Early elevations of RAS protein level and activity are critical for the development of PDAC in the context of inflammation.

The KRASG12D mutation was believed to be locked in a GTP-bound form, rendering it fully active. However, recent studies have indicated that the presence of mutant KRAS alone is insufficient; it requires additional activation through inflammatory stimuli to effectively drive the development of pancreatic ductal adenocarcinoma (PDAC). It remains unclear to what extent RAS activation occurs during the development of PDAC in the context of inflammation. Here, in a mouse model with the concurrent expression of KrasG12D/+ and inflammation mediator IKK2 in pancreatic acinar cells, we showed that, compared to KRASG12D alone, the cooperative interaction between KRASG12D and IKK2 rapidly elevated both the protein level and activity of KRASG12D and NRAS in a short term. This high level was sustained throughout the rest phase of PDAC development. These results suggest that inflammation not only rapidly augments the activity but also the protein abundance, leading to an enhanced total amount of GTP-bound RAS (KRASG12D and NRAS) in the early stage. Notably, while KRASG12D could be further activated by IKK2, not all KRASG12D proteins were in the GTP-bound state. Overall, our findings suggest that although KRASG12D is not fully active in the context of inflammation, concurrent increases in both the protein level and activity of KRASG12D as well as NRAS at the early stage by inflammation contribute to the rise in total GTP-bound RAS.

Social media consumption and depressive symptoms during the COVID-19 lockdown: the mediating effect of physical activity.

Introduction: Social media platforms played a critical role during the COVID-19 pandemic. This study aimed to explore: (1) the changes in social media consumption patterns, physical activity levels/sedentary behavior, and depressive symptoms, and (2) how the changes in social media consumption patterns predict the changes in depressive symptoms while investigating the mediating role of changes in physical activity levels/sedentary behavior between before, and after the COVID-19 lockdown among U.S. adults with different age clusters. Methods: A total of 695 U.S. participants completed an online questionnaire via MTurk, and participants were asked to recall their social media consumption patterns, physical activity/sedentary behavior, depressive symptoms in January and May of 2020 while covariates included non-physical activity health behavior including diet quality, alcohol consumption, smoking, and sleep quality. Results: The results of Bayesian significance testing of changes showed that the older participants tended to spend more time with content-focused social media platforms during the lockdown. While significantly increased sitting time was reported by all age clusters, no significant changes were found in activity levels. Additionally, the middle-aged and older participants reported significantly higher depressive symptoms. The findings of a multigroup structural analysis showed the significant mediating effect of moderate-to-vigorous physical activity on the relationship between changes in social media consumption and depressive symptoms. Discussion: This study highlights the need for targeting specific social media platforms for older adults and the importance of moderate-to-vigorous physical activity to alleviate the mental health issues resulting from social media consumption. The result of this study also highlights the need for sport-based intervention programs in the future and the need for more social media campaigns at the institution/organization levels established by public health stakeholders and policy makers to promote physical activity and maximize population perception and reach during the pandemic.

Oncogenic KRASG12D Reprograms Lipid Metabolism by Upregulating SLC25A1 to Drive Pancreatic Tumorigenesis.

Pancreatic cancer is a highly lethal disease with obesity as one of the risk factors. Oncogenic KRAS mutations are prevalent in pancreatic cancer and can rewire lipid metabolism by altering fatty acid (FA) uptake, FA oxidation (FAO), and lipogenesis. Identification of the underlying mechanisms could lead to improved therapeutic strategies for treating KRAS-mutant pancreatic cancer. Here, we observed that KRASG12D upregulated the expression of SLC25A1, a citrate transporter that is a key metabolic switch to mediate FAO, fatty acid synthesis, glycolysis, and gluconeogenesis. In genetically engineered mouse models and human pancreatic cancer cells, KRASG12D induced SLC25A1 upregulation via GLI1, which directly stimulated SLC25A1 transcription by binding its promoter. The enhanced expression of SLC25A1 increased levels of cytosolic citrate, FAs, and key enzymes in lipid metabolism. In addition, a high-fat diet (HFD) further stimulated the KRASG12D-GLI1-SLC25A1 axis and the associated increase in citrate and FAs. Pharmacologic inhibition of SLC25A1 and upstream GLI1 significantly suppressed pancreatic tumorigenesis in KrasG12D/+ mice on a HFD. These results reveal a KRASG12D-GLI1-SLC25A1 regulatory axis, with SLC25A1 as an important node that regulates lipid metabolism during pancreatic tumorigenesis, thus indicating an intervention strategy for oncogenic KRAS-driven pancreatic cancer. SIGNIFICANCE: Upregulation of SLC25A1 induced by KRASG12D-GLI1 signaling rewires lipid metabolism and is exacerbated by HFD to drive the development of pancreatic cancer, representing a targetable metabolic axis to suppress pancreatic tumorigenesis.

