Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions.

α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson's disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer's disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn.

Non-antibiotic pharmaceuticals are toxic against Escherichia coli with no evolution of cross-resistance to antibiotics.

Antimicrobial resistance can arise in the natural environment via prolonged exposure to the effluent released by manufacturing facilities. In addition to antibiotics, pharmaceutical plants also produce non-antibiotic pharmaceuticals, both the active ingredients and other components of the formulations. The effect of these on the surrounding microbial communities is less clear.

Targeting TRPC channels for control of arthritis-induced bone erosion.

Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca-selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels.

A Randomized, Blinded, Vehicle-Controlled Dose-Ranging Study to Evaluate and Characterize Remdesivir Efficacy Against Ebola Virus in Rhesus Macaques.

Ebola virus (EBOV) causes severe disease in humans, with mortality as high as 90%. The small-molecule antiviral drug remdesivir (RDV) has demonstrated a survival benefit in EBOV-exposed rhesus macaques. Here, we characterize the efficacy of multiple intravenous RDV dosing regimens on survival of rhesus macaques 42 days after intramuscular EBOV exposure.

The impact of implementing and sustaining the international guidelines for skin-to-skin contact in the first hour after birth in Uganda.

Skin-to-skin contact between the mother and baby during the first hour after birth has significant benefits for mother, newborn and breastfeeding. However, optimal implementation is highly variable. The 2023 International Guidelines on skin-to-skin contact in the first hour after birth place high confidence in the evidence that immediate, continuous, uninterrupted skin-to-skin contact should be routine for all mothers and all babies over 1000 g, regardless of mode of delivery.

Software codesign between end users and developers to enhance utility for biodiversity conservation.

Creating software tools that address the needs of a wide range of decision-makers requires the inclusion of differing perspectives throughout the development process. Software tools for biodiversity conservation often fall short in this regard, partly because broad decision-maker needs may exceed the toolkits of single research groups or even institutions. We show that participatory, collaborative codesign enhances the utility of software tools for better decision-making in biodiversity conservation planning, as demonstrated by our experiences developing a set of integrated tools in Colombia.

Heterogeneity and Penumbra of White Matter Hyperintensities in Small Vessel Diseases Determined by Quantitative MRI.

Background: White matter hyperintensities (WMHs) are established structural imaging markers of cerebral small vessel disease. The pathophysiologic condition of brain tissue varies over the core, the vicinity, and the subtypes of WMH and cannot be interpreted from conventional magnetic resonance imaging. We aim to improve our pathophysiologic understanding of WMHs and the adjacently injured normal-appearing white matter in terms of microstructural and microvascular alterations using quantitative magnetic resonance imaging in patients with sporadic and genetic cerebral small vessel disease.

Benefit of early oseltamivir therapy for adults hospitalized with influenza A: an observational study.

Background: clinical guidelines recommend initiation of antiviral therapy as soon as possible for patients hospitalized with confirmed or suspected influenza.

Methods: A multicenter US observational sentinel surveillance network prospectively enrolled adults (aged ≥18 years) hospitalized with laboratory-confirmed influenza at 24 hospitals during October 1, 2022-July 21, 2023. A multivariable proportional odds model was used to compare peak pulmonary disease severity (no oxygen support, standard supplemental oxygen, high-flow oxygen/non-invasive ventilation, invasive mechanical ventilation, or death) after the day of hospital admission among patients starting oseltamivir treatment on the day of admission (early) versus those who did not (late or not treated), adjusting for baseline (admission day) severity, age, sex, site, and vaccination status.

Rethinking how mobile units can catalyze progress on lung cancer screening: a scoping review of what we have learned.

Background: Despite United States Preventive Services Task Force (USPSTF) recommendations, low uptake of lung cancer screening (LCS) highlights the need for measures to promote adoption. This scoping review aims to outline the global landscape of mobile low-dose computed tomography (LDCT) platforms, summarizing research and evaluating efficacy in screening at-risk populations.

Methods: We comprehensively searched Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Embase, Scopus, and Web of Science for articles published between 2017 and 2023.

A first-in-human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults.

