Effect of Uracil DNA Glycosylase Activity on the Efficacy of Thymidylate Synthase Inhibitor/HDAC Inhibitor Combination Therapies in Colon Cancer

Human uracil DNA glycosylase (UNG2) is responsible for removing uracil bases from DNA and initiates base excision repair pathways. Accumulation of uracil or its fluorinated analogs in DNA is one of the killing mechanisms of thymidylate synthase (TS) inhibitors in cancer cells, and depletion of UNG2 often enhances the toxicity of these anticancer drugs. We tested the effect of UNG2 KO on the efficacy of multiple TS inhibitors (5-fluorouracil, fluorodeoxyuridine, and pemetrexed) and we determined that, except for 5-fluorouracil, all other TS inhibitors were significantly more potent in UNG2 KO cells compared to wild-type HT29 cells. Interestingly, UNG2 protein levels can also be depleted by the HDAC inhibitors SAHA and MS275, providing a pharmacologic strategy to reduce UNG2 activity in cells. Unexpectedly, the HDAC inhibitors synergized with 5-fluorouracil but not fluorodeoxyuridine in both wild-type and UNG2-knockout cells. Similarly, HDAC inhibitors synergized with pemetrexed in wild-type HT29 but not UNG2-knockout cells. This suggested that HDAC inhibitors sensitized cells to 5-fluorouracil through an UNG2-independent mechanism. Interestingly, SAHA depleted the UNG2 level, whereas TS inhibitors alone and their combination with SAHA upregulated the level of UNG2 at 24 hours. This suggests HDAC inhibitors deplete UNG2 but, when combined with TS inhibitors, it did not affect UNG2, at least at a concentration of 100nM. Our future aim is to study these pharmacological drug combinations targeting UNG2 activity in cells and elucidate exact mechanisms of cell death

Evaluation of the changes in pre-extraction blood pressure and pulse rate values with post-extraction blood pressure and pulse rate values

Background: Aim and objectives were to compare the differences in blood pressure and pulse rate readings before and after extraction of a tooth. Methods: A total of 250 patients were selected for the study, out of which, 124 were males and 126 were females. All the patients were in an age group from 20 till beyond 73 years of age. Blood pressure and pulse rate readings were measured before the start of the procedure. Extraction procedure was performed and post extraction blood pressure and pulse rate values were recorded. Both the values were compared and evaluated. Results: There was an obvious increase in systolic blood pressure and pulse rate values after a tooth extraction. Conclusions: Blood pressure and pulse rate values showed changes before and after tooth extraction but were within normal limits

Fox’s Head or Lion’s Tail? Work Life Balance of Women Entrepreneurs in Agriculture and farm Ventures and its Antecedent Effect on Quality of Life

Purpose: The objective of this study was to identify the factors that influence work life balance of women entrepreneurs in the field of agriculture and allied products and how the family demands affect their work-life balance. Further, the paper explores the conflict between parental demand and running a business.   Theoretical framework: Literature review points out that despite, an increase in the number of women entrepreneurs over the years, according to the (Global entrepreneurship monitor report, 2020), fewer women pursue entrepreneurship due to various challenges of managing personal and business responsibilities and striking the right balance. Work-life balance is frequently examined in the context of human resource management (Etienne St-Jean and Duhamel M.,2020)but not much has been explored in an entreprenurial context.Hence this study is to investigate and understand the influence of various factors affecting work life balance from an entrepreneurial standpoint.   Design/methodology/approach: Triangulation method was used for the study by utilizing both quantitative and qualitative data. The researchers developed a questionnaire to measure work-life balance experienced by women entrepreneurs with 12 independent variables to measure the dependent variable work-life balance.The sample consisted of 450 women agripreneurs   Findings: The findings reveal that the age of the children is a major determinant of the extent of parental demand a woman goes through in her life and family support systems are critical in reducing overlap and conflict between the life domains. A positive spillover between the domains significantly enhances quality of life of women entrepreneurs.   Research, Practical & Social implications: We suggest a future research into other Personality traits and macro environmental factors which can have a bearing on work life balance of women entrepreneurs which would enable an inclusive entrepreneurial ecosystem.   Originality/value: The researchers have concluded that positive spillover between the domains significantly enhances quality of life of women entrepreneurs

Algorithmic Approach in Cytopathology : A Mode of Training the New Residents

Objectives: To compare the traditional teaching with algorithm or flowchart-based teaching method in cytology and to assess the performance of newly joined residents in cytopathology after training them with algorithm-based approach. Materials & Methods: The study included 20 newly joined residents who were divided into two groups I.e., group A and group B and was conducted in two different sets. In set 1, group A residents were trained with the algorithmic approach and group B residents by theoretical method for 10 different cytological cases of thyroid and breast. In set 2, group B residents were taught the algorithmic approach and group A residents by theoretical method for 10 different cytological cases of salivary gland and lymph node. The performance of the residents in both the sets was assessed and pre-test and post-test scores were given based on their ability to diagnose the lesions before and after the training. The feedback on the utility of algorithmic approach in cytopathology was received from the participated residents after the study. Results: The performance of the residents was compared using Mann Whitney U test of post-test scores and was found that in set 1, group A residents’ performance was greater than that of group B residents. Similarly for the set 2, the performance of group B residents was greater than group A residents. The performance of group A residents in set 2 was found to be better than their performance in set 1. Conclusion: The algorithm or flowchart-based teaching is a unique teaching method which enhances case solving skills and effective reasoning in the residents. Keywords: Algorithm based approach, Cytopathology, FNAC, Pathology resident trainin

