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 i.

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.

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.

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.

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.

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.

Dynamics of neural activity in early nervous system evolution.

New techniques for largescale neural recordings from diverse animals are reshaping comparative systems neuroscience. This growth necessitates fresh conceptual paradigms for comparing neural circuits and activity patterns. Here, we take a systems neuroscience approach to early neural evolution, emphasizing the importance of considering nervous systems as multiply modulated, continuous dynamical systems.

Experimental medicine study with stabilised native-like HIV-1 Env immunogens drives long-term antibody responses, but lacks neutralising breadth.

Background: We report findings from an experimental medicine study of rationally designed prefusion stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global circulating strains, delivered by sequential intramuscular injection.

Methods: Healthy adult volunteers were enrolled into one of five groups (A to E) each receiving a different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO, either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic Env immunogens (Mos3.1 and Mos3.

Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein.

The most advanced monoclonal antibodies (mAbs) and vaccines against malaria target the central repeat region or closely related sequences within the circumsporozoite protein (PfCSP). Here, using an antigen-agnostic strategy to investigate human antibody responses to whole sporozoites, we identified a class of mAbs that target a cryptic PfCSP epitope that is only exposed after cleavage and subsequent pyroglutamylation (pGlu) of the newly formed N terminus. This pGlu-CSP epitope is not targeted by current anti-PfCSP mAbs and is not included in the licensed malaria vaccines.

A single mutation in dairy cow-associated H5N1 viruses increases receptor binding breadth.

Clade 2.3.4.

Structural Immunology of SARS-CoV-2.

The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, and escape mechanisms. Antibodies targeting the receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in SARS-CoV-2 variants.

Prognostic Relevance of Relative Ellipsoid Zone Reflectivity for Ellipsoid Zone Loss in Macular Telangiectasia Type 2.

Purpose: The relative ellipsoid zone reflectivity (rEZR) is an innovative biomarker for photoreceptor alterations and showed association with disease staging in macular telangiectasia type 2 (MacTel). However, its prognostic relevance for the ellipsoid zone (EZ) loss is unclear.

Methods: Longitudinal spectral-domain optical coherence tomography (SD-OCT) imaging of patients with MacTel from an observational natural history study was used for en face determination of manifest EZ loss.

Sugar Auxiliary Group Assisted Diversity-Oriented Enzymatic Modular Synthesis of 0-Series Ganglioside Glycans.

Owing to the inaccessibility of β1-4-N-acetylgalactosaminyltransferase for direct glycan chain elongation, the enzymatic synthesis of 0-series gangliosides with extended backbones has not been explored. In this study, sialic acid was enzymatically introduced as an auxiliary group to overcome the limitation of substrate specificity of Campylobacter jejuni β1-4-N-acetylgalactosaminyltransferase (CjCgtA) to achieve the synthesis of desired extended 0-series ganglioside core structures, and the sialic acid auxiliary group could be removed by sialidase at appropriate stages. A bacterial α2-6-sialyltransferase from Photobacterium damselae (Pd2,6ST) exhibited unexpected acceptor substrate specificity for 0-series ganglioside core structures, providing ready access to complex gangliosides bearing the sialyl N-acetylgalactosamine unit.

Structural and Functional Insights into the Evolution of SARS-CoV-2 KP.3.1.1 Spike Protein.

The JN.1-sublineage KP.3.

Structural serology of polyclonal antibody responses to mRNA-1273 and NVX-CoV2373 COVID-19 vaccines.

Current COVID-19 vaccines are largely limited in their ability to induce broad, durable immunity against emerging viral variants. Design and development of improved vaccines utilizing existing platforms requires an in-depth understanding of the antigenic and immunogenic properties of available vaccines. Here we examined the antigenicity of two of the original COVID-19 vaccines, mRNA-1273 and NVX-CoV2373, by electron microscopy-based polyclonal epitope mapping (EMPEM) of serum from immunized non-human primates (NHPs) and clinical trial donors.

Experimental and computational investigations of RNA duplexes containing N7-regioisomers of adenosine and LNA-adenosine.

Although glycosidic bonds in purines typically involve the N9 position, the chemical synthesis of adenosine produces N7-ribofuranosyladenine (7A) as a kinetically favorable ribosylation product. Similarly, in the synthesis of LNA-adenosine (AL), a minor product, N7-LNA-adenosine (7AL), is observed. While extensive research has focused on investigating the properties of N9-regioisomers of adenosine, 7A has been largely overlooked and considered as a side-product.

Maternal separation stress increases alcohol preference regardless of DNA methylation and histone acetylation or methylation in the amygdala.

Alcohol use disorder (AUD) is a condition with multifactorial causes, including biopsychosocial factors. Childhood exposure to stress may increase susceptibility to AUD in adulthood. Despite its significance, the interaction between stress and AUD remains unclear.

Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRAS inhibitor.

Objective: This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600 mg dose (1 µCi [C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600 mg twice daily.

Methods: Plasma, urine, and feces were collected post [C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine.

Exploiting the DCAF16-SPIN4 interaction to identify DCAF16 ligands for PROTAC development.

Traditional small molecule drugs often target protein activity directly, but challenges arise when proteins lack suitable functional sites. An alternative approach is targeted protein degradation (TPD), which directs proteins to cellular machinery for proteolytic degradation. Recent studies have identified additional E3 ligases suitable for TPD, expanding the potential of this approach.