Discovery and characterization of stereodefined PMO-gapmers targeting tau.

Antisense oligonucleotides (ASOs) are an important class of therapeutics to treat genetic diseases, and expansion of this modality to neurodegenerative disorders has been an active area of research. To realize chronic administration of ASO therapeutics to treat neurodegenerative diseases, new chemical modifications that improve activity and safety profiles are still needed. Furthermore, it is highly desirable to develop a single stereopure ASO with a defined activity and safety profile to avoid any efficacy and safety concerns due to the batch-to-batch variation in the composition of diastereomers.

Ca²⁺ signaling in myenteric interstitial cells of Cajal (ICC-MY) and their role as conditional pacemakers in the colon.

Interstitial cells of Cajal in the plane of the myenteric plexus (ICC-MY) serve as electrical pacemakers in the stomach and small intestine. A similar population of cells is found in the colon, but these cells do not appear to generate regular slow wave potentials, as characteristic in more proximal gut regions. Ca handling mechanisms in ICC-MY of the mouse proximal colon were studied using confocal imaging of muscles from animals expressing GCaMP6f exclusively in ICC.

Double Whammy: A Case Report of Immune Checkpoint Inhibitor Colitis and Concomitant Colitis in a Patient on Nivolumab.

Immune checkpoint inhibitors commonly cause gastrointestinal immune-related adverse effects. These patients also carry an increased risk of concomitant infections. This 66-year-old man with immune checkpoint inhibitor colitis was discovered to have concurrent and colitis.

Technology literacy and access to digital resources for remote assessment among adults enrolled in Alzheimer's disease research.

Background: The SARS-CoV-2 pandemic accelerated development of innovative methods for conducting research remotely via digital technologies. However, few studies have examined participant technological literacy skills or access as key social determinants of brain health in aging populations at risk of Alzheimer's disease and other dementias.

Objective: To identify associations of sociodemographic and clinical characteristics, cognitive status and geolocation with digital technology access and skill within dementia research cohorts.

The crystal and cryo-EM structures of PLCγ2 reveal dynamic interdomain recognitions in autoinhibition.

Phospholipase C gamma 2 (PLCγ2) plays important roles in cell signaling downstream of various membrane receptors. PLCγ2 contains a multidomain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLCγ2 activity modulation. Here we determined three structures of human PLCγ2 in autoinhibited states, which reveal dynamic interactions at the autoinhibition interface, involving the conformational flexibility of the Src homology 3 (SH3) domain in the inhibitory region, and its previously unknown interaction with a carboxyl-terminal helical domain in the core region.

Immunohistochemical characterization of interstitial cells and their spatial relationship to motor neurons within the mouse esophagus.

Interstitial cells of Cajal (ICC) and PDGFRα cells regulate smooth muscle motility in the gastrointestinal (GI) tract, yet their function in the esophagus remains unknown. The mouse esophagus has been described as primarily skeletal muscle; however, ICC  have been identified in this region. This study characterizes the distribution of skeletal and smooth muscle cells (SMCs) and their spatial relationship to ICC, PDGFRα cells, and intramuscular motor neurons in the mouse esophagus.

Association of Postpartum Temperature Exposure with Postpartum Depression: A Retrospective Cohort Study in Southern California.

Background: Postpartum depression (PPD) has been associated with biological, emotional, social, and environmental factors. However, evidence regarding the effect of temperature on PPD is extremely limited.

Objectives: We aimed to examine the associations between postpartum temperature exposure and PPD.

Integrated responses of the SIP syncytium generate a major motility pattern in the colon.

The peristaltic reflex has been a central concept in gastrointestinal motility; however, evidence was published recently suggesting that post-stimulus responses that follow inhibitory neural responses provide the main propulsive force in colonic motility. This new concept was based on experiments on proximal colon where enteric inhibitory neural inputs are mainly nitrergic. However, the nature of inhibitory neural inputs changes from proximal to distal colon where purinergic inhibitory regulation dominates.

Simplifying Complex Figure scoring: Data from the Emory Healthy Brain Study and initial clinical validation.

Objective: To introduce the Emory 10-element Complex Figure (CF) scoring system and recognition task. We evaluated the relationship between Emory CF scoring and traditional Osterrieth CF scoring approach in cognitively healthy volunteers. Additionally, a cohort of patients undergoing deep brain stimulation (DBS) evaluation was assessed to compare the scoring methods in a clinical population.

Automated denoising software for calcium imaging signals using deep learning.

Dynamic Ca signaling is crucial for cell survival and death, and Ca imaging approaches are commonly used to study and measure cellular Ca patterns within cells. However, the presence of image noise from instrumentation and experimentation protocols can impede the accurate extraction of Ca signals. Removing noise from Ca Spatio-Temporal Maps (STMaps) is essential for precisely analyzing Ca datasets.

Mannich-Type Condensation and Domino Quinazolinone-Amidine Rearrangement Affords Ring-Fused Mackinazolinones with Anti-Amoebic Activity.

A three-step synthesis of anti-amoebic, ring-fused mackinazolinones has been developed. A Mannich-type reaction between quinazolin-4-ones and -Cbz propanal in the presence of AgOTf afforded quinazolinones (19-94% isolated yield) bearing a newly formed heterocycle with an alkylamine appendage that, upon -Cbz deprotection and basification, triggered a domino rearrangement to afford 45 separable, ring-fused products. Several compounds inhibited growth of parasites that can cause a lethal human brain infection.

