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The Cut homeobox 1 (CUX1) gene is a target of loss-of-heterozygosity in many cancers, yet elevated CUX1 expression is frequently observed and is associated with shorter disease-free survival. The dual role of CUX1 in cancer is illustrated by the fact that most cell lines with CUX1 LOH display amplification of the remaining allele, suggesting that decreased CUX1 expression facilitates tumor development while increased CUX1 expression is needed in tumorigenic cells. Indeed, CUX1 was found in a genome-wide RNAi screen to identify synthetic lethal interactions with oncogenic RAS. Here we show that CUX1 functions in base excision repair as an ancillary factor for the 8-oxoG-DNA glycosylase, OGG1. Single cell gel electrophoresis (comet assay) reveals that Cux1⁺/⁻ MEFs are haploinsufficient for the repair of oxidative DNA damage, whereas elevated CUX1 levels accelerate DNA repair. In vitro base excision repair assays with purified components demonstrate that CUX1 directly stimulates OGG1's enzymatic activity. Elevated reactive oxygen species (ROS) levels in cells with sustained RAS pathway activation can cause cellular senescence. We show that elevated expression of either CUX1 or OGG1 prevents RAS-induced senescence in primary cells, and that CUX1 knockdown is synthetic lethal with oncogenic RAS in human cancer cells. Elevated CUX1 expression in a transgenic mouse model enables the emergence of mammary tumors with spontaneous activating Kras mutations. We confirmed cooperation between Kras(G12V) and CUX1 in a lung tumor model. Cancer cells can overcome the antiproliferative effects of excessive DNA damage by inactivating a DNA damage response pathway such as ATM or p53 signaling. Our findings reveal an alternate mechanism to allow sustained proliferation in RAS-transformed cells through increased DNA base excision repair capability. The heightened dependency of RAS-transformed cells on base excision repair may provide a therapeutic window that could be exploited with drugs that specifically target this pathway.

Ascorbic acid is a redox regulator in many physiological processes. Besides its antioxidant activity, many intriguing functions of ascorbic acid in the expression of immunoregulatory genes have been suggested. Ascorbic acid acts as a co‐factor for the Fe+2‐containing α‐ketoglutarate‐dependent Jumonji‐C domain‐containing histone demethylases (JHDM) and Ten eleven translocation (TET) methylcytosine dioxygenasemediated epigenetic modulation. By influencing JHDM and TET, ascorbic acid facilitates the differentiation of double negative (CD4−CD8−) T cells to double positive (CD4+CD8+) T cells and of T‐helper cells to different effector subsets. Ascorbic acid modulates plasma cell differentiation and promotes early differentiation of hematopoietic stem cells (HSCs) to NK cells. These findings indicate that ascorbic acid plays a significant role in regulating both innate and adaptive immune cells, opening up new research areas in Immunonutrition. Being a water‐soluble vitamin and a safe micro‐nutrient, ascorbic acid can be used as an adjunct therapy for many disorders of the immune system. [ABSTRACT FROM AUTHOR]

Herein, two novel mononuclear transition metal Zn2+ complexes i.e. [Zn(HL)(N3)(OAc)] (NS-1) & [Zn(HL)2(ClO4)2] (NS-2) have been synthesised using a tridentate clickable Schiff base ligand, HL (2-methyl-2-((pyridin-2-ylmethyl)amino)propan-1-ol), and the polyatomic monoanions N3− and ClO4− for NS-1 and NS-2 respectively. Interestingly, NS-1 and NS-2 have been explored for the detection of Cu2+ with an LOD of 48.6 fM (response time ∼6 s) and 2.4 μM respectively through two mutually independent pathways that were studied using sophisticated methods like UV-Vis, cyclic voltammetry, ESI-MS etc. with theoretical DFT support. Herein, both chemosensors are equally responsive towards the detection of Cu2+ in aqueous as well as other targeted real field samples with appreciable recovery percentage (74.8–102%), demonstrating their practical applicability. Moreover, the detection of unbound Cu2+ in a human urine specimen was also analysed which may be helpful for the diagnosis of Cu2+-related disorders like Wilson's disease. Taking one step ahead, TLC strips have been employed for on-field detection of the targeted analytes by contact mode analysis. Additionally, the anti-cancer activity of these complexes has also been studied on breast cancer cells with the help of the MTT assay. It has been found that at a 0.5 mM dose, both NS-1 and NS-2 could kill 81.4% and 73.2% of cancer cells respectively. However, it has been found that NS-1 destroys normal cells together with cancer cells. Hence, NS-2 could be administered as a better anticancer drug for MDA-MB-231 cancer cells in comparison with NS-1. In a nutshell, the present work describes how anion-directed synthesis of two architecturally different metal complexes leads toward the detection of the same analyte via an independent chemodosimetric pathway along with their anti-cancer activities on breast cancer cells. [ABSTRACT FROM AUTHOR]

