A Brain Reward Circuit Inhibited By Next-Generation Weight Loss Drugs.

Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes, yet established peptide-based therapies require injections and complex manufacturing. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. The neural circuits through which these emerging therapeutics modulate feeding behavior remain undefined, particularly in comparison to established peptide-based GLP1RAs.

Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial.

Background: The rate of antibiotic resistance continues to grow, outpacing small-molecule-drug development efforts. Novel therapies are needed to combat this growing threat, particularly for the treatment of urinary tract infections (UTIs), which are one of the largest contributors to antibiotic use and associated antibiotic resistance. LBP-EC01 is a novel, genetically enhanced, six-bacteriophage cocktail developed by Locus Biosciences (Morrisville, NC, USA) to address UTIs caused by Escherichia coli, regardless of antibiotic resistance status.

Dorsal motor vagal neurons can elicit bradycardia and reduce anxiety-like behavior.

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVN) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVN) is less clear. We therefore aimed to characterize CVN anatomically, physiologically, and functionally.

Dorsal Motor Vagal Neurons Can Elicit Bradycardia and Reduce Anxiety-Like Behavior.

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVN) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVN) is less clear. We therefore aimed to characterize CVN anatomically, physiologically, and functionally.

Social Determinants of Health, Chronic Disease Management, and the Role of the Primary Care Provider-to Include Cardiovascular Disease, Cancer, Diabetes, Major Causes of Morbidity and Mortality as Affected by Social Determinants of Health.

Despite advances in health science and medical technology, health outcomes continue to fall behind in certain communities. A recent study linking health outcomes to zip code may explain part of this disparity, social determinants of health. Although well known that patients in resource-poor environments have worse outcomes than patients with advantages, the exact reason for this disparity may not be so well known.

Meta-analysis of primary care delivered buprenorphine treatment retention outcomes.

Currently, the capacity to provide buprenorphine treatment (BT) is not sufficient to treat the growing number of people in the United States with opioid use disorder (OUD). We sought to examine participant retention in care rates of primary care delivered BT programs and to describe factors associated with retention/attrition for participants receiving BT in this setting. A PRISMA-guided search of various databases was performed to identify the articles focusing on efficacy of BT treatment and OUD.

A Pooled Case-only Analysis of Reproductive Risk Factors and Breast Cancer Subtype Among Black Women in the Southeastern United States.

Background: We investigated the association between reproductive risk factors and breast cancer subtype in Black women. On the basis of the previous literature, we hypothesized that the relative prevalence of specific breast cancer subtypes might differ according to reproductive factors.

Methods: We conducted a pooled analysis of 2,188 (591 premenopausal, 1,597 postmenopausal) Black women with a primary diagnosis of breast cancer from four studies in the southeastern United States.

The Property-Based Practical Applications and Solutions of Genetically Encoded Acetylcholine and Monoamine Sensors.

Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional features of neuromodulatory transmission remains challenging because of limitations of available monitoring tools. Recently developed genetically encoded neuromodulatory transmitter sensors, when combined with superresolution and/or deconvolution microscopy, allow the first visualization of neuromodulatory transmission with nanoscale or microscale spatiotemporal resolution. and experiments have validated several high-performing sensors to have the qualities necessary for demarcating fundamental synaptic properties of neuromodulatory transmission, and initial analysis has unveiled unexpected fine control and precision of neuromodulation.

High School Students as Citizen Scientists to Decrease Radon Exposure.

Residents in rural Kentucky (KY) and suburban Ohio (OH) expressed concerns about radon exposure and lung cancer. Although 85% of lung cancer cases are caused by tobacco smoke, radon exposure accounts for 10-15% of lung cancer cases. Academic and community members from the University of KY and the University of Cincinnati developed and pilot-tested a family-centered, youth-engaged home radon testing toolkit.

The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits.

SIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVH population, melanocortin-4 receptor-expressing (PVH) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVH neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVH) neurons, which notably lack MC4Rs, function independently and additively with PVH neurons to account for the totality of PVH neuron-mediated satiety.

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma.

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB.

Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma.

The Hedgehog (Hh) signaling pathway has been implicated in the most common childhood brain tumor, medulloblastoma (MB). Given the toxicity of post-surgical treatments for MB, continued need exists for new, targeted therapies. Based upon our finding that Neuropilin (Nrp) transmembrane proteins are required for Hh signal transduction, we investigated the role of Nrp in MB cells.

A selenium analogue of firefly D-luciferin with red-shifted bioluminescence emission.

A selenium analogue of amino-D-luciferin, aminoseleno-D-luciferin, is synthesized and shown to be a competent substrate for the firefly luciferase enzyme. It has a red-shifted bioluminescence emission maximum at 600 nm and is suitable for bioluminescence imaging studies in living subjects.