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B-cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN-303; TACI vTD-Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild-type TACI-Fc or BAFF- or APRIL-specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models.

Activity-Based DNA-Encoded Library Screening for Selective Inhibitors of Eukaryotic Translation.

Small molecule probes exist for only ∼2% of human proteins because most lack functional binding pockets or cannot be assayed for high-throughput screening. Selective translation modulation circumvents canonical druggability and assay development constraints by using in vitro transcription-translation (IVTT) as a universal biochemical screening assay. We developed an IVTT activity assay by fusing a GFP reporter to various target gene sequences and screened the target sequences for inhibitors in microfluidic picoliter-scale droplets using a 5,348-member translation inhibitor DNA-encoded library (DEL).

Childhood neglect is associated with alterations in neural prediction error signaling and the response to novelty.

Background: One in eight children experience early life stress (ELS), which increases risk for psychopathology. ELS, particularly neglect, has been associated with reduced responsivity to reward. However, little work has investigated the computational specifics of this disrupted reward response - particularly with respect to the neural response to Reward Prediction Errors (RPE) - a critical signal for successful instrumental learning - and the extent to which they are augmented to novel stimuli.

Association of Adherence to a MIND-Style Diet With the Risk of Cognitive Impairment and Decline in the REGARDS Cohort.

Background And Objectives: Diet may influence the development of cognitive impairment and affect cognitive decline, but whether this relationship varies between Black American and White American people is unclear. This study examined the association of Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) and incident cognitive impairment and cognitive trajectories in a biracial prospective cohort study.

Methods: Using data derived from the Food Frequency Questionnaire in the REasons for Geographic and Racial Differences in Stroke study, we compared MIND diet adherence with incident cognitive impairment and cognitive trajectory in Black participants and White participants.

Clinical Utility of LC-MS/MS for Blood Myo-Inositol in Patients with Acute Kidney Injury and Chronic Kidney Disease.

Background: Diagnosing acute kidney injury (AKI) and chronic kidney disease (CKD) relies on creatinine, which lacks optimal diagnostic sensitivity. The kidney-specific proximal tubular enzyme myo-inositol oxygenase (MIOX) catalyzes the conversion of myo-inositol (MI) to D-glucuronic acid. We hypothesized that proximal tubular damage, which occurs in AKI and CKD, will decrease MIOX activity, causing MI accumulation.

Observation of Medium-Induced Yield Enhancement and Acoplanarity Broadening of Low-p_{T} Jets from Measurements in pp and Central Pb-Pb Collisions at sqrt[s_{NN}]=5.02 TeV.

The ALICE Collaboration reports the measurement of semi-inclusive distributions of charged-particle jets recoiling from a high transverse momentum (high p_{T}) hadron trigger in proton-proton and central Pb-Pb collisions at sqrt[s_{NN}]=5.02  TeV. A data-driven statistical method is used to mitigate the large uncorrelated background in central Pb-Pb collisions.

Validation of Lung Ultrasound for Coronavirus Disease 2019 Prognostication in an International Multicenter Cohort Study.

Background: Despite many studies evaluating lung ultrasound (LUS) for coronavirus disease 2019 (COVID-19) prognostication, the generalizability and utility across clinical settings are uncertain.

Methods: Adults (≥18 years of age) with COVID-19 were enrolled at 2 military hospitals, an emergency department, home visits, and a homeless shelter in the United States, and in a referral hospital in Uganda. Participants had a 12-zone LUS scan performed at time of enrollment and clips were read off-site.

Arenavirus-Based Vectors Generate Robust SIV Immunity in Non-Human Primates.

Arenavirus-based vectors are being investigated as therapeutic vaccine candidates with the potential to elicit robust CD8 T-cell responses. We compared the immunogenicity of replicating (artPICV and artLCMV) and non-replicating (rPICV and rLCMV) arenavirus-based vectors expressing simian immunodeficiency virus (SIV) Gag and Envelope (Env) immunogens in treatment-naïve non-human primates. Heterologous regimens with non-replicating and replicating vectors elicited more robust SIV IFN-γ responses than a homologous regimen, and replicating vectors elicited significantly higher cellular immunogenicity than non-replicating vectors.