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Highlights: [•] Tamoxifen produces cytotoxicity via estrogen-receptor (ER) independent mechanisms. [•] Tamoxifen binds to CB1 and CB2 cannabinoid receptors and acts as an inverse agonist. [•] CB1 and CB2 receptors are novel molecular targets for Tamoxifen. [•] ER-independent effects for Tamoxifen may be mediated via CB1 and/or CB2 receptors. [Copyright &y& Elsevier]

Objective: There is a dearth of empirical studies aimed at examining the impact of differential cultural adaptation of evidence-based clinical and prevention interventions. This prevention study consisted of a randomized controlled trial aimed at comparing the impact of 2 differentially culturally adapted versions of the evidence-based parenting intervention known as Parent Management Training, the Oregon Model (PMTOR ). Method: The sample consisted of 103 Latina/o immigrant families (190 individual parents). Each family was allocated to 1 of 3 conditions: (a) a culturally adapted PMTO (CA), (b) culturally adapted and enhanced PMTO (CE), and (c) a wait-list control. Measurements were implemented at baseline (Tl), treatment completion (T2) and 6-month follow up (T3). Results: Multilevel growth modeling analyses indicated statistically significant improvements on parenting skills for fathers and mothers (main effect) at 6-month follow-up in both adapted interventions, when compared with the control condition. With regard to parent-reported child behaviors, child internalizing behaviors were significantly lower for both parents in the CE intervention (main effect), compared with control at 6-month follow-up. No main effect was found for child externalizing behaviors. However, a Parent X Condition effect was found indicating a significant reduction of child externalizing behaviors for CE fathers compared with CA and control fathers at posttest and 6-month follow-up. Conclusion: Present findings indicate the value of differential cultural adaptation research designs and the importance of examining effects for both mothers and fathers, particularly when culturally focused and gender variables are considered for intervention design and implementation. [ABSTRACT FROM AUTHOR]

This study examined the association between ownership of high-risk ('vicious') dogs and the presence of deviant behaviors in the owners as indicated by court convictions. We also explored whether two characteristics of dog ownership (abiding licensing laws and choice of breed) could be useful areas of inquiry when assessing risk status in settings where children are present. Our matched sample consisted of 355 owners of either licensed or cited dogs that represented high or low-risk breeds. Categories of criminal convictions examined were aggressive crimes, drugs, alcohol, domestic violence, crimes involving children, firearm convictions, and major and minor traffic citations. Owners of cited high-risk ('vicious') dogs had significantly more criminal convictions than owners of licensed low-risk dogs. Findings suggest that the ownership of a high-risk ('vicious') dog can be a significant marker for general deviance and should be an element considered when assessing risk for child endangerment. [ABSTRACT FROM AUTHOR]

Focuses on the issues and problems in the field of journalism and mass communication in the United States. Overview of the commentaries from several educators; Assessment of the pedagogical approaches applied in teaching the disciplines in Higher Education; Educational and career background of the symposium contributors.

Adhesion G protein-coupled receptor (aGPCR) signaling influences development and homeostasis in a wide range of tissues. In the current model for aGPCR signaling, ligand binding liberates a conserved sequence that acts as an intramolecular, tethered agonist (TA), yet this model has not been evaluated systematically for all aGPCRs. Here, we assessed the TA-dependent activities of all 33 aGPCRs in a suite of transcriptional reporter, G protein activation, and β-arrestin recruitment assays using a new fusion protein platform. Strikingly, only ∼50% of aGPCRs exhibited robust TA-dependent activation, and unlike other GPCR families, aGPCRs showed a notable preference for G 12/13 signaling. AlphaFold2 predictions assessing TA engagement in the predicted intramolecular binding pocket aligned with the TA dependence of the cellular responses. This dataset provides a comprehensive resource to inform the investigation of all human aGPCRs and for targeting aGPCRs therapeutically., Competing Interests: Declaration of interests S.C.B. is on the board of directors for the non-profit Revson Foundation and non-profit Institute for Protein Innovation, is on the scientific advisory board for and receives funding from Erasca, Inc. for an unrelated project, is an advisor to MPM Capital, and is a consultant for Scorpion Therapeutics, Odyssey Therapeutics, Droia Ventures, and Ayala Pharmaceuticals for unrelated projects. A.C.K. is a co-founder and consultant for Tectonic Therapeutic and Seismic Therapeutic and for the Institute for Protein Innovation, a non-profit research institute. J.S.S. has received consulting fees from Biogen for an unrelated project., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The M3 muscarinic acetylcholine receptor (M 3 R) is a G protein-coupled receptor (GPCR) that regulates important physiologic processes, including vascular tone, bronchoconstriction, and insulin secretion. It is expressed on a wide variety of cell types, including pancreatic beta, smooth muscle, neuronal, and immune cells. Agonist binding to the M 3 R is thought to initiate intracellular signaling events primarily through the heterotrimeric G protein Gq. However, reports differ on the ability of M 3 R to couple to other G proteins beyond Gq. Using members from the four primary G protein families (Gq, Gi, Gs, and G13) in radioligand binding, GTP turnover experiments, and cellular signaling assays, including live cell G protein dissociation and second messenger assessment of cAMP and inositol trisphosphate, we show that other G protein families, particularly Gi and Gs, can also interact with the human M 3 R. We further show that these interactions are productive as assessed by amplification of classic second messenger signaling events. Our findings demonstrate that the M 3 R is more promiscuous with respect to G protein interactions than previously appreciated. SIGNIFICANCE STATEMENT: The study reveals that the human M3 muscarinic acetylcholine receptor (M 3 R), known for its pivotal roles in diverse physiological processes, not only activates intracellular signaling via Gq as previously known but also functionally interacts with other G protein families such as Gi and Gs, expanding our understanding of its versatility in mediating cellular responses. These findings signify a broader and more complex regulatory network governed by M 3 R and have implications for therapeutic targeting., (Copyright © 2024 by The Author(s).)