Sensing cooperativity in ATP hydrolysis for single multisubunit enzymes in solution.

In order to operate in a coordinated fashion, multisubunit enzymes use cooperative interactions intrinsic to their enzymatic cycle, but this process remains poorly understood. Accordingly, ATP number distributions in various hydrolyzed states have been obtained for single copies of the mammalian double-ring multisubunit chaperonin TRiC/CCT in free solution using the emission from chaperonin-bound fluorescent nucleotides and closed-loop feedback trapping provided by an Anti-Brownian ELectrokinetic trap. Observations of the 16-subunit complexes as ADP molecules are dissociating shows a peak in the bound ADP number distribution at 8 ADP, whose height falls over time with little shift in the position of the peak, indicating a highly cooperative ADP release process which would be difficult to observe by ensemble-averaged methods.

Molecules and methods for super-resolution imaging.

By looking at a fluorescently labeled structure one molecule at a time, it is possible to side-step the optical diffraction limit and obtain "super-resolution" images of small nanostructures. In the Moerner Lab, we seek to develop both molecules and methods to extend super-resolution fluorescence imaging. Methodologies and protocols for designing and characterizing fluorophores with switchable fluorescence required for super-resolution imaging are reported.

Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that are strongly associated with elevated fasting glucose levels.

Objective: Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal.

Azido push-pull fluorogens photoactivate to produce bright fluorescent labels.

Dark azido push-pull chromophores have the ability to be photoactivated to produce bright fluorescent labels suitable for single-molecule imaging. Upon illumination, the aryl azide functionality in the fluorogens participates in a photochemical conversion to an aryl amine, thus restoring charge-transfer absorption and fluorescence. Previously, we reported that one compound, DCDHF-V-P-azide, was photoactivatable.

DCDHF fluorophores for single-molecule imaging in cells.

There is a persistent need for small-molecule fluorescent labels optimized for single-molecule imaging in the cellular environment. Application of these labels comes with a set of strict requirements: strong absorption, efficient and stable emission, water solubility and membrane permeability, low background emission, and red-shifted absorption to avoid cell autofluorescence. We have designed and characterized several fluorophores, termed "DCDHF" fluorophores, for use in live-cell imaging based on the push-pull design: an amine donor group and a 2-dicyanomethylene-3-cyano-2,5-dihydrofuran (DCDHF) acceptor group, separated by a pi-rich conjugated network.

Cy3-Cy5 covalent heterodimers for single-molecule photoswitching.

Covalent heterodimers of the Cy3 and Cy5 fluorophores have been prepared from commercially available starting materials and characterized at the single-molecule level. This system behaves as a discrete molecular photoswitch, in which photoexcitation of the Cy5 results in fluorescence emission or, with a much lower probability, causes the Cy5 to enter into a long-lived, but metastable, dark state. Photoinduced recovery of the emissive Cy5 is achieved by very low intensity excitation (5 W cm(-2)) of the Cy3 fluorophore at a shorter wavelength.

A photoactivatable push-pull fluorophore for single-molecule imaging in live cells.

We have reengineered a red-emitting dicyanomethylenedihydrofuran push-pull fluorophore so that it is dark until photoactivated with a short burst of low-intensity violet light. Photoactivation of the dark fluorogen leads to conversion of an azide to an amine, which shifts the absorption to long wavelengths. After photoactivation, the fluorophore is bright and photostable enough to be imaged on the single-molecule level in living cells.

Bulk and single-molecule characterization of an improved molecular beacon utilizing H-dimer excitonic behavior.

Pairs of fluorophores in close proximity often show self-quenching of fluorescence by the well-known H-dimer mechanism. We use a pair of fluorophores in the new dicyanomethylenedihydrofuran (DCDHF) dye family in the design and characterization of a new fluorescent probe for nucleic acid detection, which we refer to as a self-quenched intramolecular dimer (SQuID) molecular beacon (MB). We obtain a quenching efficiency of 97.

Toward nanometer-scale optical photolithography: utilizing the near-field of bowtie optical nanoantennas.

Optically resonant metallic bowtie nanoantennas are utilized as fabrication tools for the first time, resulting in the production of polymer resist nanostructures <30 nm in diameter at record low incident multiphoton energy densities. The nanofabrication is accomplished via nonlinear photopolymerization, which is initiated by the enhanced, confined optical fields surrounding the nanoantenna. The position, size, and shape of the resist nanostructures directly correlate with rigorous finite-difference time-domain computations of the field distribution, providing a nanometer-scale measurement of the actual field confinement offered by single optical nanoantennas.