Left and right vagus nerve stimulation: historical perspectives, clinical efficacy, and future directions.

Neuromodulation has profoundly transformed medical science, offering new treatments for various neurological conditions. Stimulation techniques that target the brain, spinal cord, trigeminal nerve, and vagus nerve (VN) use electrical impulses to modulate neural functions. Among these, vagus nerve stimulation (VNS) is distinguished for its use to stimulate the VN to modulate neural functions.

Vagus nerve stimulation ameliorates cognitive impairment caused by hypoxia.

Introduction: Hypoxia significantly impairs cognitive function due to the brain's high demand for oxygen. While emerging evidence suggests that vagus nerve stimulation (VNS) can enhance cognition, its effectiveness in mitigating behavioral and molecular impairments caused by hypoxia remains unknown. This study investigated whether VNS could alleviate hypoxia-induced deficits in cognitive performance and neurotrophin expression in rats.

VNS paired with training enhances recognition memory: mechanistic insights from proteomic analysis of the hippocampal synapse.

Introduction: Recognition memory, an essential component of cognitive health, can suffer from biological limitations of stress, aging, or neurodegenerative disease. Vagus nerve stimulation (VNS) is a neuromodulation therapy with the potential to improve cognitive function. This study investigated the effectiveness of multiple sessions of VNS to enhance recognition memory in healthy rodents and the underlying cognitive benefits of VNS by proteomic analysis of the synaptosome.

RNA-based translation activators for targeted gene upregulation.

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs.

Phage-Assisted Continuous Evolution and Selection of Enzymes for Chemical Synthesis.

Ligand-dependent biosensors are valuable tools for coupling the intracellular concentrations of small molecules to easily detectable readouts such as absorbance, fluorescence, or cell growth. While ligand-dependent biosensors are widely used for monitoring the production of small molecules in engineered cells and for controlling or optimizing biosynthetic pathways, their application to directed evolution for biocatalysts remains underexplored. As a consequence, emerging continuous evolution technologies are rarely applied to biocatalyst evolution.

Antiviral evaluation of hydroxyethylamine analogs: Inhibitors of SARS-CoV-2 main protease (3CLpro), a virtual screening and simulation approach.

The continued toll of COVID-19 has halted the smooth functioning of civilization on a global scale. With a limited understanding of all the essential components of viral machinery and the lack of structural information of this new virus, initial drug discovery efforts had limited success. The availability of high-resolution crystal structures of functionally essential SARS-CoV-2 proteins, including 3CLpro, supports the development of target-specific therapeutics.

Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.

There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells.

Rapid Multicomponent Bioluminescence Imaging Substrate Unmixing.

Studies of biological function demand probes that can report on processes in real time and in physiological environments. Bioluminescent tools are uniquely suited for this purpose, as they enable sensitive imaging in cells and tissues. Bioluminescent reporters can also be monitored continuously over time without detriment, as excitation light is not required.

Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors.

The pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to expand. Papain-like protease (PLpro) is one of two SARS-CoV-2 proteases potentially targetable with antivirals. PLpro is an attractive target because it plays an essential role in cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex, and disruption of host responses.

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening pipeline and in-vitro validation assays.

SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2'-O-MT.

Small Molecule-Inducible RNA-Targeting Systems for Temporal Control of RNA Regulation.

All aspects of mRNA lifetime and function, including its stability, translation into protein, and trafficking through the cell, are tightly regulated through coordinated post-transcriptional modifications and interactions with a multitude of RNA effector proteins. Despite the increasing recognition of RNA regulation as a critical layer of mammalian gene expression control and its increasing excitement as a therapeutic target, tools to study and control RNA regulatory mechanisms with temporal precision in their endogenous environment are lacking. Here, we present small molecule-inducible RNA-targeting effectors based on our previously developed CRISPR/Cas-inspired RNA targeting system (CIRTS).

Drug repurposing screen identifies masitinib as a 3CLpro inhibitor that blocks replication of SARS-CoV-2 .

There is an urgent need for anti-viral agents that treat SARS-CoV-2 infection. The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first screened a library of 1,900 clinically safe drugs for inhibiting replication of OC43, a human beta-coronavirus that causes the common-cold and is a relative of SARS-CoV-2, and identified 108 effective drugs.

Site-Selective C-H Halogenation Using Flavin-Dependent Halogenases Identified via Family-Wide Activity Profiling.

