Trazodone rescues dysregulated synaptic and mitochondrial nascent proteomes in prion neurodegeneration.

The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation results in sustained translational repression leading to synapse loss and neurodegeneration. In mouse models of these disorders, from Alzheimer's to prion disease, modulation of the pathway-including by the licensed drug, trazodone-restores global protein synthesis rates with profound neuroprotective effects. However, the precise nature of the translational impairment, in particular the specific proteins affected in disease, and their response to therapeutic UPR modulation are poorly understood.

ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo.

Neurodegenerative diseases are increasingly prevalent in the aging population, yet no disease-modifying treatments are currently available. Increasing the expression of the cold-shock protein RBM3 through therapeutic hypothermia is remarkably neuroprotective. However, systemic cooling poses a health risk, strongly limiting its clinical application.

Major Features of the 2021 WHO Classification of CNS Tumors.

Advances in the understanding of the molecular biology of central nervous system (CNS) tumors prompted a new World Health Organization (WHO) classification scheme in 2021, only 5 years after the prior iteration. The 2016 version was the first to include specific molecular alterations in the diagnoses of a few tumors, but the 2021 system greatly expanded this approach, with over 40 tumor types and subtypes now being defined by their key molecular features. Many tumors have also been reconceptualized into new "supercategories," including adult-type diffuse gliomas, pediatric-type diffuse low- and high-grade gliomas, and circumscribed astrocytic gliomas.

Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.

Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world's population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed-particularly any that can slow down the disease's progression.

Dominant and recessive congenital myasthenic syndromes caused by SYT2 mutations.

Introduction/aims: We studied a patient with a congenital myasthenic syndrome (CMS) caused by a dominant mutation in the synaptotagmin 2 gene (SYT2) and compared the clinical features of this patient with those of a previously described patient with a recessive mutation in the same gene.

Methods: We performed electrodiagnostic (EDX) studies, genetic studies, muscle biopsy, microelectrode recordings and electron microscopy (EM).

Results: Both patients presented with muscle weakness and bulbar deficits, which were worse in the recessive form.

TrkB signaling regulates the cold-shock protein RBM3-mediated neuroprotection.

Increasing levels of the cold-shock protein, RNA-binding motif 3 (RBM3), either through cooling or by ectopic over-expression, prevents synapse and neuronal loss in mouse models of neurodegeneration. To exploit this process therapeutically requires an understanding of mechanisms controlling cold-induced RBM3 expression. Here, we show that cooling increases RBM3 through activation of TrkB via PLCγ1 and pCREB signaling.

Prognostic value of cardiac magnetic resonance septal late gadolinium enhancement patterns for periaortic ventricular tachycardia ablation: Heterogeneity of the anteroseptal substrate in nonischemic cardiomyopathy.

Background: Ventricular tachycardia (VT) from the anteroseptal subtype of nonischemic cardiomyopathy has a high probability of recurrence after catheter ablation.

Objective: The purpose of this study was to determine the predictive value of septal scar patterns by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) on ablation outcomes in patients with VT arising from an anteroseptal substrate.

Methods: Patients with periaortic VT arising from an anteroseptal substrate with preprocedural wideband LGE-CMR were divided into 2 groups by the degree of longitudinal septal LGE extension as full-length septal (≥80% anteroposterior length) or partial septal (<80% anteroposterior length).

Targeting the kinase insert loop of PERK selectively modulates PERK signaling without systemic toxicity in mice.

Chronic activation of the unfolded protein response (UPR), notably the branch comprising the kinase PERK and the translation initiation factor eIF2α, is a pathological feature of many neurodegenerative diseases caused by protein misfolding. Partial reduction of UPR signaling at the level of phosphorylated eIF2α is neuroprotective and avoids the pancreatic toxicity caused by full inhibition of PERK kinase activity. However, other stress pathways besides the UPR converge on phosphorylated eIF2α in the integrated stress response (ISR), which is critical to normal cellular function.

ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction.

Rationale: ZO-1 (Zona occludens 1), encoded by the tight junction protein 1 () gene, is a regulator of paracellular permeability in epithelia and endothelia. ZO-1 interacts with the actin cytoskeleton, gap, and adherens junction proteins and localizes to intercalated discs in cardiomyocytes. However, the contribution of ZO-1 to cardiac physiology remains poorly defined.

Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration.

Recent interest in astrocyte activation states has raised the fundamental question of how these cells, normally essential for synapse and neuronal maintenance, become pathogenic. Here, we show that activation of the unfolded protein response (UPR), specifically phosphorylated protein kinase R-like endoplasmic reticulum (ER) kinase (PERK-P) signaling-a pathway that is widely dysregulated in neurodegenerative diseases-generates a distinct reactivity state in astrocytes that alters the astrocytic secretome, leading to loss of synaptogenic function in vitro. Further, we establish that the same PERK-P-dependent astrocyte reactivity state is harmful to neurons in vivo in mice with prion neurodegeneration.

