Harnessing Multi-Center-2-Electron Bonds for Carbene Metal-Hydride Nanocluster Catalysis.

N-Heterocyclic carbene (NHC) ligands possess the ability to stabilize metal-based nanomaterials for a broad range of applications. With respect to metal-hydride nanomaterials, however, carbenes are rare, which is surprising if one considers the importance of metal-hydride bonds across the chemical sciences. In this study, we introduce a bottom-up approach leveraging preexisting metal-metal m-center-n-electron (mc-ne) bonds to access a highly stable cyclic(alkyl)amino carbene (CAAC) copper-hydride nanocluster, [(CAAC)6Cu14H12][OTf]2 with superior stability compared to Stryker's reagent, a popular commercial phosphine-based copper hydride catalyst.

Synthesis of Chiral Saturated Heterocycles Bearing Quaternary Centers via Enantioselective β-C(sp)-H Activation of Lactams.

The development of catalytic methods for the synthesis of enantiopure saturated heterocycles has been a long-standing challenge in asymmetric catalysis. We describe the first highly enantioselective palladium-catalyzed βC(sp)-H arylation and olefination of lactams for the preparation of various chiral N-heterocycles bearing quaternary carbon centers. The presence of strongly electron-withdrawing groups on the chiral bifunctional MPAThio ligand is crucial to the reactivity of weakly coordinating lactams.

Daily sleep and physical activity from accelerometry in adults: Temporal associations and lag effects.

Objectives: Insufficient sleep is linked to various health issues, while physical activity is a protective measure against chronic diseases. Despite the importance of sleep and physical activity for supporting public health, there remains scant research investigating daily and cumulative associations between objectively measured physical activity and sleep. Understanding the associations of physical activity and sleep behaviors over multiple days may inform the efficacy of interventions to synergistically support both behaviors.

Spatial covariance reveals isothiocyanate natural products adjust redox stress to restore function in alpha-1-antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is a monogenic disease caused by misfolding of AAT variants resulting in gain-of-toxic aggregation in the liver and loss of monomer activity in the lung leading to chronic obstructive pulmonary disease (COPD). Using high-throughput screening, we discovered a bioactive natural product, phenethyl isothiocyanate (PEITC), highly enriched in cruciferous vegetables, including watercress and broccoli, which improves the level of monomer secretion and neutrophil elastase (NE) inhibitory activity of AAT-Z through the endoplasmic reticulum (ER) redox sensor protein disulfide isomerase (PDI) A4 (PDIA4). The intracellular polymer burden of AAT-Z can be managed by combination treatment of PEITC and an autophagy activator.

2024 HRS perspective on advancing workflows for CIED remote monitoring.

Cardiac implantable electronic devices (CIEDs) generate substantial data, often stored in image or PDF formats. Remote monitoring, now an integral component of patient care, places considerable administrative burdens on clinicians and staff, in large part due to the challenge of integrating these data seamlessly into electronic health records. Since 2006, the Heart Rhythm Society, in collaboration with the CIED industry, has led an initiative to establish a unified standard nomenclature.

Comparison of clinical and radiological outcomes of three-column lumbar osteotomies with and without interbody cages for adult spinal deformity.

Background Context: Correcting sagittal malalignment in adult spinal deformity (ASD) is a challenging task, often requiring complex surgical interventions like pedicle subtraction osteotomies (PSOs). Different types of three-column osteotomies (3COs), including Schwab 3, Schwab 4, Schwab 4 with interbody cages, and the "sandwich" technique, aim to optimize alignment and fusion outcomes. The role of interbody cages in enhancing fusion and segmental correction remains unclear.

Antibody-drug conjugates targeting SSEA-4 inhibits growth and migration of SSEA-4 positive breast cancer cells.

Although breast cancer treatment has evolved significantly in recent years, drug resistance remains a major challenge. To identify new targets for breast cancer, we found that stage-specific embryonic antigen 4 (SSEA-4) is expressed in all subtypes of breast cancer cell lines, and the increased expression of the associated enzymes β3GalT5 and ST3Gal2 correlates with poor recurrence-free survival (RFS) in breast cancer. We also found that SSEA-4 antibodies can be rapidly internalized into breast cancer cells, a property that makes SSEA-4 an attractive target for antibody-drug conjugates (ADCs).

Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates.

mRNA delivered using lipid nanoparticles (LNPs) has become an important subunit vaccine modality, but mechanisms of action for mRNA vaccines remain incompletely understood. Here, we synthesized a metal chelator-lipid conjugate enabling positron emission tomography (PET) tracer labeling of LNP/mRNA vaccines for quantitative visualization of vaccine trafficking in live mice and non-human primates (NHPs). Following intramuscular injection, we observed LNPs distributing through injected muscle tissue, simultaneous with rapid trafficking to draining lymph nodes (dLNs).

Radiosynthesis and evaluation of novel F labeled PET ligands for imaging monoacylglycerol lipase.

Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production.

Signaling Dynamics in Osteogenesis: Unraveling Therapeutic Targets for Bone Generation.

Diseases affecting bone encompass a spectrum of disorders, from prevalent conditions such as osteoporosis and Paget's disease, collectively impacting millions, to rare genetic disorders including Fibrodysplasia Ossificans Progressiva (FOP). While several classes of drugs, such as bisphosphonates, synthetic hormones, and antibodies, are utilized in the treatment of bone diseases, their efficacy is often curtailed by issues of tolerability and high incidence of adverse effects. Developing therapeutic agents for bone diseases is hampered by the fact that numerous pathways regulating bone metabolism also perform pivotal functions in other organ systems.