Enzymes are powerful catalysts for site-selective C-H bond functionalization. Identifying suitable enzymes for this task and for biocatalysis in general remains challenging, however, due to the fundamental difficulty of predicting catalytic activity from sequence information. In this study, family-wide activity profiling was used to obtain sequence-function information on flavin-dependent halogenases (FDHs).

Development of a Split Esterase for Protein-Protein Interaction-Dependent Small-Molecule Activation.

Split reporters based on fluorescent proteins and luciferases have emerged as valuable tools for measuring interactions in biological systems. Relatedly, biosensors that transduce measured input signals into outputs that influence the host system are key components of engineered gene circuits for synthetic biology applications. While small-molecule-based imaging agents are widely used in biological studies, and small-molecule-based drugs and chemical probes can target a range of biological processes, a general method for generating a target small molecule in a biological system based on a measured input signal is lacking.

Pyridone Luciferins and Mutant Luciferases for Bioluminescence Imaging.

New applications for bioluminescence imaging require an expanded set of luciferase enzymes and luciferin substrates. Here, we report two novel luciferins for use in vitro and in cells. These molecules comprise regioisomeric pyridone cores that can be accessed from a common synthetic route.

Parallel Screening for Rapid Identification of Orthogonal Bioluminescent Tools.

Bioluminescence imaging with luciferase enzymes and luciferin small molecules is a well-established technique for tracking cells and other biological features in rodent models. Despite its popularity, bioluminescence has long been hindered by a lack of distinguishable probes. Here we present a method to rapidly identify new substrate-selective luciferases for multicomponent imaging.

Orthogonal Luciferase-Luciferin Pairs for Bioluminescence Imaging.

Bioluminescence imaging with luciferase-luciferin pairs is widely used in biomedical research. Several luciferases have been identified in nature, and many have been adapted for tracking cells in whole animals. Unfortunately, the optimal luciferases for imaging in vivo utilize the same substrate and therefore cannot easily differentiate multiple cell types in a single subject.

Brominated Luciferins Are Versatile Bioluminescent Probes.

We report a set of brominated luciferins for bioluminescence imaging. These regioisomeric scaffolds were accessed by using a common synthetic route. All analogues produced light with firefly luciferase, although varying levels of emission were observed.

Extracellular Toxoplasma gondii tachyzoites metabolize and incorporate unnatural sugars into cellular proteins.

Toxoplasma gondii is an obligate intracellular parasite that infects all nucleated cell types in diverse warm-blooded organisms. Many of the surface antigens and effector molecules secreted by the parasite during invasion and intracellular growth are modified by glycans. Glycosylated proteins in the nucleus and cytoplasm have also been reported.

Vitamin D Metabolites Inhibit Hepatitis C Virus and Modulate Cellular Gene Expression.

Background And Aims: Previous studies suggest that low serum 25-hydroxyvitamin D [25(OH) D] levels are associated with reduced responsiveness to interferon and ribavirin therapy. We investigated the impact of vitamin D metabolites on HCV and cellular gene expression in cultured hepatoma cells.

Methods: HCV Replicon cell lines stably expressing luciferase reporter constructs (genotype 1b and 2a replicon) or JC1-Luc2a were incubated in the presence of vitamin D2, vitamin D3 or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3).

A "Caged" Luciferin for Imaging Cell-Cell Contacts.

Cell-cell interactions underlie fundamental biological processes but remain difficult to visualize over long times and large distances in tissues and live organisms. Bioluminescence imaging with luciferase-luciferin pairs is sufficiently sensitive to image cells in vivo but lacks the spatial resolution to identify cellular locations and interactions. To repurpose this technology for visualizing cellular networks, we developed a "caged" luciferin that produces light only when cells are in close contact.

Visualizing cell proximity with genetically encoded bioluminescent reporters.

Cell-cell interactions underlie diverse physiological processes ranging from immune function to cell migration. Dysregulated cellular crosstalk also potentiates numerous pathologies, including infections and metastases. Despite their ubiquity in organismal biology, cell-cell interactions are difficult to examine in tissues and whole animals without invasive procedures.

Improved cyclopropene reporters for probing protein glycosylation.

Cyclopropenes have emerged as a new class of bioorthogonal chemical reporters. These strained rings can be metabolically introduced into target biomolecules and covalently modified via mild cycloaddition chemistries. While versatile, existing cyclopropene scaffolds are inefficient reporters of protein glycosylation, owing to their branched structures and sluggish rates of reactivity.