COMPARATIVE PHYSICOCHEMICAL, PHYTOCHEMICAL AND HIGH PERFORMANCE THIN LAYER CHROMATOGRAPHY EVALUATION OF HEART WOOD AND SMALL BRANCHES OF AQUILARIA AGALLOCHA ROXB.

Aquilaria agallocha Roxb. commonly called as Agaru is a medicinal plant. Heartwood of this tree is widely used in Ayurveda for various diseases. Removal of heart wood from trunk of this tree may make this plant weak and susceptible to damage due to which availability of this plant may be difficult in near future. Present study outlines the concept of plant part substitution. Heart wood and small branches of A. agallocha are compared on the basis of physicochemical analysis, phytochemical analysis, total phenolic contents, total flavonoid contents and high performance thin layer chromatography (HPTLC) to evaluate the possibilities of using small branches instead of heart wood. Physicochemical parameters of heartwood and small branches and phytochemical analysis of n-hexane, ethyl acetate and ethanol extract of both heart wood and small branches were carried out using standard methods. Total phenolics and total flavonoids were estimated spectrophotometrically using Folin-ciocalteu assayand aluminum chloride assaymethods, respectively. CAMAG HPTLC system equipped with semi-automatic applicator was used for HPTLC of n-hexane, ethyl acetate and ethanol extracts of stem bark and small braches using suitable mobile phases. Results of phytochemical analysis and HPTLC of n-hexane, ethyl acetate and ethanol extracts showed many similarities whichsuggest that small branches may have nearly similar active potency like heart wood and may be used as a substitute of heart wood after comparison and confirmation of same for pharmacological activities

SUBSTITUTION OF ROOTS WITH SMALL BRANCHES OF RAUWOLFIA SERPENTINA FOR THERAPEUTIC USES - A PHYTOCHEMICAL APPROACH

Rauwolfia serpentina commonly called Sarpagandha is a medicinal plant widely used in Ayurveda. As per the Ayurvedic literature, roots of this plant are used in cardiac disorder, cancer, mental illness and psychiatric disorder. To collect roots for medicinal purpose whole plant is uprooted on a mass scale from their natural habitat which is leading to depletion of resources, due to which plant may be difficult in near future for use in traditional systems of medicine. Present study was carried out to assess possibilities of using small branches of R. serpentina in place of its roots which will help in conservation of this plant and availability of raw material for therapeutic purposes. Roots and small branches of R. serpentina are compared on the basis of physicochemical analysis, phytochemical analysis, total phenolic contents, total flavonoid contents and high performance thin layer chromatography (HPTLC) to evaluate the possibilities of using small branches in place of its roots. Results of phytochemical analysis and HPTLC of n-hexane, ethyl acetate and ethanol extracts showed many similarities whichsuggest that small branches may have nearly similar active constituents like roots and may be used as a substitute of roots after comparison and confirmation of same for pharmacological activities

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors

Radiation Effects in Ultraviolet Sensitive Pd/4H-SiC Schottky Detectors

9-154H-SiC, by virtue of its intrinsic properties, is a very promising semiconductor material for fabricating rad-hard UV detectors suitable for harsh radiation environments. This paper aims to investigate the radiation tolerance of indigenously developed Pd/4H-SiC Schottky detectors, in order to determine their feasibility for space applications. 4H-SiC detectors of active area 1 × 1 mm2 were irradiated with electrons of energy 10 MeV at fluence of 2×1013 e-/cm2 and gamma rays from a Co-60 source with a total dose of 1 Mrad. The impact of these irradiations on electro-optical characteristics of the devices was studied by analyzing the changes in electrical parameters like reverse saturation current (Is), ideality factor (n), barrier height (ɸB), effective doping concentration (Neff) derived from I-V and C-V characteristics as well as in the UV spectral responsivity (i.e., from 248 to 365 nm) of the irradiated detectors. The electron irradiated device showed negligible change in I-V and C-V characteristics whereas its UV spectral responsivity at the peak wavelength of 290 nm reduced by 48.7 %. Gamma irradiated device displayed a noticeable variation in its electrical characteristics and 15.8 % reduction in the spectral responsivity (optical characteristics) at the peak wavelength. The results show that the radiation hardness of 4H-SiC detectors is better than that of conventional semiconductor ones, making it a more appealing choice as radiation detectors in space systems

GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment

The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting

On-Orbit Performance of Pd/4H-SiC Schottky UV Detectors in a Low-Earth Orbit

The monitoring of solar ultraviolet radiation from a space platform is now considered essential for a wide range of fieldsincluding solar physics, atmospheric science and astrobiology. 4H-Silicon Carbide (4H-SiC) is a superior alternative toconventional materials like silicon for the fabrication of UV detectors for adverse space conditions due to its inherentradiation hardness and visible-blind nature. This paper describes the space qualification and deployment of indigenouslydeveloped Pd/4H-SiC Schottky UV detectors in a low-earth orbit (LEO) and their on-board performance. Two SiC UVdetectors were flown as a rad-hard sun detection sensor in the nanosatellite INS-2TD. The sensor has carried out solar UVflux observations continuously since its launch in February 2022 and the data gathered during the first seven months offlight is discussed in this paper

A Risk Score for Predicting Multiple Sclerosis

Multiple sclerosis (MS) develops as a result of environmental influences on the genetically susceptible. Siblings of people with MS have an increased risk of both MS and demonstrating asymptomatic changes in keeping with MS. We set out to develop an MS risk score integrating both genetic and environmental risk factors. We used this score to identify siblings at extremes of MS risk and attempted to validate the score using brain MRI.78 probands with MS, 121 of their unaffected siblings and 103 healthy controls were studied. Personal history was taken, and serological and genetic analysis using the illumina immunochip was performed. Odds ratios for MS associated with each risk factor were derived from existing literature, and the log values of the odds ratios from each of the risk factors were combined in an additive model to provide an overall score. Scores were initially calculated using log odds ratio from the HLA-DRB1*1501 allele only, secondly using data from all MS-associated SNPs identified in the 2011 GWAS. Subjects with extreme risk scores underwent validation studies. MRI was performed on selected individuals.There was a significant difference in the both risk scores between people with MS, their unaffected siblings and healthy controls (p<0.0005). Unaffected siblings had a risk score intermediate to people with MS and controls (p<0.0005). The best performing risk score generated an AUC of 0.82 (95%CI 0.75–0.88).The risk score demonstrates an AUC on the threshold for clinical utility. Our score enables the identification of a high-risk sibling group to inform pre-symptomatic longitudinal studies

Maturation-Dependent Licensing of Naive T Cells for Rapid TNF Production

The peripheral naïve T cell pool is comprised of a heterogeneous population of cells at various stages of development, which is a process that begins in the thymus and is completed after a post-thymic maturation phase in the periphery. One hallmark of naïve T cells in secondary lymphoid organs is their unique ability to produce TNF rapidly after activation and prior to acquiring other effector functions. To determine how maturation influences the licensing of naïve T cells to produce TNF, we compared cytokine profiles of CD4+ and CD8+ single positive (SP) thymocytes, recent thymic emigrants (RTEs) and mature-naïve (MN) T cells during TCR activation. SP thymocytes exhibited a poor ability to produce TNF when compared to splenic T cells despite expressing similar TCR levels and possessing comparable activation kinetics (upregulation of CD25 and CD69). Provision of optimal antigen presenting cells from the spleen did not fully enable SP thymocytes to produce TNF, suggesting an intrinsic defect in their ability to produce TNF efficiently. Using a thymocyte adoptive transfer model, we demonstrate that the ability of T cells to produce TNF increases progressively with time in the periphery as a function of their maturation state. RTEs that were identified in NG-BAC transgenic mice by the expression of GFP showed a significantly enhanced ability to express TNF relative to SP thymocytes but not to the extent of fully MN T cells. Together, these findings suggest that TNF expression by naïve T cells is regulated via a gradual licensing process that requires functional maturation in peripheral lymphoid organs

Characterisation of tissue-type metabolic content in secondary progressive multiple sclerosis: a magnetic resonance spectroscopic imaging study

Proton magnetic resonance spectroscopy yields metabolic information and has proved to be a useful addition to structural imaging in neurological diseases. We applied short-echo time Spectroscopic Imaging in a cohort of 42 patients with secondary progressive multiple sclerosis (SPMS). Linear modelling with respect to brain tissue type yielded metabolite levels that were significantly different in white matter lesions compared with normal-appearing white matter, suggestive of higher myelin turnover (higher choline), higher metabolic rate (higher creatine) and increased glial activity (higher myo-inositol) within the lesions. These findings suggest that the lesions have ongoing cellular activity that is not consistent with the usual assumption of ‘chronic’ lesions in SPMS, and may represent a target for repair therapies

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era