Generation of a Compendium of Transcription Factor Cascades and Identification of Potential Therapeutic Targets using Graph Machine Learning

Transcription factors (TFs) play a vital role in the regulation of gene expression thereby making them critical to many cellular processes. In this study, we used graph machine learning methods to create a compendium of TF cascades using data extracted from the STRING database. A TF cascade is a sequence of TFs that regulate each other, forming a directed path in the TF network. We constructed a knowledge graph of 81,488 unique TF cascades, with the longest cascade consisting of 62 TFs. Our results highlight the complex and intricate nature of TF interactions, where multiple TFs work together to regulate gene expression. We also identified 10 TFs with the highest regulatory influence based on centrality measurements, providing valuable information for researchers interested in studying specific TFs. Furthermore, our pathway enrichment analysis revealed significant enrichment of various pathways and functional categories, including those involved in cancer and other diseases, as well as those involved in development, differentiation, and cell signaling. The enriched pathways identified in this study may have potential as targets for therapeutic intervention in diseases associated with dysregulation of transcription factors. We have released the dataset, knowledge graph, and graphML methods for the TF cascades, and created a website to display the results, which can be accessed by researchers interested in using this dataset. Our study provides a valuable resource for understanding the complex network of interactions between TFs and their regulatory roles in cellular processes

A Prismatic View of the Epigenetic-Metabolic Regulatory Axis in Breast Cancer Therapy Resistance

Epigenetic regulation established during development to maintain patterns of transcriptional expression and silencing for metabolism and other fundamental cell processes can be reprogrammed in cancer, providing a molecular mechanism for persistent alterations in phenotype. Metabolic deregulation and reprogramming are thus an emerging hallmark of cancer with opportunities for molecular classification as a critical preliminary step for precision therapeutic intervention. Yet, acquisition of therapy resistance against most conventional treatment regimens coupled with tumor relapse, continue to pose unsolved problems for precision healthcare, as exemplified in breast cancer where existing data informs both cancer genotype and phenotype. Furthermore, epigenetic reprograming of the metabolic milieu of cancer cells is among the most crucial determinants of therapeutic resistance and cancer relapse. Importantly, subtype-specific epigenetic-metabolic interplay profoundly affects malignant transformation, resistance to chemotherapy, and response to targeted therapies. In this review, we therefore prismatically dissect interconnected epigenetic and metabolic regulatory pathways and then integrate them into an observable cancer metabolism-therapy-resistance axis that may inform clinical intervention. Optimally coupling genome-wide analysis with an understanding of metabolic elements, epigenetic reprogramming, and their integration by metabolic profiling may decode missing molecular mechanisms at the level of individual tumors. The proposed approach of linking metabolic biochemistry back to genotype, epigenetics, and phenotype for specific tumors and their microenvironment may thus enable successful mechanistic targeting of epigenetic modifiers and oncometabolites despite tumor metabolic heterogeneity

Association between Incidental Pelvic Inflammation and Aggressive Prostate Cancer

The impact of pelvic inflammation on prostate cancer (PCa) biology and aggressive phenotype has never been studied. Our study objective was to evaluate the role of pelvic inflammation on PCa aggressiveness and its association with clinical outcomes in patients following radical prostatectomy (RP). This study has been conducted on a retrospective single-institutional consecutive cohort of 2278 patients who underwent robot-assisted laparoscopic prostatectomy (RALP) between 01/2013 and 10/2019. Data from 2085 patients were analyzed to study the association between pelvic inflammation and adverse pathology (AP), defined as Gleason Grade Group (GGG) > 2 and ≥ pT3 stage, at resection. In a subset of 1997 patients, the association between pelvic inflammation and biochemical recurrence (BCR) was studied. Alteration in tumor transcriptome and inflammatory markers in patients with and without pelvic inflammation were studied using microarray analysis, immunohistochemistry, and culture supernatants derived from inflamed sites used in functional assays. Changes in blood inflammatory markers in the study cohort were analyzed by O-link. In univariate analyses, pelvic inflammation emerged as a significant predictor of AP. Multivariate cox proportional-hazards regression analyses showed that high pelvic inflammation with pT3 stage and positive surgical margins significantly affected the time to BCR (p ≤ 0.05). PCa patients with high inflammation had elevated levels of pro-inflammatory cytokines in their tissues and in blood. Genes involved in epithelial-to-mesenchymal transition (EMT) and DNA damage response were upregulated in patients with pelvic inflammation. Attenuation of STAT and IL-6 signaling decreased tumor driving properties of conditioned medium from inflamed sites. Pelvic inflammation exacerbates the progression of prostate cancer and drives an aggressive phenotype.</p

