Influence of Epithelial-Mesenchymal Transition on Risk of Relapse and Outcome to Eribulin or Cyclin-Dependent Kinase Inhibitors in Metastatic Breast Cancer.

Purpose: The presence of epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells has been linked to worse prognosis and may influence response to systemic treatment. We explored the effect of EMT in tumor samples of patients with metastatic BC on disease-free interval and overall survival in those patients receiving eribulin or cyclin-dependent kinase 4/6 inhibitors (CDK4/6i).

Materials And Methods: Key inclusion criteria included available archived primary BC tissue and, where available, matched metastatic biopsy.

Chemogenomic Screening in a Patient-Derived 3D Fatty Liver Disease Model Reveals the CHRM1-TRPM8 Axis as a Novel Module for Targeted Intervention.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver model from primary human hepatocytes and non-parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease-relevant endpoints, such as steatosis, inflammation and fibrosis, and multi-omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls.

Experimental measurements of the granular density of modes via impact.

The jamming transition is an important feature of granular materials, with prior work showing an excess of low-frequency modes in the granular analog to the density of states, the granular density of modes. In this work, we present an experimental method for acoustically measuring the granular density of modes using a single impact event to excite vibrational modes in an experimental, three-dimensional, granular material. We test three different granular materials, all of which are composed of spherical beads.

Discovery of a novel inhibitor of macropinocytosis with antiviral activity.

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using high-throughput microscopy, where we identified chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2.

Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge.

Background And Purpose: The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose-stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR-targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C-terminus.

Conformation- and activation-based BRET sensors differentially report on GPCR-G protein coupling.

G protein-coupled receptors (GPCRs) regulate cellular signaling processes by coupling to diverse combinations of heterotrimeric G proteins composed of Gα, Gβ, and Gγ subunits. Biosensors based on bioluminescence resonance energy transfer (BRET) have advanced our understanding of GPCR functional selectivity. Some BRET biosensors monitor ligand-induced conformational changes in the receptor or G proteins, whereas others monitor the recruitment of downstream effectors to sites of G protein activation.

Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide and AMG-133 (ref. ) combining GIPR antagonism with GLP-1R agonism.

The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.

Objective: Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs - and thus inducing cardiovascular complications - are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.

Epitaxial Metal Electrodeposition Controlled by Graphene Layer Thickness.

Control over material structure and morphology during electrodeposition is necessary for material synthesis and energy applications. One approach to guide crystallite formation is to take advantage of epitaxy on a current collector to facilitate crystallographic control. Single-layer graphene on metal foils can promote "remote epitaxy" during Cu and Zn electrodeposition, resulting in growth of metal that is crystallographically aligned to the substrate beneath graphene.

GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics.

G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events.

Girls are good at STEM: Opening minds and providing evidence reduces boys' stereotyping of girls' STEM ability.

Girls and women face persistent negative stereotyping within STEM (science, technology, engineering, mathematics). This field intervention was designed to improve boys' perceptions of girls' STEM ability. Boys (N = 667; mostly White and East Asian) aged 9-15 years in Canadian STEM summer camps (2017-2019) had an intervention or control conversation with trained camp staff.

Cancel culture can be collectively validating for groups experiencing harm.

Introduction: Social psychological research on collective action and intergroup harm has yet to adequately consider the potential role of cancel culture or feelings of collective validation in motivating collective action. The current research will begin to fill this gap and may broaden our understanding of the psychological mechanisms that inspire and maintain collective action in response to intergroup harm. To our knowledge, this research is the first social psychological analysis of the impact of cancel culture on collective action and as means for producing feelings of collective validation.

Killian Jamieson Diverticulum, the Great Mimicker: A Case Series and Contemporary Review.

Objective: To assess barium esophagram (BAS) as a diagnostic marker for patients with Killian Jamieson diverticula (KJD).

Methods: Prospective, multicenter cohort study of individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative. Patient demographics, comorbidities, radiographic imaging reports, laryngoscopy findings, patient-reported outcome measures (PROM), and operative reporting were abstracted from a REDCap database and summarized using means, medians, percentages, frequencies.

The chemistry of AlF and CaF production in buffer gas sources.

