Tumour suppressor role of s-phase kinase associated protein 1-cullin-F box-S-phase kinase associated protein 2 (SCFSkp2)

Spontaneous duplications of the genome give rise to polyploid cells and polyploidy can lead to aneuploidy. Aneuploidy is a well-documented phenomenon that could cause cancer. Therefore, a thorough knowledge of how cells maintain diploidy can help us prevent cancer. E3 ubiquitin ligases regulate the cellular levels of a wide variety of oncoproteins. The multi-protein complex, SCF (Skp1-Cullins-F-box) is an E3 ligase that is responsible for ubiquitination-mediated degradation of a large number of proteins involved in cell cycle regulation, transcription and tumor suppression. S‐phase kinaseassociated protein‐2 (Skp2) is the receptor of the SCF complex that promotes the degradation of specific target proteins. The SCFSkp2 targets a wide variety of proteins including tumor suppressor protein p27. Cdc kinase subunit 1 (Cks1) is a small Cyclin – dependent kinase (CDK) interacting protein that is essential for Skp2 mediated degradation of p27. We have generated null alleles of Skp2 and Cks1 (Cks85A) in fruit flies and found that loss of these genes results in polyploidy and abnormal mitosis. These genes are also essential for normal growth of the fruit fly. Skp2 was first identified as a protein that associates with Cyclin A/ Cdk2. We provide the evidence for the first time that Skp2 is required in G2 to protect Cyclin A from premature degradation. Furthermore, our data for the first time suggest a mitotic role of Skp2. We show that Skp2 is required for maintaining the levels of mitotic cyclins and is also required for mitotic entry. Skp2 and Cks85A mutant imaginal discs undergo extensive apoptosis. We provide the first evidence of a stress response pathway that is activated upon the loss of Skp2. Our results suggest that loss of Skp2 results in polyploidy related abnormal mitosis that triggers the spindle assembly checkpoint and the DNA damage response. We also provide evidence of JNK pathway activation and autophagy in the Skp2 null background. Taken together, our finding suggests a novel Skp2 –Cyclin A interaction that plays an important role in maintaining diploidy and thus, genome stability

Withania somnifera ameliorates nandrolone-decanoate-induced brain damage in rats by inhibiting cell death, prodynorphin mRNA expression and acetylcholinesterase activity

685-693The misuse of anabolic-androgenic steroids by athletes and non-athletes causes harmful effects on the central nervous system. In Ayurvedic medicine, Withania somnifera (WS) as an herbal drug has been reported for several functions including adaptogenic, anticonvulsant, cytoprotective and antioxidant. The present study investigated the neuroprotective functions of WS (100, 200 and 400 mg/kg body weight) in nandrolone decanoate (ND)-induced (16 mg/kg body weight) brain injury in male Wistar rats. ND was injected intramuscularly twice weekly for 4 weeks. The water emulsion of WS root powder was administered orally once daily for 30 days to ND-treated rats. At the end of the experiment, anxiety-like behaviour was assessed in rats using the elevated plus maze. Haematoxylin-and-eosin-stained coronal sections of the parietal cortex and hippocampus of ND rats showed severe alterations in brain histology compared with control rats. Acetylcholinesterase (AChE) activity in the striatum and prodynorphin gene expression in the hippocampus was significantly elevated in the ND group compared with the control group. Treating ND induced rats with various doses of WS significantly reversed the brain damage, anxiety behaviour, increased striatal AChE activity and reduced prodynorphin gene expression in the hippocampus. In conclusion, WS extract can be used as a neuroprotective agent to reduce the effects of anabolic steroids

Hybrid nerve sheath tumour, a conglomerate of separate entities

Hybrid nerve sheath tumours (HNSTs) are benign tumours showing combined features of more than one peripheral nerve sheath tumour (PNST) entities. Most literature highlight combination of two entities. Only few reported cases involve all three components of PNST. Herein, we report a case of 33-year-old Malay lady, with left proximal middle finger soft tissue swelling for three months. Microscopically, the tumour is well-circumscribed, containing all three components of PNST, with each displaying its typical morphology and immunohistochemical staining pattern. This case suggests that PNSTs may be more closely related than what was earlier believed. However, whether HNSTs are part of the PNSTs spectrum with tumour syndromes association or a distinct entity is still a continuous debate. We also highlight the possibilities of recurrence and risk of malignant transformation in HNSTs. The exact pathogenesis, potential for recurrence and malignant transformation criteria for HNSTs are still vague due to their extreme rarity

Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations

BackgroundIntrahepatic cholestasis of pregnancy (ICP) is associated with increased stillbirth risk. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in ICP with or without ursodeoxycholic acid (UDCA) treatment.MethodsBile acid profiles and NT-proBNP, a marker of ventricular dysfunction, were assayed in umbilical venous serum from 15 controls and 76 ICP cases (36 untreated, 40 UDCA-treated). Fetal ECG traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability parameters (RMSSD, SDNN) were measured in two behavioural states (quiet and active sleep). Partial correlation coefficients (r) and median [IQR] are reported.ResultsIn untreated ICP, fetal total serum bile acids (TSBA, r=0.49, p=0.019), their hydrophobicity index (r=0.20, p=0.039), glycocholate (r=0.56, p=0.007) and taurocholate (r=0.44, p=0.039) positively correlated with fetal NT-proBNP. Maternal TSBA (r=0.40, p=0.026) and alanine aminotransferase (r=0.40, p=0.046) also positively correlated with fetal NT-proBNP. No significant correlations to NT-proBNP were observed in the UDCA-treated cohort. Fetal PR interval length positively correlated with maternal TSBA in untreated (r=0.46, p=0.027) and UDCA-treated ICP (r=0.54, p=0.026). Fetal RMSSD in active sleep (9.6 [8.8,11.3] vs. 8.7 [7.6,9.6] ms, p=0.028) and SDNN in quiet sleep (11.0 [9.5,14.9] vs. 7.9 [5.1,9.7] ms, p=0.013) and active sleep (25.4 [21.0,32.4] vs. 18.2 [14.7,25.7] ms, p=0.003) were significantly higher in untreated ICP cases than controls. Heart rate variability values in UDCA-treated cases did not differ to controls.ConclusionsElevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterised by increased NT-proBNP concentration, PR interval length and heart rate variability. UDCA treatment partially attenuates this phenotype

Numerical study on the autoignition of biogas in moderate or intense low oxygen dilution nonpremixed combustion systems

The ignition delay of biogas in mixing layers is investigated using a one-dimensional combustion model, with its application in Moderate or Intense Low oxygen Dilution (MILD) combustion being the focus. The current study reveals the key aspects of the ignition of biogas in a nonpremixed, igniting mixing layer with a hot oxidizer of low oxygen content. The observed characteristics are contrasted against the existing studies on ignition in homogeneous mixtures under similar conditions. Biogas is considered here as a mixture of CH4 with variable amounts CO2. The influence of reactive, thermal, and transport properties of CO2 on the ignition is evaluated using artificial species to mimic the respective characteristics of CO2. While the ignition delay in homogeneous mixtures shows a strong dependence on CO2 content in the fuel, the ignition delay predictions from one-dimensional mixing layers show no significant influence of CO2 levels in biogas. In addition, the influence of oxidizer composition and temperature on ignition delay is determined for CO2 levels ranging from 0% to 90%. A sensitivity analysis of chemical reactions on the ignition delay shows a negligible effect of CO2 concentration in biogas. The current study emphasizes the role of oxidizer composition and temperature on the ignition characteristics of a MILD biogas flame