An oral non-covalent non-peptidic inhibitor of SARS-CoV-2 Mpro ameliorates viral replication and pathogenesis in vivo.

Safe, effective, and low-cost oral antiviral therapies are needed to treat those at high risk for developing severe COVID-19. To that end, we performed a high-throughput screen to identify non-peptidic, non-covalent inhibitors of the SARS-CoV-2 main protease (Mpro), an essential enzyme in viral replication. NZ-804 was developed from a screening hit through iterative rounds of structure-guided medicinal chemistry.

Synthesis of the 5/5-spiroindimicin alkaloids: development of a general synthetic approach and biological investigations.

We describe the development of a unified synthetic strategy for the preparation of all known 5/5-spirocyclic spiroindimicin (SPM) alkaloids, namely spiroindimicins B-G. The present synthetic route relies on four fundamental transformations: Grignard-based fragment coupling between halogenated pyrrolemetal and isatin partners, Suzuki coupling to generate a triaryl scaffold encompassing all requisite skeletal atoms of the natural products, Lewis acid-mediated spirocyclization to construct the 5/5-spirocyclic core, and chemoselective lactam reduction. The developed syntheses are step-economic (6-7 steps from commercial materials), scalable, and amenable to analogue synthesis.

Systematic Evaluation of Macromolecular Carbohydrate-Lectin Recognition Using Precision Glycopolymers.

The precise modulation of protein-carbohydrate interactions is critical in glycobiology, where multivalent binding governs key cellular processes. As such, synthetic glycopolymers are useful for probing these interactions. Herein, we developed precision glycopolymers (PGPs) with unambiguous local chemical composition and well-defined global structure and systematically evaluated the effect of polymer length, hydrophobicity, and backbone hybridization as well as glycan density and identity on the binding to both mammalian and plant lectins.

Low-frequency (0-450 cm) dynamics of -alkyl cyanide liquids studied by optical Kerr effect spectroscopy and density functional theory.

This article presents a study of the dynamics of -alkyl cyanides (CHCN with = 1-5) in the 0-450 cm spectral region as a function of alkyl chain length. The spectra were measured using femtosecond optical Kerr effect (OKE) spectroscopy. The OKE spectra are characterized by a broad band in the 0-150 cm region arising mainly from intermolecular modes and by narrow bands in the 150-450 cm region arising from intramolecular modes.

High-Entropy Electrolyte Driven by Multi-Solvation Structures for Long-Lifespan Aqueous Zinc Metal Pouch Cells.

Aqueous zinc metal batteries (AZMBs) are promising candidates for grid-scale energy storage due to their low cost and high safety. However, the poor stability and the unfavorable freezing point of aqueous electrolytes hinder their actual application. Herein, a ternary salts-based high-entropy electrolyte (HEE) composed of ZnNaLi(ClO) ⋅ 7HO is proposed to address the above issues.

Intratumoral Injectable Redox-Responsive Immune Niche Improves the Abscopal Effect in Radiotherapy.

Radiotherapy (XRT) is often utilized to improve the immune checkpoint blockade response in cancer management. Such combination treatment can enhance the abscopal effect, facilitating a prolonged and durable systemic response. However, despite intense research efforts, only a minority of patients respond to this approach, and novel strategies to increase the abscopal effect are urgently needed.

Self-Assembly of Microstructured Protein Coatings with Programmable Functionality for Fluorescent Biosensors.

Proteins, as genetically programmable functional macromolecules, hold immense potential as biocompatible self-assembling building blocks, owing to their versatility in building coating materials and programming their functionality genetically. In this study, we demonstrate a modular self-assembly of protein coatings that are genetically programmable for a biosensor application. We designed and produced recombinant fusion protein building blocks to form microstructured coatings on diverse substrates, such as glass or polymers, through thermally triggered liquid-liquid phase separation and an orthogonal high-affinity coiled-coil interaction.

Nexus of Soil Microbiomes, Genes, Classes of Carbon Substrates, and Biotransformation of Fluorotelomer-Based Precursors.

The unpredictable biodegradation of fluorotelomer (FT)-based per- and polyfluoroalkyl substances (PFAS) causes complicated risk management of PFAS-impacted sites. Here, we have successfully used redundancy analysis to link FT-based precursor biodegradation to key microbes and genes of soil microbiomes shaped by different classes of carbon sources: alcohols (C2-C4), alkanes (C6 and C8), an aromatic compound (phenol), or a hydrocarbon surfactant (cocamidopropyl betaine [CPB]). All the enrichments defluorinated fluorotelomer alcohols (:2 FtOH; = 4, 6, 8) effectively and grew on 6:2 fluorotelomer sulfonate (6:2 FtS) as a sulfur source.

FRESH 3D printing of zoledronic acid-loaded chitosan/alginate/hydroxyapatite composite thermosensitive hydrogel for promoting bone regeneration.

The aim of this study was to develop a composite thermosensitive hydrogel for bone regeneration applications. This hydrogel consisted of chitosan, alginate and hydroxyapatite, and was loaded with zoledronic acid as a model drug. The feasibility of three-dimensional (3D) printing of the thermosensitive hydrogel using the extrusion based technique was investigated.