In this work, we explore the role of chemical reactions on the properties of buffer gas cooled molecular beams. In particular, we focus on scenarios relevant to the formation of AlF and CaF via chemical reactions between the Ca and Al atoms ablated from a solid target in an atmosphere of a fluorine-containing gas, in this case, SF and NF. Reactions are studied following an ab initio molecular dynamics approach, and the results are rationalized following a tree-shaped reaction model based on Bayesian inference.

High-Quality Contact With Fellow Majority Group Students Is Associated With Better Academic Performance of Minority Group Students.

We examined the association between intergroup contact and academic performance at university among minority students in a context with a segregated pre-university school system. Study 1 tested whether participation in a group dynamics course, which involves intimate interpersonal contact between Israeli Arab ( = 125) and Jewish students, was associated with better grade point average (GPA). As expected, Arab students who participated in the course had a higher GPA than those who did not, even when controlling for pre-university achievements.

Hyperfine-resolved optical spectroscopy of the AΠ ← XΣ transition in MgF.

We report on hyperfine-resolved laser spectroscopy of the AΠ ← XΣ transition of magnesium monofluoride (MgF), relevant for laser cooling. We recorded 25 rotational transitions with an absolute accuracy of better than 20 MHz, assigned 56 hyperfine lines, and determined precise rotational, fine, and hyperfine structure parameters for the AΠ state. The radiative lifetime of the AΠ state was determined to be 7.

Structural basis of Apt48 inhibition of the BCL6 BTB domain.

B cell lymphoma 6 (BCL6) is a transcriptional repressor that is deregulated in diffuse large B cell lymphoma, and the peptide aptamer, Apt48, inhibits BCL6 by an unknown mechanism. We report the crystal structure of BCL6 in complex with an Apt48 peptide, and show that Apt48 binds to a therapeutically uncharacterized region at the bottom of the BCL6 BTB domain. We show that the corepressor binding site of the BTB domain may be divided conceptually into two low-affinity, peptide-binding regions.

Melting, Crystallization, and Alloying Dynamics in Nanoscale Bismuth Telluride.

It is critical to understand the transformation mechanisms in layered metal chalcogenides to enable controlled synthesis and processing. Here, we develop an alumina encapsulation layer-based transmission electron microscopy (TEM) setup that enables the investigation of melting, crystallization, and alloying of nanoscale bismuth telluride platelets while limiting sublimation in the high-vacuum TEM environment. Heating alumina-encapsulated platelets to 700 °C resulted in melting that initiated at edge planes and proceeded via the movement of a sharp interface.

The Demographics of Patients Presenting for Laryngological Care at an Academic Medical Center.

Objectives/hypothesis: Few studies address the demographics/epidemiology/socioeconomic status of patients presenting to a laryngologist at a tertiary care center for treatment. To identify any possible disparities in voice, airway, and swallowing care, we sought to analyze the aforementioned data for new patients presenting to the voice center at an academic medical center.

Methods: This is a retrospective cohort study of prospectively collected data from an institutional database of 4,623 new adult patients presenting for laryngological care at a tertiary care, academic medical center from 2015 to 2020.

Normative Value for the Laryngopharyngeal Measure of Perceived Sensation.

Objectives/hypothesis: The Laryngopharyngeal Measure of Perceived Sensation (LUMP) is a recently validated patient-reported outcome measure (PROM) aimed at evaluating the symptom severity of patients with globus pharyngeus (GP). The objective of this study was to define the normative values for the LUMP questionnaire.

Study Design: Prospectively collected, descriptive research/scale development.

Need satisfaction in intergroup contact: A multinational study of pathways toward social change.

What role does intergroup contact play in promoting support for social change toward greater social equality? Drawing on the needs-based model of reconciliation, we theorized that when inequality between groups is perceived as illegitimate, disadvantaged group members will experience a need for empowerment and advantaged group members a need for acceptance. When intergroup contact satisfies each group's needs, it should result in more mutual support for social change. Using four sets of survey data collected through the Zurich Intergroup Project in 23 countries, we tested several preregistered predictions, derived from the above reasoning, across a large variety of operationalizations.

Illuminating the complexity of GPCR pathway selectivity - advances in biosensor development.

It should come as no surprise that G protein-coupled receptors (GPCRs) continue to occupy the focus of drug discovery efforts. Their widespread expression and broad role in signal transduction underline their importance in human physiology. Despite more than 800 GPCRs sharing a common architecture, unique differences govern ligand specificity and pathway selectivity.