Neurobehavioral plasticity in the rodent gustatory system induced by regular consumption of a low-calorie sweetener during adolescence.

Habitual consumption of low-calorie sweeteners (LCS) during juvenile-adolescence can lead to greater sugar intake later in life. Here, we investigated if exposure to the LCS Acesulfame Potassium (Ace-K) during this critical period of development reprograms the taste system in a way that would alter hedonic responding for common dietary compounds. Results revealed that early-life LCS intake not only enhanced the avidity for a caloric sugar (fructose) when rats were in a state of caloric need, it increased acceptance of a bitterant (quinine) in Ace-K-exposed rats tested when middle-aged.

Neutralizing antibody immune correlates in COVAIL trial recipients of an mRNA second COVID-19 vaccine boost.

Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic's evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate's contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.

The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes.

Bacterial artificial chromosome transgenic models, including most Cre-recombinases, enable potent interrogation of gene function in vivo but require rigorous validation as limitations emerge. Due to its high relevance to metabolic studies, we perform comprehensive analysis of the Ucp1-Cre line which is widely used for brown fat research. Hemizygotes exhibit major brown and white fat transcriptomic dysregulation, indicating potential altered tissue function.

Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation.

The bottleneck in enhanced sampling lies in finding collective variables that effectively accelerate protein conformational changes; true reaction coordinates that accurately predict the committor are the well-recognized optimal choice. However, identifying them requires unbiased natural reactive trajectories, which, paradoxically, require effective enhanced sampling. Using the generalized work functional method, we uncover that true reaction coordinates control both conformational changes and energy relaxation, enabling us to compute them from energy relaxation simulations.

Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells.

Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8 T cells.

Tuning Dual Catalytic Active Sites of Pt Single Atoms Paired with High-Entropy Alloy Nanoparticles for Advanced Li-O Batteries.

To achieve a long cycle life and high-capacity performance for Li-O batteries, it is critical to rationally modulate the formation and decomposition pathway of the discharge product LiO. Herein, we designed a highly efficient catalyst containing dual catalytic active sites of Pt single atoms (Pt) paired with high-entropy alloy (HEA) nanoparticles for oxygen reduction reaction (ORR) in Li-O batteries. HEA is designed with a moderate d-band center to enhance the surface adsorbed LiO intermediate (LiO(ads)), while Pt active sites exhibit weak adsorption energy and promote the soluble LiO pathway (LiO(sol)).

Investigation into Drug-Induced Liver Damage Using Multimodal Mass Spectrometry Imaging.

Drug toxicity during the development of candidate pharmaceuticals is the leading cause of discontinuation in preclinical drug discovery and development. Traditionally, the cause of the toxicity is often determined by histological examination, clinical pathology, and the detection of drugs and/or metabolites by liquid chromatography-mass spectrometry (LC-MS). While these techniques individually provide information on the pathological effects of the drug and the detection of metabolites, they cannot provide specific molecular spatial information without additional experiments.

Upcycling polynorbornene derivatives into chemically recyclable multiblock linear and thermoset plastics.

Synthetic polymers have found widespread use with functional lifetimes from seconds to decades. However, the lack of end-of-life treatment for these plastics is causing a significant environmental and human health crisis due to their persistence and bioaccumulation. Upcycling post-consumer plastic waste to products with inherent recyclability is an attractive strategy to tackle this problem, as it can broaden the range of accessible materials and uncover unprecedented features while dealing with current plastic waste.

Toward Sustainable Polydienes.

The sustainable management of polydiene waste represents a formidable challenge in the realm of polymer chemistry, given the extensive industrial utilization of polydienes due to their superior elastomeric properties. This comprehensive Perspective addresses the multifaceted obstacles hindering efficient recycling of polydienes, encompassing environmental concerns, technical limitations, and economic disincentives. We systematically dissect the influence of polydienes' chemical structures on their recyclability, tracing the evolution of polydiene utilization and disposal practices while assessing the current landscape of waste management strategies.

Mismatch in productivity calculated from wRVU metric and the actual number of images in musculoskeletal radiographic studies.

The work relative value unit (wRVU) measures the physician's work involved in performing a service and is commonly used to quantify physician productivity. A critical component factored in wRVUs is the time required to perform a service. In musculoskeletal radiology, this time correlates directly with the number of images produced per radiograph.

Comparing the incidence of hypospadias across the United States: A contemporary analysis.

Introduction: Hypospadias is a common congenital malformation occurring in up to 80 in 10,00 live male births, with emerging evidence associating exogenous environmental exposures with increased disease incidence. Military personnel are at particularly higher risk for such exposures and indeed, the rate of hypospadias in infant males born to United States military servicewomen deployed during the Gulf War has been reported to be more than 5 times greater compared to undeployed female military personnel.

Objective: To characterize contemporary trends in hypospadias incidence in the general population as well as high risk groups such as males born from US servicewomen using the National Birth Defects Prevention Network.

The 2021 American Hand Therapy Foundation research priorities survey.

Background: In 1998, the American Hand Therapy Foundation (AHTF) surveyed Certified Hand Therapists and active Charter Members of the American Society of Hand Therapists to identify hand rehabilitation research priorities, guide grant awards, and confirm alignment with the foundation's mission.

Purpose: The American Hand Therapy Foundation repeated the survey in 2021 to confirm that its award funding was consistent with hand therapists' research priorities.

Study Design: Convergent parallel mixed method study design.

Differential impacts of strabismic and anisometropic amblyopia on the mesoscale functional organization of the human visual cortex.