Notch signaling relies on ligand-induced proteolysis of the transmembrane receptor Notch to liberate a nuclear effector that drives cell fate decisions. Upon ligand binding, sequential cleavage of Notch by the transmembrane protease ADAM10 and the intracellular protease γ-secretase releases the Notch intracellular domain (NICD), which translocates to the nucleus and forms a complex that induces target gene transcription. To map the location and timing of the individual steps required for the proteolysis and movement of Notch from the plasma membrane to the nucleus, we used proximity labeling with quantitative, multiplexed mass spectrometry to monitor the interaction partners of endogenous NOTCH2 after ligand stimulation in the presence of a γ-secretase inhibitor and as a function of time after inhibitor removal. Our studies showed that γ-secretase-mediated cleavage of NOTCH2 occurred in an intracellular compartment and that formation of nuclear complexes and recruitment of chromatin-modifying enzymes occurred within 45 min of inhibitor washout. These findings provide a detailed spatiotemporal map tracking the path of Notch from the plasma membrane to the nucleus and identify signaling events that are potential targets for modulating Notch activity.

Adhesion G Protein Coupled Receptors (aGPCRs) have evolved an activation mechanism to translate extracellular force into liberation of a tethered agonist (TA) to effect cell signalling. We report here that ADGRF1 can signal through all major G protein classes and identify the structural basis for a previously reported Gα q preference by cryo-EM. Our structure shows that Gα q preference in ADGRF1 may derive from tighter packing at the conserved F569 of the TA, altering contacts between TM helix I and VII, with a concurrent rearrangement of TM helix VII and helix VIII at the site of Gα recruitment. Mutational studies of the interface and of contact residues within the 7TM domain identify residues critical for signalling, and suggest that Gα s signalling is more sensitive to mutation of TA or binding site residues than Gα q . Our work advances the detailed molecular understanding of aGPCR TA activation, identifying features that potentially explain preferential signal modulation., (© 2023. The Author(s).)

Kinetochores are the chromosomal attachment points for spindle microtubules. They are also signaling hubs that control major cell cycle transitions and coordinate chromosome folding. Most well-studied eukaryotes rely on a conserved set of factors, which are divided among two loosely-defined groups, for these functions. Outer kinetochore proteins contact microtubules or regulate this contact directly. Inner kinetochore proteins designate the kinetochore assembly site by recognizing a specialized nucleosome containing the H3 variant Cse4/CENP-A. We previously determined the structure, resolved by cryo-electron microscopy (cryo-EM), of the yeast Ctf19 complex (Ctf19c, homologous to the vertebrate CCAN), providing a high-resolution view of inner kinetochore architecture (Hinshaw and Harrison, 2019). We now extend these observations by reporting a near-atomic model of the Ctf3 complex, the outermost Ctf19c sub-assembly seen in our original cryo-EM density. The model is sufficiently well-determined by the new data to enable molecular interpretation of Ctf3 recruitment and function., Competing Interests: SH, AD, SH No competing interests declared, (© 2019, Hinshaw et al.)