Dural Ectasia in Neurofibromatosis 1: Case Series, Management, and Review.

Background: The natural history and management of dural ectasia in Neurofibromatosis 1 (NF1) is still largely unknown. Dural ectasias are one of the common clinical manifestations of NF1; however, the treatment options for dural ectasias remain unstudied.

Objective: To investigate the natural history, diagnosis, management, and outcome of the largest case series of patients with NF1-associated dural ectasia to date.

Exploration of Functional Limitation Codes for Outpatient Physical Therapy in the Medicare Population: A Retrospective Cohort Study.

Background: The Centers for Medicare & Medicaid Services (CMS) introduced functional limitation reporting (FLR) to capture patient progress in functional status in outpatient rehabilitation settings. FLR along with the severity modifier (SM) measure the effectiveness of the rehabilitation services at the physical therapist evaluation (initial examination [IE]) after 10 days of therapy and at discharge.

Objective: The objective of this study was to explore the completeness of FLR codes and describe changes in SMs at scheduled checkpoints for patients receiving outpatient physical therapy.

Origins and spread of fluted-point technology in the Canadian Ice-Free Corridor and eastern Beringia.

Fluted projectile points have long been recognized as the archaeological signature of early humans dispersing throughout the Western Hemisphere; however, we still lack a clear understanding of their appearance in the interior "Ice-Free Corridor" of western Canada and eastern Beringia. To solve this problem, we conducted a geometric morphometric shape analysis and a phylogenetic analysis of technological traits on fluted points from the archaeological records of northern Alaska and Yukon, in combination with artifacts from further south in Canada, the Great Plains, and eastern United States to investigate the plausibility of historical relatedness and evolutionary patterns in the spread of fluted-point technology in the latest Pleistocene and earliest Holocene. Results link morphologies and technologies of Clovis, certain western Canadian, and northern fluted points, suggesting that fluting technology arrived in the Arctic from a proximate source in the interior Ice-Free Corridor and ultimately from the earliest populations in temperate North America, complementing new genomic models explaining the peopling of the Americas.

Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP.

Mitochondria support synaptic transmission through production of ATP, sequestration of calcium, synthesis of glutamate, and other vital functions. Surprisingly, less than 50% of hippocampal CA1 presynaptic boutons contain mitochondria, raising the question of whether synapses without mitochondria can sustain changes in efficacy. To address this question, we analyzed synapses from postnatal day 15 (P15) and adult rat hippocampus that had undergone theta-burst stimulation to produce long-term potentiation (TBS-LTP) and compared them to control or no stimulation.

The unfolded protein response: mechanisms and therapy of neurodegeneration.

Activation of the unfolded protein response is emerging as a common theme in protein-misfolding neurodegenerative diseases, with relevant markers observed in patient tissue and mouse models. Genetic and pharmacological manipulation of the pathway in several mouse models has shown that this is not a passive consequence of the neurodegeneration process. Rather, overactivation of the protein kinase RNA-like ER kinase (PERK, encoded by EIF2AK3) branch of the unfolded protein response directly contributes to disease pathogenesis through the critical reduction in neuronal protein synthesis rates, essential for learning and memory and for neuronal survival.

PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy.

Mitochondrial fission is essential for the degradation of damaged mitochondria. It is currently unknown how the dynamin-related protein 1 (DRP1)-associated fission machinery is selectively targeted to segregate damaged mitochondria. We show that PTEN-induced putative kinase (PINK1) serves as a pro-fission signal, independently of Parkin.

Automatic Classification of the Vestibulo-Ocular Reflex Nystagmus: Integration of Data Clustering and System Identification.

The vestibulo-ocular reflex (VOR) plays an important role in our daily activities by enabling us to fixate on objects during head movements. Modeling and identification of the VOR improves our insight into the system behavior and improves diagnosis of various disorders. However, the switching nature of eye movements (nystagmus), including the VOR, makes dynamic analysis challenging.

Molecular chaperones and neuronal proteostasis.

Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases.

Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy.

Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses.

A comprehensive approach to zinc-finger recombinase customization enables genomic targeting in human cells.

Zinc-finger recombinases (ZFRs) represent a potentially powerful class of tools for targeted genetic engineering. These chimeric enzymes are composed of an activated catalytic domain derived from the resolvase/invertase family of serine recombinases and a custom-designed zinc-finger DNA-binding domain. The use of ZFRs, however, has been restricted by sequence requirements imposed by the recombinase catalytic domain.

Tonic signaling from O₂ sensors sets neural circuit activity and behavioral state.

Tonic receptors convey stimulus duration and intensity and are implicated in homeostatic control. However, how tonic homeostatic signals are generated and how they reconfigure neural circuits and modify animal behavior is poorly understood. Here we show that Caenorhabditis elegans O(2)-sensing neurons are tonic receptors that continuously signal ambient [O(2)] to set the animal's behavioral state.