We employed high-resolution fMRI to distinguish the impacts of anisometropia and strabismus amblyopia on the evoked ocular dominance (OD) response. Sixteen amblyopic participants (8 females) plus 8 individuals with normal vision (1 female), participated in this study for whom, we measured the difference between the response to stimulation of the two eyes, across areas V1-V4.In controls, the evoked OD response formed the expected striped pattern within V1.

Mapping the Energy Carrier Diffusion Tensor in Perovskite Semiconductors.

Understanding energy transport in semiconductors is critical for the design of electronic and optoelectronic devices. Semiconductor material properties, such as charge carrier mobility or diffusion length, are commonly measured in bulk crystals and determined using models that describe transport behavior in homogeneous media, where structural boundary effects are minimal. However, most emerging semiconductors exhibit nano- and microscale heterogeneity.

Current approaches in CRISPR-Cas systems for diabetes.

In the face of advancements in health care and a shift towards healthy lifestyle, diabetes mellitus (DM) still presents as a global health challenge. This chapter explores recent advancements in the areas of genetic and molecular underpinnings of DM, addressing the revolutionary potential of CRISPR-based genome editing technologies. We delve into the multifaceted relationship between genes and molecular pathways contributing to both type1 and type 2 diabetes.

Single-cell RNA flow cytometry to assess intratumoral production of cytokines/chemokines.

The tumor microenvironment (TME) consists of complex interactions between cellular and extracellular components, among which the immune system is known to play an integral role in disease progression and response to therapy. Cytokines and chemokines are cell signaling proteins used by immune cells to communicate with each other as well as with other cell types in the body. These proteins control systemic and local immune responses and levels of cytokines/chemokines in the TME have been associated with tumor outcomes.

Expression, purification and characterization of phosphatidylserine-targeting antibodies for biochemical and therapeutic applications.

The externalization of Phosphatidylserine (PS) from the inner surface of the plasma membrane to the outer surface of the plasma membrane is an emblematic event during apoptosis and serves as a potent "eat-me" signal for the efferocytosis of apoptotic cells. Although less well understood, PS is also externalized on live cells in the tumor microenvironment and on live virus-infected cells whereby it serves as an immune modulatory signal that drives tolerance and immune escape. Given the importance of PS in cancer immunology and immune escape, PS-targeting monoclonal antibodies have been characterized with promising immunotherapeutic potential.

Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer.

After L858R and ex19del epidermal growth factor receptor (EGFR) mutations, ex20ins mutations are the third most common class of driver-mutations in non-small cell lung cancer (NSCLC). Unfortunately, first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs) are generally ineffective for ex20ins patients due to insufficient mutant activity and selectivity over wild-type EGFR, leading to dose-limiting toxicities. While significant advances in recent years have been made toward identifying potent EGFR ex20ins mutant inhibitors, mutant vs wild-type EGFR selectivity remains a significant challenge.

Intracellular Pocket Conformations Determine Signaling Efficacy through the μ Opioid Receptor.

It has been challenging to determine how a ligand that binds to a receptor activates downstream signaling pathways and to predict the strength of signaling. The challenge is compounded by functional selectivity, in which a single ligand binding to a single receptor can activate multiple signaling pathways at different levels. Spectroscopic studies show that in the largest class of cell surface receptors, 7 transmembrane receptors (7TMRs), activation is associated with ligand-induced shifts in the equilibria of intracellular pocket conformations in the absence of transducer proteins.

Novel Quinazoline Derivatives Inhibit Splicing of Fungal Group II Introns.

We report the discovery of small molecules that target the RNA tertiary structure of self-splicing group II introns and display potent antifungal activity against yeasts, including the major public health threat . High-throughput screening efforts against a yeast group II intron resulted in an inhibitor class which was then synthetically optimized for enhanced inhibitory activity and antifungal efficacy. The most highly refined compounds in this series display strong, gene-specific antifungal activity against .

T follicular helper cell expansion and hyperimmunoglobulinemia with spontaneous IgE production to dietary antigens in IgA-deficient mice.

Immunoglobulin A (IgA), the most abundantly produced antibody at mucosal surfaces, is thought to play key roles in immune responses to respiratory and enteric pathogens and in the regulation of commensal colonization. Low IgA levels have been associated with recurrent infections and immune dysregulation, including inflammatory bowel disease and autoimmunity. Levels of IgA in maternal breast milk and infant stool are both inversely associated with the emergence of immune responses to food antigens in infants and, in naturally resolving food sensitivity and immunotherapy protocols, the induction of IgA antibodies to dietary antigens has been associated with the acquisition of food tolerance.

Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD.

Background & Aims: Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with MASH. We tested its effect on insulin resistance at the level of different target tissues in relationship to change in intrahepatic triglyceride (IHTG) content.

Methods: This phase 2, single center, study randomized (1:1) 38 patients with T2D and MASLD to receive lanifibranor 800 mg or placebo for 24 weeks.

Rapid luminescence-based screening method for SARS- CoV-2 inhibitors discovery.

The COVID-19 pandemic has emphasized the necessity for rapid and adaptable drug screening platforms against live pathogenic viruses that require high levels of biosafety containment. Conventional antiviral testing is time-consuming and labor-intensive. Here, we outline the design and validation of a semi-automated drug-screening platform for SARS-CoV-2 that utilizes multiple liquid handlers, a stable A549 cell line expressing ACE2 and TMPRSS2 receptors, and a recombinant SARS-CoV-2 strain harboring the nano-luciferase gene.