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The tumour suppressor p120-catenin (p120) controls cadherin-based adhesion. Here, the authors demonstrate that p120 regulates cytokinesis through binding to the centralspindlin component MKLP1 and controls RhoA activity. Loss of p120 in cancer induces multinucleation and chromosomal instability, independent of cell-cell adhesion.

Abstract Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first‐in‐class small molecule inhibitor, RK‐33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK‐33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3‐overexpressing cells. Importantly, RK‐33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK‐33 impaired Wnt signaling through disruption of the DDX3–β‐catenin axis and inhibited non‐homologous end joining—the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK‐33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.

The 21-item Intuitive Eating Scale (IES; Tylka, 2006) measures individuals' tendency to follow their physical hunger and satiety cues when determining when, what, and how much to eat. While its scores have demonstrated reliability and validity with college women, the IES-2 was developed to improve upon the original version. Specifically, we added 17 positively scored items to the original IES items (which were predominantly negatively scored), integrated an additional component of intuitive eating (Body-Food Choice Congruence), and evaluated its psychometric properties with 1,405 women and 1,195 men across three studies. After we deleted 15 items (due to low item-factor loadings, high cross-loadings, and redundant content), the results supported the psychometric properties of the IES-2 with women and men. The final 23-item IES-2 contained 11 original items and 12 added items. Exploratory and second-order confirmatory factor analyses upheld its hypothesized 4-factor structure (its original 3 factors, plus Body-Food Choice Congruence) and a higher order factor. The IES-2 was largely invariant across sex, although negligible differences on 1 factor loading and 2 item intercepts were detected. Demonstrating validity, the IES-2 total scores and most IES-2 subscale scores were (a) positively related to body appreciation, self-esteem, and satisfaction with life; (b) inversely related to eating disorder symptomatology, poor interoceptive awareness, body surveillance, body shame, body mass index, and internalization of media appearance ideals; and (c) negligibly related to social desirability. IES-2 scores also garnered incremental validity by predicting psychological well-being above and beyond eating disorder symptomatology. The IES-2's applications for empirical research and clinical work are discussed. (Contains 5 tables.)

Background: In asthma and allergic rhinitis, beliefs about what triggers allergic reactions often do not match objective allergy tests. This may be due to insensitivity for expectancy violations as a result of holding trigger beliefs based on conceptual relationships among triggers. In this laboratory experiment, we aimed to investigate how pre-existing beliefs and conceptual relationships among triggers interact with actual experience when learning differential symptom expectations.Methods: Healthy participants (N = 48) received information that allergic reactions were a result of specific sensitivities versus general allergic vulnerability. Next, they performed a trigger learning task using a differential conditioning paradigm: brief inhalation of CO2 enriched air was used to induce symptoms, while participants were led to believe that the symptoms came about as a result of inhaled allergens (conditioned stimuli, CS’s; CS+ followed by symptoms, CS- not followed by symptoms). CS+ and CS- stimuli either shared (e.g., birds-mammals) or did not share (e.g. birds-fungi) category membership. During Acquisition, participants reported symptom expectancy and symptom intensity for all triggers. During a Test 1 day later, participants rated symptom expectancies for old CS+/CS- triggers, for novel triggers within categories, and for exemplars of novel trigger categories. Data were analyzed using multilevel models.Findings: Only a subgroup of participants (n = 22) showed differences between CO2 and room air symptoms. In this group of responders, analysis of symptom expectancies during acquisition did not result in significant differential symptom CS+/CS- acquisition. A retention test 1 day later showed differential CS+/CS- symptom expectancies: When CS categories did not share category membership, specific sensitivity beliefs improved retention of CS+/CS- differentiation. However, when CS categories shared category membership, general vulnerability beliefs improved retention of CS+/CS- differentiation. Furthermore, participants showed some selectivity in generalization of symptom expectancies to novel categories, as symptom expectancies did not generalize to novel categories that were unrelated to CS+ or CS- categories. Generalization to novel categories was not affected by information about general vulnerability or specific sensitivities.Discussion: Pre-existing vulnerability beliefs and conceptual relationships between trigger categories influence differential symptom expectancies to allergic triggers.

ABSTRACT Alpaca-derived single-domain antibody fragments (VHHs) that target the influenza A virus nucleoprotein (NP) can protect cells from infection when expressed in the cytosol. We found that one such VHH, αNP-VHH1, exhibits antiviral activity similar to that of Mx proteins by blocking nuclear import of incoming viral ribonucleoproteins (vRNPs) and viral transcription and replication in the nucleus. We determined a 3.2-Å crystal structure of αNP-VHH1 in complex with influenza A virus NP. The VHH binds to a nonconserved region on the body domain of NP, which has been associated with binding to host factors and serves as a determinant of host range. Several of the NP/VHH interface residues determine sensitivity of NP to antiviral Mx GTPases. The structure of the NP/αNP-VHH1 complex affords a plausible explanation for the inhibitory properties of the VHH and suggests a rationale for the antiviral properties of Mx proteins. Such knowledge can be leveraged for much-needed novel antiviral strategies. IMPORTANCE Influenza virus strains can rapidly escape from protection afforded by seasonal vaccines or acquire resistance to available drugs. Additional ways to interfere with the virus life cycle are therefore urgently needed. The influenza virus nucleoprotein is one promising target for antiviral interventions. We have previously isolated alpaca-derived single-domain antibody fragments (VHHs) that protect cells from influenza virus infection if expressed intracellularly. We show here that one such VHH exhibits antiviral activities similar to those of proteins of the cellular antiviral defense (Mx proteins). We determined the three-dimensional structure of this VHH in complex with the influenza virus nucleoprotein and identified the interaction site, which overlaps regions that determine sensitivity of the virus to Mx proteins. Our data define a new vulnerability of influenza virus, help us to better understand the cellular antiviral mechanisms, and provide a well-characterized tool to further study them.