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Mortalin [also known as heat shock protein family A (HSP70) member 9 (HSPA9) or glucose-regulated protein 75 (GRP75)] is a mitochondrial molecular chaperone that is often up-regulated and mislocalized in tumors with abnormal activation of the kinases MEK and ERK. Here, we found that mortalin depletion was selectively lethal to tumor and immortalized normal cells expressing the mutant kinase B-RafV600E or the chimeric protein ΔRaf-1:ER and that MEK-ERK-sensitive regulation of the peptide-binding domain in mortalin was critical to cell survival or death. Proteomics screening identified adenine nucleotide translocase 3 (ANT3) as a previously unknown mortalin substrate and cell survival/death effector. Mechanistically, increased MEK-ERK signaling activity and mortalin function converged opposingly on the regulation of mitochondrial permeability. Specifically, whereas MEK-ERK activity increased mitochondrial permeability by promoting the interaction between ANT3 and the peptidyl-prolyl isomerase cyclophilin D (CypD), mortalin decreased mitochondrial permeability by inhibiting this interaction. Hence, mortalin depletion increased mitochondrial permeability in MEK-ERK-deregulated cells to an extent that triggered cell death. HSP70 inhibitor derivatives that effectively inhibited mortalin suppressed the proliferation of B-RafV600E tumor cells in culture and in vivo, including their B-Raf inhibitor-resistant progenies. These findings suggest that targeting mortalin has potential as a selective therapeutic strategy in B-Raf-mutant or MEK-ERK-driven tumors.

Using research from brand roles and goal pursuit as our theoretical framework, we find that the type of goal pursuit influences how consumers respond to the brand role of leader (i.e., leader brand) vs. servant (i.e., servant brand). Two experiments show that consumers in the goal attainment condition prefer a leader brand rather than a servant brand. In contrast, consumers in the goal progress condition show no difference in their preference for a leader brand or a servant brand. Mediation analyses show that the level of motivation mediates the effect of goal pursuit on consumers’ preference for leader brands. Theoretical and managerial implications are discussed.

Personalized advertisements have been increasingly employed as a marketing strategy that enables a company to build strong relationship with customers. Results from two studies show that perceived personalization of personalized advertisements is an essential factor of stronger brand love. Specifically, this research reveals that perceived personalized Facebook ads positively impact brand experience and brand self-expressiveness, which in turn enhances brand attachment and brand love. This paper contributes to branding literature by illustrating how advertisements strengthen consumer brand relationships and enable brand managers to make better informed decisions when crafting personalized advertisements. [ABSTRACT FROM AUTHOR]

Background and aim: Previous studies have suggested cardiovascular risk factors increase the risk of not only common sporadic stroke but also of stroke in patients with monogenic stroke disorders including CADASIL. We investigated the effects of the NOTCH3 Arg544Cys (R544C) variant and associated vascular risk factors on stroke in the Taiwanese population. Methods: This study was conducted using data from the Taiwan Biobank, consisting of at least 130,000 Han Chinese participants. The genotype was derived from customized genome-wide arrays for 650,000 to 750,000 single-nucleotide polymorphisms (SNPs). Individuals with NOTCH3 R544C were subsequently matched with noncarriers based on the propensity score at a 1:10 ratio by demographic and cardiovascular risk factors. The odds ratio (OR) for stroke or other phenotypes in NOTCH3 R544C carriers and matched noncarriers was then calculated. Univariate and multivariate regression analyses were performed on cardiovascular risk factors in NOTCH3 R544C carriers with and without stroke. The polygenic risk score (PRS) model, adopted from the UK Biobank, was then applied to evaluate the role of NOTCH3 R544C in stroke. Results: From the 114,282 participants with both genotype and questionnaire results, 1080 (0.95%) harbored the pathogenic NOTCH3 R544C variant. When compared to the matched controls (n = 10,800), the carriers presented with a history of stroke (OR: 2.52, 95% confidence interval (CI) (1.45, 4.37)), dementia (OR: 30.1, 95% CI (3.13, 289.43)), and sibling history of stroke (OR: 2.48, 95% CI (1.85, 3.34)) phenotypes. The risk of stroke increased with every 10-year increase in age (p = 0.006, Cochran–Mantel–Haenszel test). Among NOTCH3 R544C carriers, 16 (1.3%) of the 1080 carriers with a stroke history were older, male, and more likely to have hypertension, diabetes, dyslipidemia, and a family history of stroke. In the stepwise multivariate analysis, hypertension (OR: 11.28, 95% CI (3.54, 43.3)) and diabetes mellitus (OR: 4.10, 95% CI (1.31, 12.4)) were independently associated with stroke. Harboring the NOTCH3 R544C variant in the Taiwan Biobank is comparable with a 6.74 standard deviations increase in individual's polygenic risk score for stroke. Conclusion: While the NOTCH3 R544C variant alone increased the risk of stroke, modifiable vascular risk factors also played a role in the occurrence of stroke in Taiwanese community-dwelling individuals carrying the NOTCH3 variant. [ABSTRACT FROM AUTHOR]

People have fundamental beliefs about what constitutes a good relationship, known as implicit theories of relationship, where some people have destiny beliefs whereas others have growth beliefs. People with destiny beliefs believe that potential partners are meant either for each other or not, whereas people with growth beliefs believe that successful relationships are cultivated and developed. This research shows that different implicit theories of relationship influence consumers’ gift choice to their significant others. We demonstrate, through two studies, that consumers with destiny beliefs prefer giving gifts that are more feasible in nature, whereas consumers with growth beliefs prefer giving gifts that are more desirable in nature. We show that this effect is mediated by desirability-feasibility considerations. Specifically, consumers with destiny beliefs focus on feasibility considerations, which leads them to choose a highly feasible gift. Conversely, consumers with growth beliefs focus on desirability considerations, which leads them to choose a highly desirable gift. We also discuss the theoretical and managerial implications of our research.

People use two types of scheduling styles to schedule their daily activities, namely clock-time or event-time. When people use clock time, they organize tasks based on a clock. When they use event-time, they organize tasks based on their order of completion. This research shows that adopting different scheduling styles influence consumers’ assortment size preferences. We demonstrate, through two studies, that consumers using event-time scheduling style prefer a larger assortment size whereas consumers using clock-time scheduling style prefer a smaller assortment size. We also show that this effect is mediated by desirability-feasibility consideration. Specifically, event-time scheduling style leads consumers to focus on the desirability considerations, which leads them to prefer larger assortment size while shopping. On the other hand, clock-time scheduling style leads consumers to focus on the feasibility considerations, which leads them to prefer smaller assortment size while shopping. We also discuss the theoretical and managerial implications of our research.