Sport participation, acculturative stress, and depressive symptoms among international college students in the United States.

Introduction: The distinctive social nature of sport in its capacity to promote immigrants' adaptation to the new society has been regarded as a vehicle to cope with adverse mental health outcomes derived from acculturative stress (AS) and feelings of marginalization. However, the evidence on the relationship between sport participation (SP), AS, and mental health have been lacking and fragmented. Recognizing this challenge, we examined the mediating effect of AS on the relationship between SP and depressive symptoms (DS) among international college students in the USA. Methods: A total of 203 international college students in the USA were recruited via Prolific. The instrumentation included previously validated measures: SP (SLIM-18), AS (ASSIS), DS (CES-D-10), sense of coherence (SOC-13), and demographic characteristics. Results: Mediation analysis showed a significant association between (1) SP and DS (ß = -0.030, p < 0.05) and (2) AS and DS (ß = 0.053, p < 0.001), while (3) no significant indirect effect of AS was found [ß = -0.001, SE = 0.0003, 95% CI (-0.008, 0.004)]. Discussion: Even though several previous scholars have argued that SP is an effective tool to cope with AS among international students, the present study implies this may not be applied to all international students. Specifically, AS and DS among European participants were lower than those from non-European countries, including Asia. Future studies using meta-analysis could be beneficial to examine the external validity of the previous studies on the relationship between SP, acculturation, and mental health to address this potential heterogeneity on the level of AS based on their origin countries or continents. The current study provides meaningful implications for adopting the transformative marketing perspective, which is a marketing approach that pursues positive social outcomes by promoting positive behavior of the target population.

Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.

KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain unclear. In this study, we compared the differential effects of a high-carbohydrate diet (HCD), an HFD, and a high-protein diet (HPD) in PDAC development using a mouse model expressing an endogenous level of mutant KRASG12D specifically in pancreatic acinar cells. Our study showed that although with a lower tumorigenic capacity than chronic HFD, chronic HCD promoted acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions with increased inflammation, fibrosis, and cell proliferation compared to the normal diet (ND) in KrasG12D/+ mice. By contrast, chronic HPD showed no significant adverse effects compared to the ND. Furthermore, ablation of pancreatic acinar cell cyclooxygenase 2 (Cox-2) in KrasG12D/+ mice abrogated the adverse effects induced by HCD, suggesting that diet-induced pancreatic inflammation is critical for promoting oncogenic KRAS-mediated neoplasia. These results indicate that diets rich in different macronutrients have differential effects on pancreatic tumorigenesis in which the ensuing inflammation exacerbates the process. Management of macronutrient intake aimed at thwarting inflammation is thus an important preventive strategy for patients harboring oncogenic KRAS.

Self-Serving Bias in Performance Goal Achievement Appraisals: Evidence From Long-Distance Runners.

While working with a long-distance running event organizer, the authors of this study observed considerable differences between event participants' official finish time (i.e., bib time) and their self-reported finish time in the post-event survey. Drawing on the notion of self-serving bias, we aim to explore the source of this disparity and how such psychological bias influences participants' event experience at long-distance running events. Using evidence of 1,320 marathon runners, we demonstrated how people are more likely to be subject to a biased self-assessment contingent upon achieving their best finish time at the event. The study samples were split into record-high-achieved and record-high-missed groups, and the self-serving biases of each group were explored. Results from the t-test comparing record-high-achieved and -missed groups showed that runners in the record-high-missed group were significantly more likely to report a positively biased finish time than runners in the record-high-achieved group (p < 0.01). Additionally, results from logistic regression showed that as runners missed their best finish time by a wider margin, the probability of reporting a positively biased incorrect finish time increased. Lastly, we conducted an additional t-test and revealed that runners who are subject to self-serving bias showed a lower level of overall event satisfaction. The current study suggests one way to bypass the adverse effects of participant sport event participants' worse-than-expected athletic performance. We specifically suggest that the event organizers target runners who had worse-than-expected performance and make extra efforts on non-race service attributes (e.g., finish line experience, rest and recovery area, and transportation after the event) because these runners are more likely to be unsatisfied with the event.