Assessing Interprofessional Collaboration at Clinical Learning Sites: Methodology on Developing the IP-CLEAR Tool.

Interprofessional Clinical Learning Environment Assessment and Reflection (IP-CLEAR) tool was developed by a team of faculty from the schools of nursing, pharmacy, and medicine at University of North Carolina at Chapel Hill (UNC-CH), with the support of the North Carolina Area Health Education Consortium (NC AHEC) and the UNC-CH Office of Interprofessional Education and Practice (IPEP). The IP-CLEAR tool is intended for use by clinical sites that have or want to have clinical learners engaged and integrated into an excellent interprofessional CLE. The development of the IP-CLEAR and projections for future work are described here.

Graduate Medical Education Financing in the US Department of Veterans Affairs.

Background: The US Department of Veterans Affairs (VA) partners with 250 sponsors of graduate medical education (GME), annually providing $850 million for 11,000 full-time equivalent resident positions that support veteran patient care and provide educational opportunities for trainees from affiliated academic programs. Knowledge of VA GME financing is vital to maintain these partnerships.

Observations: In response to increased scrutiny from several federal oversight bodies, the VA revised its GME reimbursement policy and procedures, including implementing new resident tracking and auditing mechanisms.

Charting the coordinative landscape of the F-Sc/Sc/Lu triad with the tri-aza-cyclononane (tacn) scaffold.

The widely established PET isotope F does not have a therapeutic partner. We have recently established that the Sc-F bond can be formed under aqueous, high yielding conditions, paving the way to providing F as diagnostic partners to Sc and Lu radiotherapeutics. Here, we synthesized a library of tacn-based chelators comprised of 10 structurally unique permutations incorporating acetate, methyl-benzylamide and picolinate donor arms.

Resolving Structures of Paramagnetic Systems in Chemistry and Materials Science by Solid-State NMR: The Revolving Power of Ultra-Fast MAS.

Ultra-fast magic-angle spinning (100+kHz) has revolutionized solid-state NMR of biomolecular systems but has so far failed to gain ground for the analysis of paramagnetic organic and inorganic powders, despite the potential rewards from substantially improved spectral resolution. The principal blockages are that the smaller fast-spinning rotors present significant barriers for sample preparation, particularly for air/moisture-sensitive systems, and are associated with low sensitivity from the reduced sample volumes. Here, we demonstrate that the sensitivity penalty is less severe than expected for highly paramagnetic solids and is more than offset by the associated improved resolution.

Long-term efficacy and safety of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): extended follow-up of an open-label, multicentre, randomised, non-inferiority trial.

Background: STREAM stage 2 showed that two bedaquiline-containing regimens (a 9-month all-oral regimen and a 6-month regimen with 8 weeks of aminoglycoside) had superior efficacy to a 9-month injectable-containing regimen for rifampicin-resistant tuberculosis up to 76 weeks after randomisation. Our objective in this follow-up analysis was to assess the durability of efficacy and safety, including mortality, at 132 weeks.

Methods: We report the long-term outcomes from STREAM stage 2, a randomised, phase 3 non-inferiority (10% margin) trial in participants (aged ≥15 years) with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance at 13 clinical sites in seven countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda).

Activation of NPY2R-expressing amygdala neurons inhibits itch behavior in mice without lateralization.

The central amygdala (CeA) is a crucial hub in the processing of affective itch, containing a diverse array of neuronal populations. Among these components, Neuropeptide Y (NPY) and its receptors, such as NPY2R, affect various physiological and psychological processes. Despite this broad impact, the precise role of NPY2R CeA neurons in itch modulation remains unknown, particularly concerning any potential lateralization effects.

Scalable Self-Assembly of Composite Nanofibers into High-Energy-Density Li-Ion Battery Electrodes.

The application of nanosized active particles in Li-ion batteries has been the subject of intense investigation, yielding mixed results in terms of overall benefits. While nanoparticles have shown promise in improving rate performance and reducing issues related to cracking, they have also faced criticism due to side reactions, low packing density, and consequent subpar volumetric battery performance. Interesting processes such as self-assembly have been proposed to increase packing density, but these tend to be incompatible with scalable processes such as roll-to-roll coating, which are essential to manufacture electrodes at scale.

A decarbonylative approach to alkylnickel intermediates and C(sp)-C(sp) bond formation.

The myriad nickel-catalyzed cross-coupling reactions rely on the formation of an organonickel intermediate, but limitations in forming monoalkylnickel species have limited options for C(sp) cross-coupling. The formation of monoalkylnickel(II) species from abundant carboxylic acid esters would be valuable, but carboxylic acid derivatives are primarily decarboxylated to form alkyl radicals that lack the correct reactivity. In this work, we disclose a facile oxidative addition and decarbonylation sequence that forms monoalkylnickel(II) intermediates through a nonradical process.

Sinefungin, a natural nucleoside analog of S-adenosyl methionine, impairs the pathogenicity of .

, an opportunistic fungal pathogen, causes life-threatening infections in immunocompromised patients. Current antifungals are limited by toxicity, drug-drug interactions, and emerging resistance, underscoring the importance of identifying novel treatment approaches. Here, we elucidate the impact of sinefungin, an analog of S-adenosyl methionine, on the virulence of strain SC5314 and clinical isolates.

Sea snakes.

Jenna Crowe-Riddell and colleagues introduce sea snakes.