Cross-platform validation of neurotransmitter release impairments in schizophrenia patient-derived -mutant neurons.

Heterozygous deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and additionally predispose to multiple other neurodevelopmental disorders. Engineered heterozygous deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity.

Development of a Sensitive Diagnostic Assay for Parkinson Disease Quantifying α-Synuclein-Containing Extracellular Vesicles.

Objective: To develop a reliable and fast assay to quantify the α-synuclein (α-syn)-containing extracellular vesicles (EVs) in CSF and to assess their diagnostic potential for Parkinson disease (PD).

Methods: A cross-sectional, multicenter study was designed, including 170 patients with PD and 131 healthy controls (HCs) with a similar distribution of age and sex recruited from existing center studies at the University of Washington and Oregon Health and Science University. CSF EVs carrying α-syn or aggregated α-syn were quantified using antibodies against total or aggregated α-syn, respectively, and highly specific, sensitive, and rapid assays based on the novel Apogee nanoscale flow cytometry technology.

Extrathoracic multiple trauma dysregulates neutrophil function and exacerbates pneumonia-induced lung injury.

Background: Forty percent of critically ill trauma patients will develop an infectious complication. Pneumonia is the most common cause of death of trauma patients surviving their initial insult. We previously demonstrated that polytrauma (PT), defined as two or more severe injuries in at least two areas of the body, induces emergency hematopoiesis characterized by accelerated myelopoiesis in the bone marrow and increased myeloid cell frequency in the peripheral tissues.

Bellidifolin Ameliorates Isoprenaline-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads and p38 Signaling and Preventing NR4A1 Cytoplasmic Localization.

Myocardial fibrosis is closely related to high morbidity and mortality. In Inner Mongolia, (Michx.) J.

Top 100 influential manuscripts in obstructive sleep apnea: a bibliometric analysis.

Objective: This study aimed to explore the characteristics of the top 100 influential manuscripts on obstructive sleep apnea (OSA).

Methods: All manuscripts in English were searched from the Thomson Reuters Web of Science database by using OSA-related terms and ranked based on citation frequency. The top 100 influential manuscripts were selected and further analyzed by author, subject, journal, year of publication, country of origin, and institution.

Simultaneously Toughening and Stiffening Elastomers with Octuple Hydrogen Bonding.

Current synthetic elastomers suffer from the well-known trade-off between toughness and stiffness. By a combination of multiscale experiments and atomistic simulations, a transparent unfilled elastomer with simultaneously enhanced toughness and stiffness is demonstrated. The designed elastomer comprises homogeneous networks with ultrastrong, reversible, and sacrificial octuple hydrogen bonding (HB), which evenly distribute the stress to each polymer chain during loading, thus enhancing stretchability and delaying fracture.

Two-dimensional topological insulators exfoliated from NaBi-like Dirac semimetals.

Topological insulation is widely predicted in two-dimensional (2D) materials realized by epitaxial growth or van der Waals (vdW) exfoliation. Such 2D topological insulators (TI's) host many interesting physical properties such as the quantum spin Hall effect and superconductivity. Here, we extend the search of 2D TI's into the exfoliatable non-vdW 2D crystals.

Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons.

Background: Many pregnant persons in the United States are receiving messenger RNA (mRNA) coronavirus disease 2019 (Covid-19) vaccines, but data are limited on their safety in pregnancy.

Methods: From December 14, 2020, to February 28, 2021, we used data from the "v-safe after vaccination health checker" surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) to characterize the initial safety of mRNA Covid-19 vaccines in pregnant persons.

Results: A total of 35,691 v-safe participants 16 to 54 years of age identified as pregnant.

Pharmacologic activation of autophagy without direct mTOR inhibition as a therapeutic strategy for treating dry macular degeneration.

Dry age-related macular degeneration (AMD) is marked by the accumulation of extracellular and intracellular lipid-rich deposits within and around the retinal pigment epithelium (RPE). Inducing autophagy, a conserved, intracellular degradative pathway, is a potential treatment strategy to prevent disease by clearing these deposits. However, mTOR inhibition, the major mechanism for inducing autophagy, disrupts core RPE functions.

Immunosuppression of Macrophages Underlies the Cardioprotective Effects of CST (Catestatin).

[Figure: see text].

Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines.

AXIN1 mutations are observed in 8-10% of hepatocellular carcinomas (HCCs) and originally were considered to support tumor growth by aberrantly enhancing β-catenin signaling. This view has however been challenged by reports showing neither a clear nuclear β-catenin accumulation nor clearly enhanced expression of β-catenin target genes. Here, using nine HCC lines, we show that AXIN1 mutation or siRNA mediated knockdown contributes to enhanced β-catenin signaling in all AXIN1-mutant and non-mutant lines, also confirmed by reduced signaling in AXIN1-repaired SNU449 cells.

Increased Reactive Oxygen Species-Mediated Ca/Calmodulin-Dependent Protein Kinase II Activation Contributes to Calcium Handling Abnormalities and Impaired Contraction in Barth Syndrome.

Background: Mutations in tafazzin (), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood.

Methods: We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac-specific knockout mice.

Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.

Background: No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer.

Methods: We conducted CheckMate 577, a global, randomized, double-blind, placebo-controlled phase 3 trial to evaluate a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer. Adults with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease were randomly assigned in a 2:1 ratio to receive nivolumab (at a dose of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks) or matching placebo.

N-protein presents early in blood, dried blood and saliva during asymptomatic and symptomatic SARS-CoV-2 infection.

The COVID-19 pandemic continues to have an unprecedented impact on societies and economies worldwide. There remains an ongoing need for high-performance SARS-CoV-2 tests which may be broadly deployed for infection monitoring. Here we report a highly sensitive single molecule array (Simoa) immunoassay in development for detection of SARS-CoV-2 nucleocapsid protein (N-protein) in venous and capillary blood and saliva.

Global Impact of COVID-19 on Stroke Care and IV Thrombolysis.

Objective: To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods.

Methods: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.

Further prenylated anthranoids from Harungana madagascariensis.

Ten undescribed anthranoids, including three anthraquinone acetals as racemic mixtures, (±)-kenganthranol G-I, and seven prenylated anthranols, (±)-kenganthranol J-M and harunganol G-I, together with thirteen known compounds, were isolated from the stem bark of Harungana madagascariensis. The structures of (±)-kenganthranol G and (±)-kenganthranol J were confirmed by X-ray crystallography. (±)-Kenganthranol G was separated into (+)-kenganthranol G and (-)-kenganthranol G by chiral HPLC and their absolute configurations were established by electronic circular dichroism.

The Negative Allosteric Modulator EU1794-4 Reduces Single-Channel Conductance and Ca Permeability of GluN1/GluN2A -Methyl-d-Aspartate Receptors.

NMDA receptors are ligand-gated ion channels that mediate a slow, Ca-permeable component of excitatory synaptic currents. These receptors are involved in several important brain functions, including learning and memory, and have also been implicated in neuropathological conditions and acute central nervous system injury, which has driven therapeutic interest in their modulation. The EU1794 series of positive and negative allosteric modulators of NMDA receptors has structural determinants of action near the preM1 helix that is involved in channel gating.

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review.

Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants.

The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.

Knockout of the Gene Inhibits Neointima Formation in a Mouse Model of Vascular Injury.

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Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity.

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.