Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens.

The antigen-presenting molecule MR1 (MHC class I-related protein 1) presents metabolite antigens derived from microbial vitamin B synthesis to activate mucosal-associated invariant T (MAIT) cells. Key aspects of this evolutionarily conserved pathway remain uncharacterized, including where MR1 acquires ligands and what accessory proteins assist ligand binding. We answer these questions by using a fluorophore-labeled stable MR1 antigen analog, a conformation-specific MR1 mAb, proteomic analysis, and a genome-wide CRISPR/Cas9 library screen.

XEN45 Gel Stent implantation in eyes with primary open angle glaucoma: A study from a single hospital in Taiwan.

Background: To evaluate the effectiveness and safety of the XEN45 Gel Stent in East Asian patients with primary open angle glaucoma (POAG).

Methods: We retrospectively reviewed 37 medically uncontrolled POAG patients who received XEN45 Gel Stent. The primary outcomes were reduction in intraocular pressure (IOP) and in the number of glaucoma medications 12 months after surgery.

Antiplatelet Management for Stent-Assisted Coiling and Flow Diversion of Ruptured Intracranial Aneurysms: A DELPHI Consensus Statement.

Background And Purpose: There is a paucity of data regarding antiplatelet management strategies in the setting of stent-assisted coiling/flow diversion for ruptured intracranial aneurysms. This study aimed to identify current challenges in antiplatelet management during stent-assisted coiling/flow diversion for ruptured intracranial aneurysms and to outline possible antiplatelet management strategies.

Materials And Methods: The modified DELPHI approach with an on-line questionnaire was sent in several iterations to an international, multidisciplinary panel of 15 neurointerventionalists.

Interpreting Patient-Reported Outcome Measures in Orthopaedic Surgery: A Systematic Review.

Background: The Consolidated Standards of Reporting Trials (CONSORT) Statement recommends that studies report results beyond p values and include treatment effect(s) and measures of precision (e.g., confidence intervals [CIs]) to facilitate the interpretation of results.

Challenging the Ischemic Core Concept in Acute Ischemic Stroke Imaging.

Endovascular treatment is a highly effective therapy for acute ischemic stroke due to large vessel occlusion and has recently revolutionized stroke care. Oftentimes, ischemic core extent on baseline imaging is used to determine endovascular treatment-eligibility. There are, however, 3 fundamental issues with the core concept: First, computed tomography and magnetic resonance imaging, which are mostly used in the acute stroke setting, are not able to precisely determine whether and to what extent brain tissue is infarcted (core) or still viable, due to variability in tissue vulnerability, the phenomenon of selective neuronal loss and lack of a reliable gold standard.

Association of common genetic variants with brain microbleeds: A genome-wide association study.

Objective: To identify common genetic variants associated with the presence of brain microbleeds (BMBs).

Methods: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel.

Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI extension.

The SPIRIT 2013 statement aims to improve the completeness of clinical trial protocol reporting by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes.

Reporting guidelines for clinical trial reports for interventions involving artificial intelligence: the CONSORT-AI extension.

The CONSORT 2010 statement provides minimum guidelines for reporting randomized trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes.

Effect of pimavanserin on anxious depression in patients with major depression and an inadequate response to previous therapy: secondary analysis of the clarity study.

In a post hoc analysis, the effect of pimavanserin on anxious depression was determined from CLARITY, a randomized, double-blind, placebo-controlled study in patients with major depression and an inadequate response to previous therapy. Patients were randomized in a 3:1 ratio to placebo or pimavanserin 34 mg daily added to ongoing antidepressant therapy. At 5 weeks, placebo nonresponders were rerandomized to placebo or pimavanserin for an additional 5 weeks.

A Carbohydrate-Binding Protein from the Edible Lablab Beans Effectively Blocks the Infections of Influenza Viruses and SARS-CoV-2.

The influenza virus hemagglutinin (HA) and coronavirus spike (S) protein mediate virus entry. HA and S proteins are heavily glycosylated, making them potential targets for carbohydrate binding agents such as lectins. Here, we show that the lectin FRIL, isolated from hyacinth beans (Lablab purpureus), has anti-influenza and anti-SARS-CoV-2 activity.

The draft genome assembly of the critically endangered , a plant species with extremely small populations endemic to Yunnan Province, China.

is a deciduous tree species in the family Nyssaceae within the order Cornales. As only eight individual trees and two populations have been recorded in China's Yunnan province, this species has been listed among China's national Class I protection species since 1999 and also among 120 PSESP (Plant Species with Extremely Small Populations) in the (2011-2-15). Here, we present the draft genome assembly of .

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

Objective: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.

Methods: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.

Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury.

Background: Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain.

Methods: We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury.

GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death.

Background: Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications.