DEVADARU (CEDRUS DEODARA (ROXB.) LOUD.): A CRITICAL REVIEW ON THE MEDICINAL PLANT

Devadaru (Cedrus deodara) an important plant belongs to Pinaceae family found in the north-western Himalayas at altitude of 1200-3000 meter. The aromatic wood of this beautiful tree is used as carminative, anti inflammatory, diaphoretic, diuretics, antipyretic, antileprotic. In Caraka samhita it is one among the Satanya shodhana and Anuvasanopaga group of drugs and Sushruta also considered it as the Vata Shamana group, Katuvarga and Eladi group. It is the chief timber of north west India and is used for all purpose of construction of railway sleepers, bridges, and even for furniture and shingles. The oil obtained is used for mange in horses and sore feet in cattle. It is in use since vedic period in temples and in making incense even said that by sitting under its shade many diseases cures especially asthma. Here the present review study is an attempt to provide reported detail information of this herb from various Samhitas and its study in modern area like its phytoconstituents and pharmacological activities

Desing and development of precision artifact for dissemination of low forces of 1 N and 2 N

This paper describes the preliminary results of the design, development and characterization of precision artifacts for the measurement of low forces of 1 N and 2 N. For designing the elastic element, we carried out the finite element analysis (FE) to determine the stress and strain distribution on the elastic element for appropriately identifying the location for fixing the strain gauges. In order to obtain optimum performance and sensitivity, the strain gauges are emplaced on the identified location using a high quality curing adhesive. Characterization of these artifacts are performed on a recently developed low force dead weight machine having an estimated best measurement capability (BMC) of +/- 0.0012% (k=2). The repeatability and reproducibility of the developed artifact are found to be within +/- 0.003% and +/- 0.006% respectivel

Interplay between charge and antiferromagnetic ordering in Bi0.6-xPrxCa0.4MnO3 (0 <= x <= 0.6) perovskite manganite

Structure, magnetic and transport properties of polycrystalline Bi0.6-xPrxCa0.4MnO3 (x=0.0, 0.1, 0.2, 0.3, 0.4, 0.5 and 0.6) have been studied. Systematic substitution of Pr at Bi site induces an interesting interplay between the charge ordering and antiferromagnetism. The charge ordering temperature (T-CO) decreases with increasing x. The antiferromagnetic (AFM) ordering temperature (T-N) increases sharply at both the extremes but remains nearly constant from x=0.2 to 0.4. At temperatures lower than T-N a transition to the glassy state is observed. The nature of this glass like state appears to be controlled by the Pr content, and at lower values of x this is akin to a spin glass, while at higher x it has a characteristic of cluster glass. The Pr doping also leads to enhancement in the magnetic moment. In the present work it has been proposed that the local lattice distortion induced due to size mismatch between the A-site cations and 6s(2) character of Bi3+ lone pair electron is responsible for the observed magnetic and electrical properties

Effect of La-doping on magnetic properties of Bi0.6-xLaxCa0.4MnO3 (0.0 <= x <= 0.6) perovskite manganites

In this paper, we report the synthesis of polycrystalline samples with nominal compositions Bi0.6-xLaxCa0.4MnO3 (0.0 )

Development and Performance Evaluation of a Dead Weight Force Machine in 2-50N Range

Results of the performance evaluation of a newly designed, developed and fabricated dead weight machines to realize forces in the range of (2-50) N are reported in this paper. Precision load cells of 20N, 50N and 100N having an expanded uncertainty of +/- 0.03% are used for this evaluation. The calibration of these load cells against the dead weight force machine shows that the repeatability (Rep) and reproducibility (Repr) are better than 0.003% and 0.005% respectively, over the entire range. The calibration data observed is found to closely agree with the calibration results obtained directly against the Physikalsich-Technische Bundesanstalt (PTB), Germany force standard machine having the relative measurement uncertainty of the force scale in the measuring range a parts per thousand currency sign 0.002%