Conservation benefits of a large marine protected area network that spans multiple ecosystems.

Marine protected areas (MPAs) are widely implemented tools for long-term ocean conservation and resource management. Assessments of MPA performance have largely focused on specific ecosystems individually and have rarely evaluated performance across multiple ecosystems either in an individual MPA or across an MPA network. We evaluated the conservation performance of 59 MPAs in California's large MPA network, which encompasses 4 primary ecosystems (surf zone, kelp forest, shallow reef, deep reef) and 4 bioregions, and identified MPA attributes that best explain performance.

Physiologic and structural characterization of desisobutyryl-ciclesonide, a selective glucocorticoid receptor modulator in newborn rats.

Bronchopulmonary dysplasia, the most prevalent chronic lung disease of prematurity, is often treated with glucocorticoids (GCs) such as dexamethasone (DEX), but their use is encumbered with several adverse somatic, metabolic, and neurologic effects. We previously reported that systemic delivery of the GC prodrug ciclesonide (CIC) in neonatal rats activated glucocorticoid receptor (GR) transcriptional responses in lung but did not trigger multiple adverse effects caused by DEX. To determine whether limited systemic metabolism of CIC was solely responsible for its enhanced safety profile, we treated neonatal rats with its active metabolite desisobutyryl-ciclesonide (Des-CIC).

β-C-H bond functionalization of ketones and esters by cationic Pd complexes.

C-H activation is the most direct way of functionalizing organic molecules. Many advances in this field still require specific directing groups to achieve the necessary activity and selectivity. Developing C-H activation reactions directed by native functional groups is essential for their broad application in synthesis.

Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.

Neutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E.

Induced cell phenotype activity recording of DNA-tagged ligands.

Based on their ability to canvas vast genetic or chemical space at low cost and high speed, DNA-encoded libraries (DEL) have served to enable both genomic and small molecule discovery. Current DEL chemical library screening approaches focus primarily on target-based affinity or activity. Here we describe an approach to record the phenotype-based activity of DNA-encoded small molecules on their cognate barcode in living cells.

Tungsten-catalyzed stereodivergent isomerization of terminal olefins.

Catalytic alkene isomerization is a powerful synthetic strategy for preparing valuable internal alkenes from simple feedstocks. The utility of olefin isomerization hinges on the ability to control both positional and stereoisomerism to access a single product among numerous potential isomers. Within base-metal catalysis, relatively little is known about how to modulate reactivity and selectivity with group 6 metal-catalyzed isomerization.

Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes.

Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor-G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist.

Convergent Evolution of Armor: Thermal Resistance in Deep-Sea Hydrothermal Vent Crustaceans.

Organisms occupy diverse ecological niches worldwide, each with characteristics finely evolved for their environments. Crustaceans residing in deep-sea hydrothermal vents, recognized as one of Earth's extreme environments, may have adapted to withstand severe conditions, including elevated temperatures and pressure. This study compares the exoskeletons of two vent crustaceans (bythograeid crab sp.

Biomolecular Condensates can Induce Local Membrane Potentials.

Biomolecular condensates are a ubiquitous component of cells, known for their ability to selectively partition and compartmentalize biomolecules without the need for a lipid membrane. Nevertheless, condensates have been shown to interact with lipid membranes in diverse biological processes, such as autophagy and T-cell activation. Since many condensates are known to have a net surface charge density and associated electric potential(s), we hypothesized that they can induce a local membrane potential.

Investigating the Role of Glyoxalase 1 as a Therapeutic Target for Cocaine and Oxycodone Use Disorder.

Methylglyoxal (MG) is an endogenously produced non-enzymatic side product of glycolysis that acts as a partial agonist at GABA receptors. MG that is metabolized by the enzyme glyoxalase-1 (GLO1). Inhibition of GLO1 increases methylglyoxal levels, and has been shown to modulate various behaviors, including decreasing seeking of cocaine-paired cues and ethanol consumption.

Cellular Function of a Biomolecular Condensate Is Determined by Its Ultrastructure.

Biomolecular condensates play key roles in the spatiotemporal regulation of cellular processes. Yet, the relationship between atomic features and condensate function remains poorly understood. We studied this relationship using the polar organizing protein Z (PopZ) as a model system, revealing how its material properties and cellular function depend on its ultrastructure.

Impact of extended-course oral nirmatrelvir/ritonavir in established Long COVID: a case series.

Background: Prior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir.

Methods: We documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.

Electrifying P(V): Access to Polar and Radical Reactivity.

Electrochemical, fully stereoselective P(V)-radical hydrophosphorylation of olefins and carbonyl compounds using a P(V) reagent is disclosed. By strategically selecting the anode material, radical reactivity is accessible for alkene hydrophosphorylation whereas a polar pathway operates for ketone hydrophosphorylation. The mechanistic intricacies of these chemoselective transformations were explored in-depth.

Seryl-tRNA synthetase inhibits Wnt signaling and breast cancer progression and metastasis.

Tumors require ample protein synthesis to grow, and aminoacyl-tRNA synthetases, as critical translation factors, are expected to support cancer progression. Unexpectedly, overexpression of seryl-tRNA synthetase (SerRS) suppresses primary tumor growth of breast cancer. However, the effects of SerRS on metastasis have not been studied.