GSK3ß phosphorylates Six1 transcription factor and regulates its APC/CCdh1 mediated proteosomal degradation.

Sine oculis homeobox homolog 1 (Six1) is a developmentally important transcription factor that regulates cellular proliferation, apoptosis, and dissemination during embryogenesis. Six1 overexpression as reported in multiple cancers modulates expression of a repertoire of its target genes causing an increase in proliferation, metastasis and survival of cancer cells. Six1 exists as a cell cycle regulated nuclear phosphoprotein and its cellular turnover is regulated by APC/C (Anaphase promoting complex / Cyclosome) complex mediated proteolysis. However, the kinases that regulate Six1 proteolysis have not been identified and the mechanistic details that cause its overproduction in various cancers are lacking. Here, we report that Six1 is a physiological GSK3ß substrate. GSK3ß interacts with Six1 and phosphorylates it at Ser221 within the conserved consensus sequence in its carboxy terminus. Using pharmacological inhibition, siRNA mediated knockdown and protein overexpression of GSK3ß; we show that GSK3ß regulates Six1 protein stability. Pulse chase analysis of Six1 revealed that GSK3ß regulates its ubiquitin proteolysis such that Six1 phosphomimicking mutant (Six1S221E) for Ser221 site had dramatically increased half-life than its phosphodeficient (Six1S221A) and wild type variants. Furthermore, we demonstrate that GSK3ß rescues Six1 from APC dependent proteolysis by regulating its binding with APC/C co-activator protein Cdh1. Importantly, strong positive correlation exists between GSK3ß and Six1 protein levels throughout the cell cycle and in multiple cancers indicating that GSK3ß activation may in part contribute to Six1 overproduction in a subset of human cancers.

Risk analysis of fast spreading species in a Kashmir Himalayan National Park (Dachigam) for better monitoring and management.

Huge economic costs and ecological impacts of invasive alien species (IAS) in the protected areas (PAs) worldwide make their timely prediction and potential risk assessment of central importance for effective management. While the preborder weed risk assessment framework has been extensively evaluated and implemented, the postborder species risk assessment framework has not been subjected to the same degree of scrutiny. Here we used a rather more realistic modified version of the Australian Weed Risk framework (AWRM) for Dachigam National Park (DNP) in Kashmir Himalaya against 84 plant species, including 55 alien species and 29 fast spreading native species, for risk analysis. We found two very high-risk species, three high-risk species, 10 medium-risk species, 29 low-risk species, and 40 negligible-risk species in the DNP. The containment scores accordingly ranged from 14.4 to 293.5 comprising of 27 species that can be contained with very high feasibility, 23 species with high feasibility, 14 species with medium feasibility, and 12 species which cannot be contained easily thereby having low feasibility of containment (FOC) score. However, eight species which have a negligible FOC score are difficult to contain within their infestation sites. Our results demonstrate the merit of the AWRM with a caution that the necessary region-specific modifications may help in its better implementation. Overall, these results provide quite a promising tool in the hands of protected area managers to timely and effectively deal with the problem of plant invasions.

Risk assessment and management framework for rapidly spreading species in a Kashmir Himalayan Ramsar site.

In view of huge ecological impacts and exorbitantly high economic costs of biological invasions, the risk assessment for timely prediction of potential invaders and their effective management assumes central importance, yet having been little addressed. Hence, we did the risk analysis of 39 plant species, including both alien and fast-spreading native species, in Hokera wetland, an important Ramsar site in Kashmir Himalaya, using the post-border Australian Weed Risk Management (AWRM) framework. Based on the AWRM scores, we listed these species into different categories, such as alert, destroy infestation, contain spread, manage weed, manage sites and monitor, with management implications. Out of the eight decisions created for Hokera wetland, alien Alternanthera philoxeroides was identified as 'alert species', while Typha angustifolia, Typha latifolia, Phragmites australis, Sparganium ramosum and Myriophyllum aquaticum were placed under the 'manage weed' category of the management priorities. To check the predictability and reliability of the AWRM scheme, we developed the receiver operating characteristic (ROC) curve that yielded a positive diagonal value of above 0.5, with 88.6% and 83.1% area under the curve for comparative weed risk (CWR) score and the feasibility of coordinated control (FOC) score, respectively. The outcomes of the ROC analysis were compared with the results of the WRM evaluation of other regions across the globe. Our results indicate that the risk assessment using the AWRM model is quite efficient at discriminating and flagging the most troublesome plant species and offsetting their impacts on native biodiversity and ecosystem functioning in wetland ecosystems. Given the growing threat of biological invasions in the protected areas, we recommend an integrated and strategic approach, well informed by the data on the species biology and ecology, in the form of the AWRM management system to effectively deal with the alarmingly spreading species.