Changes in Physical Activity and Depressive Symptoms During COVID-19 Lockdown: United States Adult Age Groups.

This study investigates: (1) the changes in three major health-related factors-physical activity, non-physical-activity health behavior (i.e., diet quality, alcohol consumption, smoking, sleep quality), and depressive symptoms, and (2) how changes in physical activity were associated with changes in one's depressive symptoms among young adults, middle-aged adults, and older adults while controlling non-physical-activity health behavior and sociodemographic characteristics among young, middle-aged, and older adults before and after the COVID-19 outbreak lockdown in the United States. A total of 695 participants completed an online questionnaire via MTurk, and participants were asked to recall their physical activity, depressive symptoms, and non-physical-activity health behavior status in January and May of 2020. The IPAQ-SF was used to evaluate individuals' physical activity, while the CES-D-10 was used to assess depressive symptoms. Covariates included non-physical-activity health behavior and sociodemographic factors. A Bayesian significance testing of changes was used to examine significant changes in physical activity, non-physical-activity behavior, and depressive symptoms in each age group while Bayesian regression analysis was employed to examine how the changes in physical activity were associated with respondents' depressive symptoms while controlling for individual NHB and sociodemographic characteristics. The results showed that the participants tended to maintain their physical activity levels after the lockdown despite significant increases in sitting time among young and older adults. Decreases in moderate physical activity frequency were associated with a higher level of depressive symptoms (R 2 = 17.1%). Although young and middle-aged cohorts experienced fewer differences in depressive symptoms compared to their counterparts in the older group, we found no significant heterogeneity effects in the relationships of interest across all age groups. Considering different influences of physical activity on depressive symptoms depending on different levels of activity and ages, more randomized clinical trials with program-based intervention studies should be conducted with different physical activity programs for different age populations.

A Tale of Two Cities: COVID-19 and the Emotional Well-Being of Student-Athletes Using Natural Language Processing.

Student-athletes at the Division I institutions face a slew of challenges and stressors that can have negative impacts in eliciting different emotional responses during the COVID-19 pandemic. We employed machine-learning-based natural language processing techniques to analyze the user-generated content posted on Twitter of Atlantic Coast Conference (ACC) student-athletes to study changes in their sentiment as it relates to the COVID-19 crisis, major societal events, and policy decisions. Our analysis found that positive sentiment slightly outweighed negative sentiment overall, but that there was a noticeable uptick in negative sentiment in May and June 2020 in conjunction with the Black Lives Matter protests. The most commonly expressed emotions by these athletes were joy, trust, anticipation, and fear, suggesting that they used social media as an outlet to share primarily optimistic sentiments, while still publicly expressing strong negative sentiments like fear and trepidation about the pandemic and other important contemporary events. Athletic administrators, ACC coaches, support staff, and other professionals can use findings like these to guide sound, evidence-based decision-making and to better track and promote the emotional wellness of student-athletes.

Older Adults' Physical Activity and Healthcare Costs, 2003-2014.

INTRODUCTION: Research has documented the health benefits of physical activity among older adults, but the relationship between physical activity and healthcare costs remains unexplored at the population level. Using data from 50 U.S. states and the District of Columbia, this study investigates the extent to which physical activity prevalence is associated with healthcare costs among older adults. METHODS: Twelve-year state-level data (2003-2014) were obtained from 5 secondary sources (n=611). Healthcare costs were captured by Medicare Parts A and B spending. Fixed-effect models were estimated in 2019 to assess the relationship between the state-level physical activity prevalence and Medicare costs. The potential lagged associations were captured by lagged variables of physical activity prevalence (i.e., t-1, t-2, and t-3). RESULTS: Physical activity prevalence was not associated with Medicare costs occurring in the concurrent and subsequent year (p>0.05); however, the 2-year lagged variable (p=0.03) and the 3-year lagged variable (p=0.01) for physical activity prevalence were negatively associated with Medicare costs, indicating a time-lagged relationship. It was estimated that a 10 percentage point increase in physical activity prevalence in each state is associated with reduced Medicare Parts A and B costs of 0.4% after 2 years and 1.0% after 3 years. CONCLUSIONS: Results revealed a time lag effect highlighted by a delayed inverse relationship between state-level physical activity prevalence and healthcare costs among older adults. This evidence offers governments and communities new insights to guide policymaking on long-term public investment in physical activity intervention programs.