Understanding the distribution of wildlife species and their response to diverse anthropogenic pressures is important for conservation planning and management of wildlife space in human-dominated landscapes. Assessments of anthropogenic impacts on mammals of the Indian Himalayan Region have mostly been limited to locations inside protected areas. We studied the occurrence of mammals in an unexplored landscape, the 7,586 km2 Bhagirathi basin, at an altitude of 500–5,200 m. The basin encompasses wilderness areas of various habitat types and protection status that are exposed to a range of anthropogenic pressures. Camera trapping at 209 locations during October 2015–September 2017 confirmed the occurrence of 39 species of mammals, nine of which are categorized as threatened (four Vulnerable, five Endangered) and four as Near Threatened on the IUCN Red List. We recorded five mammal species that were hitherto undocumented in Uttarakhand State: the argali Ovis ammon, Tibetan sand fox Vulpes ferrilata, woolly hare Lepus oiostolus, Eurasian lynx Lynx lynx and woolly flying squirrel Eupetaurus cinereus. In addition, we recorded two Endangered species, the dhole Cuon alpinus and tiger Panthera tigris. Threatened species such as the sambar Rusa unicolor, common leopard Panthera pardus and Asiatic black bear Ursus thibetanus occur in a wide variety of habitats despite anthropogenic disturbance. We recorded the snow leopard Panthera uncia in areas with high livestock density but temporally segregated from human activities. The musk deer Moschus spp. and Himalayan brown bear Ursus arctos isabellinus were recorded in subalpine habitats and appeared to be less affected by human and livestock presence. Our findings highlight the potential of the Bhagirathi basin as a stronghold for conservation of several threatened and rare mammal species. [ABSTRACT FROM AUTHOR]

Abstract Background- Sporadic breast cancer like many other cancers is proposed to be a manifestation of abnormal genetic and epigenetic changes. For the past decade our laboratory has identified genes involved in DNA damage response (DDR), apoptosis and immunesurvelliance pathways to influence sporadic breast cancer risk in north Indian population. Further to enhance our knowledge at the epigenetic level, we performed DNA methylation study involving 17 gene promoter regions belonging to DNA damage response (DDR) and death receptor apoptotic pathway in 162 paired normal and cancerous breast tissues from 81 sporadic breast cancer patients, using a high throughput quantitative DNA methylation analysis technology. Results- The study identified five genes with statistically significant difference between normal and tumor tissues. Hypermethylation of DR5 (P = 0.001), DCR1 (P = 0.00001), DCR2 (P = 0.0000000005) and BRCA2 (P = 0.007) and hypomethylation of DR4 (P = 0.011) in sporadic breast tumor tissues suggested a weak/aberrant activation of the DDR/apoptotic pathway in breast tumorigenesis. Negative correlation was observed between methylation status and transcript expression levels for TRAIL, DR4, CASP8, ATM, CHEK2, BRCA1 and BRCA2 CpG sites. Categorization of the gene methylation with respect to the clinicopathological parameters showed an increase in aberrant methylation pattern in advanced tumors. These uncharacteristic methylation patterns corresponded with decreased death receptor apoptosis (P = 0.047) and DNA damage repair potential (P = 0.004) in advanced tumors. The observation of BRCA2 -26 G/A 5'UTR polymorphism concomitant with the presence of methylation in the promoter region was novel and emerged as a strong candidate for susceptibility to sporadic breast tumors. Conclusion- Our study indicates that methylation of DDR-apoptotic gene promoters in sporadic breast cancer is not a random phenomenon. Progressive epigenetic alterations in advancing tumors result in aberrant DDR-apoptotic pathway thereby promoting tumor development. We propose, since pathological epigenetic changes of the DDR-apoptotic genes are reversible modifications, these could further be targeted for therapeutic interventions.