Advanced glycation end products modulate amyloidogenic APP processing and Tau phosphorylation: a mechanistic link between glycation and the development of Alzheimer’s disease

Advanced glycation end products (AGEs) are implicated in the pathology of Alzheimer’s disease (AD), as they induce neurodegeneration following interaction with the receptor for AGE (RAGE). This study aimed to establish a mechanistic link between AGE-RAGE signaling and AD pathology. AGE-induced changes in the neuro2a proteome were monitored by SWATH-MS. Western blotting and cell-based reporter assays were used to investigate AGE-RAGE regulated APP processing and tau phosphorylation in primary cortical neurons. Selected protein expression was validated in brain samples affected by AD. The AGE-RAGE axis altered proteome included increased expression of cathepsin B and asparagine endopeptidase (AEP), which mediated an increase in Aβ_1–42 formation and tau phosphorylation, respectively. Elevated cathepsin B, AEP, RAGE, and pTau levels were found in human AD brain, coincident with enhanced AGEs. This study demonstrates that the AGE-RAGE axis regulates Aβ_1–42 formation and tau phosphorylation via increased cathepsin B and AEP, providing a new molecular link between AGEs and AD pathology

Physics-Informed Data Denoising for Real-Life Sensing Systems

Sensors measuring real-life physical processes are ubiquitous in today's interconnected world. These sensors inherently bear noise that often adversely affects performance and reliability of the systems they support. Classic filtering-based approaches introduce strong assumptions on the time or frequency characteristics of sensory measurements, while learning-based denoising approaches typically rely on using ground truth clean data to train a denoising model, which is often challenging or prohibitive to obtain for many real-world applications. We observe that in many scenarios, the relationships between different sensor measurements (e.g., location and acceleration) are analytically described by laws of physics (e.g., second-order differential equation). By incorporating such physics constraints, we can guide the denoising process to improve even in the absence of ground truth data. In light of this, we design a physics-informed denoising model that leverages the inherent algebraic relationships between different measurements governed by the underlying physics. By obviating the need for ground truth clean data, our method offers a practical denoising solution for real-world applications. We conducted experiments in various domains, including inertial navigation, CO2 monitoring, and HVAC control, and achieved state-of-the-art performance compared with existing denoising methods. Our method can denoise data in real time (4ms for a sequence of 1s) for low-cost noisy sensors and produces results that closely align with those from high-precision, high-cost alternatives, leading to an efficient, cost-effective approach for more accurate sensor-based systems.Comment: SenSys 202

Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells.

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective white blood cell differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity, that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics of a conditional knockout mouse, we demonstrate that Kat2a contributes to leukemia propagation through preservation of leukemia stem-like cells. Kat2a loss impacts transcription factor binding and reduces transcriptional burst frequency in a subset of gene promoters, generating enhanced variability of transcript levels. Destabilization of target programs shifts leukemia cell fate out of self-renewal into differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and distinct stages of cancer evolution

Altered Response Hierarchy and Increased T-Cell Breadth upon HIV-1 Conserved Element DNA Vaccination in Macaques

HIV sequence diversity and potential decoy epitopes are hurdles in the development of an effective AIDS vaccine. A DNA vaccine candidate comprising of highly conserved p24 gag elements (CE) induced robust immunity in all 10 vaccinated macaques, whereas full-length gag DNA vaccination elicited responses to these conserved elements in only 5 of 11 animals, targeting fewer CE per animal. Importantly, boosting CE-primed macaques with DNA expressing full-length p55 gag increased both magnitude of CE responses and breadth of Gag immunity, demonstrating alteration of the hierarchy of epitope recognition in the presence of pre-existing CE-specific responses. Inclusion of a conserved element immunogen provides a novel and effective strategy to broaden responses against highly diverse pathogens by avoiding decoy epitopes, while focusing responses to critical viral elements for which few escape pathways exist

Whole Genomes of Chandipura Virus Isolates and Comparative Analysis with Other Rhabdoviruses

The Chandipura virus (CHPV) belonging to the Vesiculovirus genus and Rhabdoviridae family, has recently been associated with a number of encephalitis epidemics, with high mortality in children, in different parts of India. No full length genome sequences of CHPV isolates were available in GenBank and little is known about the molecular markers for pathogenesis. In the present study, we provide the complete genomic sequences of four isolates from epidemics during 2003–2007. These sequences along with the deduced sequence of the prototype isolate of 1965 were analysed using phylogeny, motif search, homology modeling and epitope prediction methods. Comparison with other rhaboviruses was also done for functional extrapolations. All CHPV isolates clustered with the Isfahan virus and maintained several functional motifs of other rhabdoviruses. A notable difference with the prototype vesiculovirus, Vesicular Stomatitis Virus was in the L-domain flanking sequences of the M protein that are known to be crucial for interaction with host proteins. With respect to the prototype isolate, significant additional mutations were acquired in the 2003–2007 isolates. Several mutations in G mapped onto probable antigenic sites. A mutation in N mapped onto regions crucial for N-N interaction and a putative T-cell epitope. A mutation in the Casein kinase II phosphorylation site in P may attribute to increased rates of phosphorylation. Gene junction comparison revealed changes in the M-G junction of all the epidemic isolates that may have implications on read-through and gene transcription levels. The study can form the basis for further experimental verification and provide additional insights into the virulence determinants of the CHPV