Cdyl2-60aa encoded by CircCDYL2 accelerates cardiomyocyte death by blocking APAF1 ubiquitination in rats.

The loss of cardiomyocytes (CMs) after myocardial infarction (MI) is widely acknowledged to initiate the development of heart failure (HF). Herein, we found that circCDYL2 (583 nt) derived from chromodomain Y-like 2 (Cdyl2) is significantly upregulated in vitro (oxygen-glucose deprivation (OGD)-treated CMs) and in vivo (failing heart post-MI) and can be translated into a polypeptide termed Cdyl2-60aa (~7 kDa) in the presence of internal ribosomal entry sites (IRES). Downregulation of circCDYL2 significantly decreased the loss of OGD-treated CMs or the infarcted area of the heart post-MI. Additionally, elevated circCDYL2 significantly accelerated CM apoptosis via Cdyl2-60aa. We then discovered that Cdyl2-60aa could stabilize protein apoptotic protease activating factor-1 (APAF1) and promote CM apoptosis; heat shock protein 70 (HSP70) mediated APAF1 degradation in CMs by ubiquitinating APAF1, which Cdyl2-60aa could competitively block. In conclusion, our work substantiated the claim that circCDYL2 could promote CM apoptosis via Cdyl2-60aa, which enhanced APAF1 stability by blocking its ubiquitination by HSP70, suggesting that it is a therapeutic target for HF post-MI in rats.

Investigation of Parasitic Infection in Crocodile Lizards (Shinisaurus crocodilurus) Using High-Throughput Sequencing.

The highly endangered crocodile lizard (Shinisaurus crocodilurus) continues to be impacted by disease, especially in captive breeding populations. In this paper, based on high-throughput sequencing, we investigated parasitic infections in captive and wild crocodile lizard populations in the Daguishan National Nature Reserve and Guangdong Luokeng Shinisaurus crocodilurus National Nature Reserve. The results show that the overall parasitic infection rate in crocodile lizards was 33.33% (23/69). Four parasite genera were detected, including Eimeria, Cryptosporidium, Nematopsis, and Acanthamoeba, with infection rates of 15.94% (11/69), 17.39% (12/69), 7.25% (5/69), and 4.35% (3/69), respectively. Significant differences in the infection rate were found between the different parasite species (χ2 = 8.54, p < 0.05, chi-squared test). The parasitic infection rates in the captive and wild populations were 39.29% (22/56) and 7.69% (1/13), respectively, which were significantly different (p < 0.05, Fisher's exact test). However, no significant differences in the infection rates of the four parasite genera were found between the captive and wild populations (p > 0.05, Fisher's exact test). The parasitic infection rates in Daguishan and Luokeng were 34.09% (15/44) and 32.00% (8/25), respectively, which were not significantly different (p > 0.05, Fisher's exact test). However, significant differences in terms of species were found in the two reserves (p < 0.01, Fisher's exact test). Only Cryptosporidium infection showed a significant difference between the two regions (p < 0.01, Fisher's exact test). Our results suggest that captive crocodile lizards are more susceptible to parasitic diseases than wild crocodile lizards and that Cryptosporidium infection varies by geographical region. This study provides basic information about the parasites of endangered crocodile lizards, as well as a reference for disease control and conservation.

Screening and discrimination of optimal prognostic genes for pancreatic cancer based on a prognostic prediction model.

The prognosis of pancreatic cancer is poor because patients are usually asymptomatic in the early stage and the early diagnostic rate is low. Therefore, in this study, we aimed to identify potential prognosis-related genes in pancreatic cancer to improve diagnosis and the outcome of patients. The mRNA expression profile data from The Cancer Genome Atlas database and GSE79668, GSE62452, and GSE28735 datasets from Gene Expression Omnibus were downloaded. The prognosis-relevant genes and clinical factors were analyzed using Cox regression analysis and the optimal gene sets were screened using the Cox proportional model. Next, the Kaplan-Meier survival analysis was used to evaluate the relationship between risk grouping and patient prognosis. Finally, an optimal gene-based prognosis prediction model was constructed and validated using a test dataset to discriminate the model accuracy and reliability. The results showed that 325 expression variable genes were identified, and 48 prognosis-relevant genes and three clinical factors, including lymph node stage (pathologic N), new tumor, and targeted molecular therapy were preliminarily obtained. In addition, a gene set containing 16 optimal genes was identified and included FABP6, MAL, KIF19, and REG4, which were significantly associated with the prognosis of pancreatic cancer. Moreover, a prognosis prediction model was constructed and validated to be relatively accurate and reliable. In conclusion, a gene set consisting of 16 prognosis-related genes was identified and a prognosis prediction model was constructed, which is expected to be applicable in the clinical diagnosis and treatment guidance of pancreatic cancer in the future.

