Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation

Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1−/−) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1−/− mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism

Intrahepatic Cholangiocarcinoma Skin Metastasis in a Patient with Hidradenitis Suppurativa: A Rare Entity

We present a challenging diagnosis of disseminated intrahepatic cholangiocarcinoma presenting with perineal cutaneous masses in a young African American male with known hidradenitis suppurativa. The patient was a 39-year-old male who presented to the emergency department with difficulty walking due to severe gluteal swelling and pain. The patient had an 18-month history of biopsy-proven hidradenitis suppurativa. Examination under anesthesia disclosed a 9×6 cm left perianal mass and right 5×3 cm right peri-scrotal mass; both masses were excised and revealed adenocarcinoma with signet ring cell differentiation. The patient was diagnosed with widely metastatic adenocarcinoma of unknown primary. Initiation of palliative capecitabine was planned however the patient decompensated and expired one month from the time of his diagnosis due to septic shock. Autopsy with histologic staining revealed innumerable liver lesions consistent with rare variant Intrahepatic Cholangiocarcinoma (ICC) with signet-ring cell differentiation. Multiple red papules were noted on the aortic valve with histology similarly demonstrating signet-ring cell adenocarcinoma. Cutaneous metastasis of cholangiocarcinoma has been reported but is rare, and to our knowledge this is the first reported case of cholangiocarcinoma cutaneous metastasis in a patient with hidradenitis suppurativa. This case re-emphasizes the protean presentation and aggressive metastatic potential of ICC. It also highlights the importance of maintaining a wide differential for dermatologic lesions in patients with hidradenitis suppurativa and postulates a mechanism for metastatic seeding of areas affected by this disease.</p

Improved ENSO and PDO Prediction Skill Resulting from Finer Parameterization Schemes in a CGCM

Coupled general circulation models (CGCMs), as tools of predicting climate variability, are constantly being improved due to their immense value in a host of theoretical and practical, real-world problems. Consequently, four new parameterization schemes are introduced in the First Institute of Oceanography Earth System Model (FIO-ESM), and a new climate prediction System (CPS) is built up based on modified and original FIO-ESM. Here, turbulence from the sea surface to deep ocean were fully described, and seasonal forecasts of El Ni&ntilde;o-Southern Oscillation (ENSO) and year-to-year prediction of Pacific Decadal Oscillation (PDO) were made with both the modified and original FIO-ESM-CPS. The results illustrate that the anomaly correlation coefficient (ACC) of the Ni&ntilde;o 3.4 index significantly increased, and the root mean square error (RMSE) significantly decreased, respectively, in the modified FIO-ESM-CPS as compared to the original. The RMSE is improved by over 20% at 4- and 5-month lead times. Over longer leads, and in the modified FIO-ESM-CPS, forecast ENSO amplitudes are far closer to observations than the original CGCM, which significantly overestimates amplitudes. PDO prediction skill is also improved in the modified FIO-ESM-CPS with ACC improving by 36% at the 4-year lead time and RMSE decreasing by 21% at the 3-year lead time

A survey of parasitoid species within Eriogyna pyretorum (Lepidoptera: Saturniidae) in Fuzhou Region of China

Eriogyna pyretorum Westwood is a notorious defoliator of Cinnamomum camphora (L.) J. Presl that causes large economic and ecological losses in planted forests. To understand the importance of suppress population of E. pyretorum on natural parasitoids, a two-years investigation was conducted in the field. Four parasitoid species were identified from E. pyretorum: Gregopimpla himalayensis (Cameron, 1899), Theronia depressa (Gupta, 1962), Xanthopimpla konowi (Krieger, 1899) and Kriechbaumerella longiscutellaris Qian et He. G. himalayensis and T. depressa were first reported parasitoid wasps within E. pyretorum. Parasitism rates were 18.76% for K. longiscutellaris, 2.10% for G. himalayensis, 7.55% for T. depressa and 0.83% for X. konowi. Longevity, offspring and sex ratio were compared in four hymenopteran species, and K. longiscutellaris was the abundant parasitoid of E. pyretorum in Fujian province of China

Weight self-perception and weight loss attempts in Chinese cardiovascular patients and non-cardiovascular patients: evidence from a population-based study

Abstract Background Weight loss is a significant improvement for individuals with overweight or obesity, especially for cardiovascular patients. The driving effects of weight self-perception and attempts to lose weight are vital in weight management, yet weight misperception is a direct culprit for the undesirability of weight control and obesity prevention. This study aimed to investigate weight self-perception and misperception and weight loss attempts in Chinese adults, especially among cardiovascular and non-cardiovascular patients. Methods We collected data from China HeartRescue Global Evaluation Baseline Household Survey 2015. Questionnaires were used to assess self-reported weight and cardiovascular patients. We used kappa statistics to check the consistency between weight self-perception and BMI. Logistic regression models were fitted to identify risk factors associated with weight misperception. Results A total of 2690 participants were enrolled in the household survey, while 157 respondents were cardiovascular patients. According to questionnaire results, 43.3% of cardiovascular patients thought they were overweight and obese, while the percentage is 35.3% among non-cardiovascular patients. Kappa statistics indicated higher consistency of self-reported weight and actual weight among cardiovascular patients. Multivariate analysis showed weight misperception was significantly associated with gender, education level, and actual BMI. Lastly, 34.5% of non-cardiovascular patients and 35.0% of cardiovascular patients were trying to lose weight or keep weight. The majority of these people adopted combined strategies of controlling diet and exercise to lose or maintain weight. Conclusions Weight misperception was highly prevalent among cardiovascular or non-cardiovascular patients. Obese respondents, women, and individuals with lower education levels were more vulnerable to make weight misperception. However, no difference in the purpose of weight loss attempts was indicated among cardiovascular and non-cardiovascular patients

Anoikis and SPP1 in idiopathic pulmonary fibrosis: integrating bioinformatics, cell, and animal studies to explore prognostic biomarkers and PI3K/AKT signaling regulation

This study aims to explore the relevance of anoikis in idiopathic pulmonary fibrosis (IPF) and identify associated biomarkers and signaling pathways. Unsupervised consensus cluster analysis was employed to categorize IPF patients into subtypes. We utilized Weighted Gene Co-Expression Network Analysis (WGCNA) and Protein-Protein Interaction network construction to identify anoikis-related modules and key genes. A prognostic signature was developed using Lasso and multivariate Cox regression analysis. Single-cell sequencing assessed hub gene expression in various cell types, and both cell and animal experiments confirmed IPF-related pathways. We identified two distinct anoikis-associated subtypes with differing prognoses. WGCNA revealed essential hub genes, with SPP1 being prominent in the anoikis-related signature. The anoikis-related signature is effective in determining the prognosis of patients with IPF. Single-cell sequencing highlighted significant differences in SPP1 expression, notably elevated in fibroblasts derived from IPF patients. In vivo and in vitro experiments demonstrated that SPP1 enhances fibrosis in mouse lung fibroblasts by regulating p27 through the PI3K/Akt pathway. Our research demonstrates a robust prognostic signature associated with anoikis and highlights SPP1 as a pivotal regulator of the PI3K/AKT signaling pathway in pulmonary fibrosis.</p