The woolly flying squirrel (Eupetaurus cinereus Thomas, 1888) is one of the least-known endangered mammals of the Himalayas and recorded only from few localities at 2400–3600 m in Hindu Kush and North-Western Himalayas. We report first confirmed record of this species from Upper Bhagirathi Basin, Uttarakhand, Western Himalaya. The squirrel was photo-captured twice in camera traps placed in temperate and alpine habitats. The photo-capture at 4800 m is higher than the described upper elevation range limit of any other flying squirrels. Continuous monitoring would reveal the extent of threats to this rare species in its newly described range. [ABSTRACT FROM AUTHOR]

Background-: Sporadic breast cancer like many other cancers is proposed to be a manifestation of abnormal genetic and epigenetic changes. For the past decade our laboratory has identified genes involved in DNA damage response (DDR), apoptosis and immunesurvelliance pathways to influence sporadic breast cancer risk in north Indian population. Further to enhance our knowledge at the epigenetic level, we performed DNA methylation study involving 17 gene promoter regions belonging to DNA damage response (DDR) and death receptor apoptotic pathway in 162 paired normal and cancerous breast tissues from 81 sporadic breast cancer patients, using a high throughput quantitative DNA methylation analysis technology. Results-: The study identified five genes with statistically significant difference between normal and tumor tissues. Hypermethylation of DR5 (P = 0.001), DCR1 (P = 0.00001), DCR2 (P = 0.0000000005) and BRCA2 (P = 0.007) and hypomethylation of DR4 (P = 0.011) in sporadic breast tumor tissues suggested a weak/aberrant activation of the DDR/apoptotic pathway in breast tumorigenesis. Negative correlation was observed between methylation status and transcript expression levels for TRAIL, DR4, CASP8, ATM, CHEK2, BRCA1 and BRCA2 CpG sites. Categorization of the gene methylation with respect to the clinicopathological parameters showed an increase in aberrant methylation pattern in advanced tumors. These uncharacteristic methylation patterns corresponded with decreased death receptor apoptosis (P = 0.047) and DNA damage repair potential (P = 0.004) in advanced tumors. The observation of BRCA2 -26 G/A 5'UTR polymorphism concomitant with the presence of methylation in the promoter region was novel and emerged as a strong candidate for susceptibility to sporadic breast tumors. Conclusion-: Our study indicates that methylation of DDR-apoptotic gene promoters in sporadic breast cancer is not a random phenomenon. Progressive epigenetic alterations in advancing tumors result in aberrant DDRapoptotic pathway thereby promoting tumor development. We propose, since pathological epigenetic changes of the DDR-apoptotic genes are reversible modifications, these could further be targeted for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Herein, two novel mononuclear transition metal Zn 2+ complexes i.e. [Zn(HL)(N 3 )(OAc)] (NS-1) & [Zn(HL) 2 (ClO 4 ) 2 ] (NS-2) have been synthesised using a tridentate clickable Schiff base ligand, HL (2-methyl-2-((pyridin-2-ylmethyl)amino)propan-1-ol), and the polyatomic monoanions N 3 - and ClO 4 - for NS-1 and NS-2 respectively. Interestingly, NS-1 and NS-2 have been explored for the detection of Cu 2+ with an LOD of 48.6 fM (response time ∼6 s) and 2.4 μM respectively through two mutually independent pathways that were studied using sophisticated methods like UV-Vis, cyclic voltammetry, ESI-MS etc. with theoretical DFT support. Herein, both chemosensors are equally responsive towards the detection of Cu 2+ in aqueous as well as other targeted real field samples with appreciable recovery percentage (74.8-102%), demonstrating their practical applicability. Moreover, the detection of unbound Cu 2+ in a human urine specimen was also analysed which may be helpful for the diagnosis of Cu 2+ -related disorders like Wilson's disease. Taking one step ahead, TLC strips have been employed for on-field detection of the targeted analytes by contact mode analysis. Additionally, the anti-cancer activity of these complexes has also been studied on breast cancer cells with the help of the MTT assay. It has been found that at a 0.5 mM dose, both NS-1 and NS-2 could kill 81.4% and 73.2% of cancer cells respectively. However, it has been found that NS-1 destroys normal cells together with cancer cells. Hence, NS-2 could be administered as a better anticancer drug for MDA-MB-231 cancer cells in comparison with NS-1. In a nutshell, the present work describes how anion-directed synthesis of two architecturally different metal complexes leads toward the detection of the same analyte via an independent chemodosimetric pathway along with their anti-cancer activities on breast cancer cells.