Precision Targeting of -Null Triple-Negative Breast Tumors Guided by Electrophilic Metabolite Sensing.

Off-target effects continue to impede disease interventions, particularly when targeting a specific protein within a family of similar proteins, such as kinase isoforms that play tumor-subtype-specific roles in cancers. Exploiting the specific electrophilic-metabolite-sensing capability of Akt3, versus moderate or no sensing, respectively, by Akt2 and Akt1, we describe a first-in-class functionally Akt3-selective covalent inhibitor [MK-H(F)NE], wherein the electrophilic core is derived from the native reactive lipid metabolite HNE. Mechanistic profiling and pathway interrogations point to retention of the metabolite's structure-as opposed to implicit electrophilicity-as being essential for biasing isoform preference, which we found translates to tumor-subtype specificity against -null triple-negative breast cancers (TNBCs).

Developing Smartphone-Based Objective Assessments of Physical Function in Rheumatoid Arthritis Patients: The PARADE Study.

Background: Digital biomarkers that measure physical activity and mobility are of great interest in the assessment of chronic diseases such as rheumatoid arthritis, as it provides insights on patients' quality of life that can be reliably compared across a whole population.

Objective: To investigate the feasibility of analyzing iPhone sensor data collected remotely by means of a mobile software application in order to derive meaningful information on functional ability in rheumatoid arthritis patients.

Methods: Two objective, active tasks were made available to the study participants: a wrist joint motion test and a walk test, both performed remotely and without any medical supervision.

Validation and Disease Risk Assessment of Previously Reported Genome-Wide Genetic Variants Associated With Brugada Syndrome: SADS-TW BrS Registry.

Background: Brugada syndrome (BrS) is an oligogenic arrhythmic disease with increased risk of sudden cardiac arrest. Several BrS or ECG traits-related single-nucleotide polymorphisms (SNPs) were identified through previous genome-wide association studies in white patients. We aimed to validate these SNPs in BrS patients in the Taiwanese population, assessing the cumulative effect of risk alleles and the BrS-polygenic risk score in predicting cardiac events.

Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models.

Background: Stroke is a leading cause of adult disability that can severely compromise the quality of life of patients, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNA) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of the potential therapeutic roles for circRNAs.

Stability of Plasma Amyloid-β 1-40, Amyloid-β 1-42, and Total Tau Protein over Repeated Freeze/Thaw Cycles.

Introduction: Blood biomarkers of Alzheimer's disease (AD) have attracted much attention of researchers in recent years. In clinical studies, repeated freeze/thaw cycles often occur and may influence the stability of biomarkers. This study aims to investigate the stability of amyloid-β 1-40 (Aβ), amyloid-β 1-42 (Aβ), and total tau protein (T-tau) in plasma over freeze/thaw cycles.

Time Dependence of Few-Body Förster Interactions among Ultracold Rydberg Atoms.

Rubidium Rydberg atoms in either |m_{j}| sublevel of the 36p_{3/2} state can exchange energy via Stark-tuned Förster resonances, including two-, three-, and four-body dipole-dipole interactions. Three-body interactions of this type were first reported and categorized by Faoro et al. [Nat.

Selective Serotonin Reuptake Inhibitors and Intracerebral Hemorrhage Risk and Outcome.

Background and Purpose- Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications and conflicting reports on outcome after stroke. We sought to evaluate whether pre-intracerebral hemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome. Methods- Through post hoc analysis of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage), SSRI use was categorized into no use, pre-ICH only, pre- and post-ICH use (termed "continuous"), and post-ICH only (termed "new").

Commonly observed RNF43 mutations retain functionality in attenuating Wnt/β-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers.

Cancer-associated RNF43 mutations lead to activation of β-catenin signaling through aberrantly increasing Wnt-receptor levels at the membrane. Importantly, inactivating RNF43 mutations have been suggested to render cancer cells sensitive to Wnt-based therapeutics. However, the extent to which RNF43 mutations lead to impaired regulation of Wnt/β-catenin signaling has been poorly investigated.

BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice.

Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours.

Transforming Growth Factor Beta-Activated Kinase 1-Dependent Microglial and Macrophage Responses Aggravate Long-Term Outcomes After Ischemic Stroke.

Background and Purpose- Microglia/macrophages (Mi/MΦ) can profoundly influence stroke outcomes by acquiring functionally dominant phenotypes (proinflammatory or anti-inflammatory; deleterious or salutary). Identification of the molecular mechanisms that dictate the functional status of Mi/MΦ after brain ischemia/reperfusion may reveal novel therapeutic targets for stroke. We hypothesized that activation of TAK1 (transforming growth factor beta-activated kinase 1), a key MAP3K upstream of multiple inflammation-regulating pathways, drives Mi/MΦ toward a proinflammatory phenotype and potentiates ischemia/reperfusion brain injury.