SUMO suppresses and MYC amplifies transcription globally by regulating CDK9 sumoylation.

Regulation of transcription is fundamental to the control of cellular gene expression and function. Although recent studies have revealed a role for the oncoprotein MYC in amplifying global transcription, little is known as to how the global transcription is suppressed. Here we report that SUMO and MYC mediate opposite effects upon global transcription by controlling the level of CDK9 sumoylation. On one hand, SUMO suppresses global transcription via sumoylation of CDK9, the catalytic subunit of P-TEFb kinase essential for productive transcriptional elongation. On the other hand, MYC amplifies global transcription by antagonizing CDK9 sumoylation. Sumoylation of CDK9 blocks its interaction with Cyclin T1 and thus the formation of active P-TEFb complex. Transcription profiling analyses reveal that SUMO represses global transcription, particularly of moderately to highly expressed genes and by generating a sumoylation-resistant CDK9 mutant, we confirm that sumoylation of CDK9 inhibits global transcription. Together, our data reveal that SUMO and MYC oppositely control global gene expression by regulating the dynamic sumoylation and desumoylation of CDK9.

MOF as an evolutionarily conserved histone crotonyltransferase and transcriptional activation by histone acetyltransferase-deficient and crotonyltransferase-competent CBP/p300.

Recent studies indicate that histones are subjected to various types of acylation including acetylation, propionylation and crotonylation. CBP and p300 have been shown to catalyze multiple types of acylation but are not conserved in evolution, raising the question as to the existence of other enzymes for histone acylation and the functional relationship between well-characterized acetylation and other types of acylation. In this study, we focus on enzymes catalyzing histone crotonylation and demonstrate that among the known histone acetyltransferases, MOF, in addition to CBP and p300, also possesses histone crotonyltransferase (HCT) activity and this activity is conserved in evolution. We provide evidence that CBP and p300 are the major HCTs in mammalian cells. Furthermore, we have generated novel CBP/p300 mutants with deficient histone acetyltransferase but competent HCT activity. These CBP/p300 mutants can substitute the endogenous CBP/p300 to enhance transcriptional activation in the cell, which correlates with enhanced promoter crotonylation and recruitment of DPF2, a selective reader for crotonylated histones. Taken together, we have identified MOF as an evolutionarily conserved HCT and provide first cellular evidence that CBP/p300 can facilitate transcriptional activation through histone acylation other than acetylation, thus supporting an emerging role for the non-acetylation type of histone acylation in transcription and possibly other chromatin-based processes.

The lysine methyltransferase SMYD2 methylates the kinase domain of type II receptor BMPR2 and stimulates bone morphogenetic protein signaling.

Lysine methylation of chromosomal and nuclear proteins is a well-known mechanism of epigenetic regulation, but relatively little is known about the role of this protein modification in signal transduction. Using an RNAi-based functional screening of the SMYD family of lysine methyltransferases (KMTs), we identified SMYD2 as a KMT essential for robust bone morphogenic protein (BMP)- but not TGFß-induced target gene expression in HaCaT keratinocyte cells. A role for SMYD2 in BMP-induced gene expression was confirmed by shRNA knockdown and CRISPR/Cas9-mediated knock-out of SMYD2 We further demonstrate that SMYD2 knockdown or knock-out impairs BMP-induced phosphorylation of the signal-transducing protein SMAD1/5 and SMAD1/5 nuclear localization and interaction with SMAD4. The SMYD2 KMT activity was required to facilitate BMP-mediated signal transduction, as treatment with the SMYD2 inhibitor AZ505 suppressed BMP2-induced SMAD1/5 phosphorylation. Furthermore, we present evidence that SMYD2 likely modulates the BMP response through its function in the cytosol. We show that, although SMYD2 interacted with multiple components in the BMP pathway, it specifically methylated the kinase domain of BMP type II receptor BMPR2. Taken together, our findings suggest that SMYD2 may promote BMP signaling by directly methylating BMPR2, which, in turn, stimulates BMPR2 kinase activity and activation of the BMP pathway.

Acidic domains differentially read histone H3 lysine 4 methylation status and are widely present in chromatin-associated proteins.