SIX1 transcription factor: A review of cellular functions and regulatory dynamics.

Sine Oculis Homeobox 1 (SIX1) is a member of homeobox transcription factor family having pivotal roles in organismal development and differentiation. This protein functionally acts to regulate the expression of different proteins that are involved in organ development during embryogenesis and in disorders like cancer. Aberrant expression of this homeoprotein has therefore been reported in multiple pathological complexities like hearing impairment and renal anomalies during development and tumorigenesis in adult life. Most of the cellular effects mediated by it are mostly due to its role as a transcription factor. This review presents a concise narrative of its structure, interaction partners and cellular functions vis a vis its role in cancer. We thoroughly discuss the reported molecular mechanisms that govern its function in cellular milieu. Its post-translational regulation by phosphorylation and ubiquitination are also discussed with an emphasis on yet to be explored mechanistic insights regulating its molecular dynamics to fully comprehend its role in development and disease.

Prevalence of type 2 diabetes mellitus and association of HbA1c with severity of coronary artery disease in patients presenting as non-diabetic acute coronary syndrome.

BACKGROUND: Acute coronary syndrome (ACS) indicates the serious clinical manifestation of coronary artery disease (CAD) and is closely associated with cardiovascular prognosis in patients with ACS. This study was aimed to study the prevalence of type 2 diabetes mellitus (T2DM) and the relation of HbA1c with the severity of CAD in patients presenting as non-diabetic ACS. Diabetic status of the patients was assessed with fasting blood sugar (FBS) and HbA1c levels, and coronary artery disease burden was assessed by coronary angiography. RESULTS: Out of 208 patients, 85.1% were males, and 14.9% were females; 73.56% cases were hypertensive. 80.77% of cases had STEMI, 17.79% had NSTEMI, and 1.44% had unstable angina. Out of 168 STEMI patients, 64.3% were thrombolysed, 21.42% presented late, 2.38% had contraindications to thrombolysis, and 11.9% underwent primary PCI. FBS in diabetic range was found in 44.23% of cases, impaired FBS in 36.54%, and 19.23% of patients had FBS in non-diabetic range. According to HbA1c, 41.8% were diabetic, 39.4% were pre-diabetic, and 18.8% were non-diabetic. A significant positive correlation was found between HbA1c and Gensini score and between HbA1c and the number of vessels involved. CONCLUSION: This study emphasises the importance of evaluating the presence of diabetes in patients presenting as non-diabetic acute coronary syndrome in developing countries. Acute coronary syndrome may be considered as one of the presentations of diabetes mellitus.

Helicobacter pylori Subdues Cytokine Signaling to Alter Mucosal Inflammation via Hypermethylation of Suppressor of Cytokine Signaling 1 Gene During Gastric Carcinogenesis.

Helicobacter pylori infection has been associated with the onset of gastric mucosal inflammation and is known to perturb the balance between T-regulatory (Treg) and T-helper 17 (Th17) cells which causes a spurt of interleukin 17 (IL17) and transforming growth factor-ß (TGF-ß) from Th17 and Treg cells within the gastric milieu. IL17 instigates a surge of interleukin 6 (IL6) from T-helper 1 (Th1) and T-helper 2 (Th2) cells. Further, H. pylori infection is known to stimulate the atypical DNA methylation in gastric mucosa. However, the precise role of cytokine signaling in induction of epigenetic modifications during gastric carcinogenesis is vaguely understood. In this study, patient samples from were examined using real-time polymerase chain reaction (qPCR), PCR, methylation-specific (MS)-PCR, and enzyme-linked immunosorbent assays. We found that H. pylori infection augments the production of interleukin 10 (IL10), IL6, and TGF-ß in the gastric milieu and systemic circulation. Together with the IL6/IL10 mediated hyperactivation of the JAK/STAT pathway, H. pylori infection causes the inactivation of suppressor of cytokine signaling 1 (SOCS1) gene through the hypermethylation of the promoter region. This study signifies that H. pylori-mediated epigenetic silencing of SOCS1 in concert with inflammatory cytokines miffs hyperactivation of the JAK/STAT cascade during gastric carcinogenesis.