Circ-HIPK3 Strengthens the Effects of Adrenaline in Heart Failure by MiR-17-3p - ADCY6 Axis.

Overactivation of ß-adrenergic receptor (ß-AR) can improve cardiac function temporarily but promotes the development and mortality of heart failure (HF) in the long run. CircRNA, a member of noncoding RNAs, can tolerate digestion of exonuclease and be a chronic stimulator to cell. But the relationship of circRNA with HF remains a puzzle and needs to be explored. Here, we found that circ-HIPK3 affected the concentration of Ca2+ in cytoplasm by miR-17-3p through ADCY6 (Adenylate cyclase type 6). The increase of ADCY6 caused by circ-HIPK3 was ameliorated by miR-17-3p overexpression and vice versa, implicating the existence of circ-HIPK3 - miR-17-3p - ADCY6 axis. And further assays showed that the level of circ-HIPK3 in heart was upregulated by adrenaline via transcription factor CREB1 (cAMP responsive element-binding protein 1). Experiments in vivo showed downregulation of circ-HIPK3 can alleviate fibrosis and maintain cardiac function post MI in mice. In conclusion, the increased circ-HIPK3 can be a helper for adrenaline but was harmful for heart in the long run and might be an ideal therapeutic target of HF.

Histone deacetylase SIRT6 regulates chemosensitivity in liver cancer cells via modulation of FOXO3 activity.

Liver cancer is the leading cause of cancer­related mortality worldwide and its incidence is increasing. Considerable effort has been made in recent decades to improve the diagnosis and treatment of liver cancer. Advanced liver cancer often exhibits a poor response to chemotherapy and poor prognosis due to acquired chemoresistance and tumor recurrence. Understanding the precise molecular mechanisms that are responsible for chemotherapeutic drug­induced cell death could potentially identify novel therapeutic targets and improve liver cancer treatment. In the present study, it was demonstrated that in response to doxorubicin, the most frequently used chemical compound for liver cancer treatment, histone deacetylase sirtuin 6 (SIRT6) is specifically downregulated. This enables forkhead box O3 (FOXO3) upregulation, translocation into the nucleus and increased expression of its target genes p27 and Bim, which further induce apoptosis. Overexpression of SIRT6, but not enzyme­inactivated mutants, prevents FOXO3 translocation into the nucleus and doxorubicin­induced cell death. SIRT6 interacts with FOXO3 and this interaction increases FOXO3 ubiquitination and decreases its stability. Finally, it was identified that the effect of SIRT6 in preventing doxorubicin­induced cell death requires FOXO3. Overexpression of SIRT6 could not prevent doxorubicin­induced cell death in FOXO3­knockdown cells. Therefore, it was concluded that SIRT6 plays a central role in determining doxorubicin­induced cell death via modulation of FOXO3 activity. Therapeutic targeting of SIRT6 and/or FOXO3 may offer novel strategies for treatment of liver cancer.

Wavelet optimal estimations for a two-dimensional continuous-discrete density function over L p risk.

The mixed continuous-discrete density model plays an important role in reliability, finance, biostatistics, and economics. Using wavelets methods, Chesneau, Dewan, and Doosti provide upper bounds of wavelet estimations on L 2 risk for a two-dimensional continuous-discrete density function over Besov spaces B r , q s . This paper deals with L p ( 1 ≤ p < ∞ ) risk estimations over Besov space, which generalizes Chesneau-Dewan-Doosti's theorems. In addition, we firstly provide a lower bound of L p risk. It turns out that the linear wavelet estimator attains the optimal convergence rate for r ≥ p , and the nonlinear one offers optimal estimation up to a logarithmic factor.