Histone methylation is believed to provide binding sites for specific reader proteins, which translate histone code into biological function. Here we show that a family of acidic domain-containing proteins including nucleophosmin (NPM1), pp32, SET/TAF1ß, nucleolin (NCL) and upstream binding factor (UBF) are novel H3K4me2-binding proteins. These proteins exhibit a unique pattern of interaction with methylated H3K4, as their binding is stimulated by H3K4me2 and inhibited by H3K4me1 and H3K4me3. These proteins contain one or more acidic domains consisting mainly of aspartic and/or glutamic residues that are necessary for preferential binding of H3K4me2. Furthermore, we demonstrate that the acidic domain with sufficient length alone is capable of binding H3K4me2 in vitro and in vivo. NPM1, NCL and UBF require their acidic domains for association with and transcriptional activation of rDNA genes. Interestingly, by defining acidic domain as a sequence with at least 20 acidic residues in 50 continuous amino acids, we identified 655 acidic domain-containing protein coding genes in the human genome and Gene Ontology (GO) analysis showed that many of the acidic domain proteins have chromatin-related functions. Our data suggest that acidic domain is a novel histone binding motif that can differentially read the status of H3K4 methylation and is broadly present in chromatin-associated proteins.

Large-Scale Identification of Protein Crotonylation Reveals Its Role in Multiple Cellular Functions.

Lysine crotonylation on histones is a recently identified post-translational modification that has been demonstrated to associate with active promoters and to directly stimulate transcription. Given that crotonyl-CoA is essential for the acyl transfer reaction and it is a metabolic intermediate widely localized within the cell, we postulate that lysine crotonylation on nonhistone proteins could also widely exist. Using specific antibody enrichment followed by high-resolution mass spectrometry analysis, we identified hundreds of crotonylated proteins and lysine residues. Bioinformatics analysis reveals that crotonylated proteins are particularly enriched for nuclear proteins involved in RNA processing, nucleic acid metabolism, chromosome organization, and gene expression. Furthermore, we demonstrate that crotonylation regulates HDAC1 activity, expels HP1α from heterochromatin, and inhibits cell cycle progression through S-phase. Our data thus indicate that lysine crotonylation could occur in a large number of proteins and could have important regulatory roles in multiple nuclei-related cellular processes.

Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer.

Global DNA hypomethylation is a most common epigenetic alteration in cancer, but the mechanism remains elusive. Previous studies demonstrate that UHRF1 but not UHRF2 is required for mediating DNA maintenance methylation by DNMT1. Here we report unexpectedly a conserved function for UHRF1 and UHRF2: inhibiting de novo DNA methylation by functioning as E3 ligases promoting DNMT3A degradation. UHRF1/2 are frequently overexpressed in cancers and we present evidence that UHRF1/2 overexpression downregulates DNMT3A proteins and consequently leads to DNA hypomethylation. Abrogating this negative regulation on DNMT3A or overexpression of DNMT3A leads to increased DNA methylation and impaired tumor growth. We propose a working model that UHRF1/2 safeguards the fidelity of DNA methylation and suggests that UHRF1/2 overexpression is likely a causal factor for widespread DNA hypomethylation in cancer via suppressing DNMT3A.

Rate of Physical Activity and Community Health: Evidence From U.S. Counties.

BACKGROUND: Although previous studies supported the health benefits of physical activity, these studies were limited to individual-level research designs. Building upon a social-ecological model, we examined the relationship between physical activity and community health-the health status of a defined group of people-while accounting for the potential endogeneity of physical activity to health. METHODS: We obtained U.S. county-level data from the 2012 Behavioral Risk Factor Surveillance System survey and the 2014 County Health Ranking Database. We first conducted an ordinary least squares (OLS) regression analysis to examine the relationship between the rate of physical activity and community health measured by the average perceived health score for each county. We then conducted a 2-stage least squares (2SLS) regression analysis to investigate this relationship after accounting for potential endogeneity. RESULTS: Results from the OLS analysis indicated that the rate of physical activity was positively associated with community health. Results from the 2SLS analysis confirmed that the physical activity rate remained positively associated with community health. CONCLUSIONS: In line with the social-ecological model, our findings provide the first evidence for the health benefits of county-level physical activity. Our results support extant research that has shown relationships between physical activity and individual-level, health-related outcomes.