Endoplasmic Reticulum Stress-Associated Lipid Droplet Formation and Type II Diabetes

Diabetes mellitus (DM), a metabolic disorder characterized by hyperglycemia, is caused by insufficient insulin production due to excessive loss of pancreatic β cells (type I diabetes) or impaired insulin signaling due to peripheral insulin resistance (type II diabetes). Pancreatic β cell is the only insulin-secreting cell type that has highly developed endoplasmic reticulum (ER) to cope with high demands of insulin synthesis and secretion. Therefore, ER homeostasis is crucial to the proper function of insulin signaling. Accumulating evidence suggests that deleterious ER stress and excessive intracellular lipids in nonadipose tissues, such as myocyte, cardiomyocyte, and hepatocyte, cause pancreatic β-cell dysfunction and peripheral insulin resistance, leading to type II diabetes. The excessive deposition of lipid droplets (LDs) in specialized cell types, such as adipocytes, hepatocytes, and macrophages, has been found as a hallmark in ER stress-associated metabolic diseases, including obesity, diabetes, fatty liver disease, and atherosclerosis. However, much work remains to be done in understanding the mechanism by which ER stress response regulates LD formation and the pathophysiologic role of ER stress-associated LD in metabolic disease. This paper briefly summarizes the recent advances in ER stress-associated LD formation and its involvement in type II diabetes

Unfolded protein response in cancer: the Physician\u27s perspective

Abstract The unfolded protein response (UPR) is a cascade of intracellular stress signaling events in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER). Cancer cells are often exposed to hypoxia, nutrient starvation, oxidative stress and other metabolic dysregulation that cause ER stress and activation of the UPR. Depending on the duration and degree of ER stress, the UPR can provide either survival signals by activating adaptive and antiapoptotic pathways, or death signals by inducing cell death programs. Sustained induction or repression of UPR pharmacologically may thus have beneficial and therapeutic effects against cancer. In this review, we discuss the basic mechanisms of UPR and highlight the importance of UPR in cancer biology. We also update the UPR-targeted cancer therapeutics currently in clinical trials

Seasonality of COVID-19 incidence in the United States

BackgroundThe surges of Coronavirus Disease 2019 (COVID-19) appeared to follow a repeating pattern of COVID-19 outbreaks regardless of social distancing, mask mandates, and vaccination campaigns.ObjectivesThis study aimed to investigate the seasonality of COVID-19 incidence in the United States of America (USA), and to delineate the dominant frequencies of the periodic patterns of the disease.MethodsWe characterized periodicity in COVID-19 incidences over the first three full seasonal years (March 2020 to March 2023) of the COVID-19 pandemic in the USA. We utilized a spectral analysis approach to find the naturally occurring dominant frequencies of oscillation in the incidence data using a Fast Fourier Transform (FFT) algorithm.ResultsOur study revealed four dominant peaks in the periodogram: the two most dominant peaks show a period of oscillation of 366 days and 146.4 days, while two smaller peaks indicate periods of 183 days and 122 days. The period of 366 days indicates that there is a single COVID-19 outbreak that occurs approximately once every year, which correlates with the dominant outbreak in the early/mid-winter months. The period of 146.4 days indicates approximately 3 peaks per year and matches well with each of the 3 annual outbreaks per year.ConclusionOur study revealed the predictable seasonality of COVID-19 outbreaks, which will guide public health preventative efforts to control future outbreaks. However, the methods used in this study cannot predict the amplitudes of the incidences in each outbreak: a multifactorial problem that involves complex environmental, social, and viral strain variables

Perception-reality bias: the differences in government trust across income groups

This paper first measures and compares the size of middle-income groups in China based on the subjective income evaluation method and the objective criteria. Second, it empirically investigates the differences in government trust of different income groups defined by the subjective evaluation method and the objective criteria. It is found that there is a significant difference between the results of the subjective evaluation of income and objective criteria. Compared with individuals in the middle-income group, individuals in the low-income group have a significantly worse overall evaluation of local government and a considerably lower trust in local government officials. On the other hand, individuals in the high-income group have a substantially better assessment of local government and a significantly higher trust in local government officials. However, the differences in trust in government across income groups defined by objective criteria are insignificant overall. In terms of policy insights, the effect of targeting low-income groups determined by subjective evaluation may be more effective in improving people’s trust in the government

Explainable Recommendation with Personalized Review Retrieval and Aspect Learning

Explainable recommendation is a technique that combines prediction and generation tasks to produce more persuasive results. Among these tasks, textual generation demands large amounts of data to achieve satisfactory accuracy. However, historical user reviews of items are often insufficient, making it challenging to ensure the precision of generated explanation text. To address this issue, we propose a novel model, ERRA (Explainable Recommendation by personalized Review retrieval and Aspect learning). With retrieval enhancement, ERRA can obtain additional information from the training sets. With this additional information, we can generate more accurate and informative explanations. Furthermore, to better capture users' preferences, we incorporate an aspect enhancement component into our model. By selecting the top-n aspects that users are most concerned about for different items, we can model user representation with more relevant details, making the explanation more persuasive. To verify the effectiveness of our model, extensive experiments on three datasets show that our model outperforms state-of-the-art baselines (for example, 3.4% improvement in prediction and 15.8% improvement in explanation for TripAdvisor)

Hepatic E4BP4 induction promotes lipid accumulation by suppressing AMPK signaling in response to chemical or diet- induced ER stress

Prolonged ER stress has been known to be one of the major drivers of impaired lipid homeostasis during the pathogenesis of non- alcoholic liver disease (NAFLD). However, the downstream mediators of ER stress pathway in promoting lipid accumulation remain poorly understood. Here, we present data showing the b- ZIP transcription factor E4BP4 in both the hepatocytes and the mouse liver is potently induced by the chemical ER stress inducer tunicamycin or by high- fat, low- methionine, and choline- deficient (HFLMCD) diet. We showed that such an induction is partially dependent on CHOP, a known mediator of ER stress and requires the E- box element of the E4bp4 promoter. Tunicamycin promotes the lipid droplet formation and alters lipid metabolic gene expression in primary mouse hepatocytes from E4bp4flox/flox but not E4bp4 liver- specific KO (E4bp4- LKO) mice. Compared with E4bp4flox/flox mice, E4bp4- LKO female mice exhibit reduced liver lipid accumulation and partially improved liver function after 10- week HFLMCD diet feeding. Mechanistically, we observed elevated AMPK activity and the AMPKβ1 abundance in the liver of E4bp4- LKO mice. We have evidence supporting that E4BP4 may suppress the AMPK activity via promoting the AMPKβ1 ubiquitination and degradation. Furthermore, acute depletion of the Ampkβ1 subunit restores lipid droplet formation in E4bp4- LKO primary mouse hepatocytes. Our study highlighted hepatic E4BP4 as a key factor linking ER stress and lipid accumulation in the liver. Targeting E4BP4 in the liver may be a novel therapeutic avenue for treating NAFLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162728/3/fsb220918_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162728/2/fsb220918-sup-0001-FigS1-S10.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162728/1/fsb220918.pd