COVID-19 patients admitted to a community hospital between 1 March 2020 and 30 May 2020. Patients were stratified according to the receipt of colchicine.