Clinical outcomes of early-stage triple-negative breast cancer after neoadjuvant chemotherapy according to HER2-low status☆.

Background: The impact of human epidermal growth factor receptor 2 (HER2) expression determined by immunohistochemistry (IHC) on outcomes in early-stage triple-negative breast cancer (eTNBC) is unclear. Using a large, multi-institutional cohort, we evaluated outcomes by HER2 IHC status in patients with eTNBC who received neoadjuvant therapy (NAT).

Patients And Methods: Patients with stage I-III TNBC who received NAT and underwent surgery from January 2016 to June 2019 were identified from three databases.

In vitro and silico activity of piperlongumine against azole-susceptible/resistant Aspergillus fumigatus and terbinafine-susceptible/resistant Trichophyton species.

In recent years, the widespread emergence of drug resistance in yeasts and filamentous fungi to existing antifungal armamentariums has become a severe threat to global health. There is also concern regarding increased rates of azole resistance in Aspergillus fumigatus and Terbinafine resistance in Trichophyton species. To overcome this concern of resistance to regular therapies, new antifungal drugs with novel and effective mechanisms are crucially needed.

Efficacy and Possible Mechanism(s) of Action of Gallium Tetraphenylporphyrin Nanoparticles against HIV-TB Coinfection in an Granuloma Structure Model.

Coinfection of (Mtb) and human immunodeficiency virus-1 (HIV) is a significant public health concern. Treatment is challenging due to prolonged duration of therapy and drug interactions between antiretroviral therapy (ART) and anti-TB drugs. Noniron gallium -tetraphenyl porphyrin (GaTP), a heme mimetic, has shown broad antimicrobial activity.

A Bond-Based Machine Learning Model for Molecular Polarizabilities and A Priori Raman Spectra.

The use of machine learning (ML) algorithms in molecular simulations has become commonplace in recent years. There now exists, for instance, a multitude of ML force field algorithms that have enabled simulations approaching level accuracy at time scales and system sizes that significantly exceed what is otherwise possible with traditional methods. Far fewer algorithms exist for predicting rotationally equivariant, tensorial properties such as the electric polarizability.

Aziridine Group Transfer via Transient -Aziridinyl Radicals.

Aziridines are the smallest nitrogen-containing heterocycles. Strain-enhanced electrophilicity renders aziridines useful synthetic intermediates and gives rise to biological activity. Classical aziridine syntheses─based on either [2 + 1] cycloadditions or intramolecular substitution chemistry─assemble aziridines from acyclic precursors.

Site-specific drug release of monomethyl fumarate to treat oxidative stress disorders.

Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer-Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress.

PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation.

Poly(ADP-ribose) polymerase 1 (PARP1) is one of the first responders to DNA damage and plays crucial roles in recruiting DNA repair proteins through its activity - poly(ADP-ribosyl)ation (PARylation). The enrichment of DNA repair proteins at sites of DNA damage has been described as the formation of a biomolecular condensate. However, it remains unclear how exactly PARP1 and PARylation contribute to the formation and organization of DNA repair condensates.

Insertable Biomaterial-Based Multianalyte Barcode Sensor toward Continuous Monitoring of Glucose and Oxygen.

Chronic diseases, including diabetes, cardiovascular diseases, and microvascular complications, contribute significantly to global morbidity and mortality. Current monitoring tools such as glucometers and continuous glucose monitors only measure one analyte; multiplexing technologies offer a promising approach for monitoring multiple biomarkers, enabling the management of comorbidities and providing more comprehensive disease insights. In this work, we describe a miniaturized optical "barcode" sensor with high biocompatibility for the continuous monitoring of glucose and oxygen.

Graphene-based gel electromembrane extraction coupled with modified screen-printed carbon electrode for detecting streptomycin in honey samples: Greener strategy for food analysis.

This paper presents a greener methodology for the first time to determine streptomycin in honey based on the modification of gel in the gel electromembrane extraction (G-EME) technique using exfoliated graphene (EG). Differential pulse voltammetry (DPV) with a modified screen-printed carbon electrode was used as a detection technique. The EG was prepared by applying an electrochemical exfoliation of pencil graphite as an environmentally friendly and simple method.

β-Cyclodextrin derivatives bind aromatic side chains of the cyclic peptide lanreotide.

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide, and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of the cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated.

Urea-Loaded PLGA Microspheres as Chemotaxis Stimulants for Helicobacter pylori.

Helicobacter pylori cells undergo chemotaxis toward several small molecules, called chemo-attractants, including urea produced by the epithelial cells of the stomach. The biophysical mechanisms of chemotaxis are not well understood in H. pylori.

Effects of dialysate potassium concentration of 3.0 mmol/l with sodium zirconium cyclosilicate on dialysis-free days versus dialysate potassium concentration of 2.0 mmol/l alone on rates of cardiac arrhythmias in hemodialysis patients with hyperkalemia.

The optimal approach towards managing serum potassium (sK) and hemodialysate potassium concentrations is uncertain. To study this, adults receiving hemodialysis for three months or more with hyperkalemia (pre-dialysis sK 5.1-6.