10 research outputs found
Regulation of proto-oncogenes and immune system genes during CSF-1-induced macrophage differentiation
No full textCSF-1-induced bone marrow-derived macrophage (BMDM) differentiating in vitro acquire both antigen presenting and tumoricidal capabilities. In order to understand the molecular origin of macrophage diversity transcriptional and post-transcriptional regulation of genes involved in affector and effector functions were studied. Transcripts of c-fms and c-fos were detected at all stages of differentiation, whereas c-myc gene expression was highest during the proliferative stages of development. Endotoxin treatment of BMDM enhanced the expression of all proto-oncogenes, however the c-myc mRNA levels were highest on day 3 of culture. IFN- treatment of BMDM cultures also enhanced the transcription of proto-oncogenes. Thus, it is felt that c-fms, c-fos and c-myc may be related to the complex mechanism of macrophage activation as evidenced by the stage-specific gene regulation. Interesting observations were made on the study of genes involved with functional state macrophage. Transcription of MHC class I and II genes occurred in the absence of any known Ia-inducing factor and the transcripts reached a maximum (3- to 4-fold) between days 5-7 of culture. IFN- enhanced the transcription of both class I (2- to 5-fold) and II (2- to 10-fold) genes. Nuclear run-off assay results demonstrated that endotoxin treatment of the BMDM cultures augmented expression of both class I (2- to 3-fold) and II (2- to 3-fold) genes suggesting a post-transcriptional control of the MHC genes in the absence of an Ia-inducing factor. Upon endotoxin stimulation, transcription of IL-1 and IL-1 showed almost similar kinetics which paralleled the kinetics of accumulation of steady state mRNA. This suggested that the expression of IL-1 genes are regulated transcriptionally. Tough both IFN- and endotoxin enhanced (4- to 5-fold) the transcription of TNF- gene, endotoxin had a more pronounced effect. The kinetics of TNF- transcription paralleled the kinetics of steady state TNF- mRNA accumulation, thereby suggesting both transcriptional and post-transcriptional control in the expression of TNF- gene. Thus, these findings indicate that during macrophage development there is a sequential expression of immune system genes which is intrinsically determined.Made available in DSpace on 2011-05-07T11:59:00Z (GMT). No. of bitstreams: 2
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Inhibition of pyruvate dehydrogenase kinase enhances the antitumor efficacy of oncolytic reovirus
No full textOncolytic viruses (OV) such as reovirus preferentially infect and kill cancer cells. Thus, the mechanisms that dictate the susceptibility of cancer cells to OV-induced cytotoxicity hold the key to their success in clinics. Here, we investigated whether cancer cell metabolism defines its susceptibility to OV and if OV-induced metabolic perturbations can be therapeutically targeted. Using mass spectrometry–based metabolomics and extracellular flux analysis on a panel of cancer cell lines with varying degrees of susceptibility to reovirus, we found that OV-induced changes in central energy metabolism, pyruvate metabolism, and oxidative stress correlate with their susceptibility to reovirus. In particular, reovirus infection accentuated Warburg-like metabolic perturbations in cell lines relatively resistant to oncolysis. These metabolic changes were facilitated by oxidative stress–induced inhibitory phosphorylation of pyruvate dehydrogenase (PDH) that impaired the routing of pyruvate into the tricarboxylic acid cycle and established a metabolic state unsupportive of OV replication. From the therapeutic perspective, reactivation of PDH in cancer cells that were weakly sensitive for reovirus, either through PDH kinase (PDK) inhibitors dichloroacetate and AZD7545 or short hairpin RNA–specific depletion of PDK1, enhanced the efficacy of reovirus-induced oncolysis in vitro and in vivo. These findings identify targeted metabolic reprogramming as a possible combination strategy to enhance the antitumor effects of OV in clinics
A study of drug utilization pattern in patients with hypertension in a tertiary care hospital
No full textBackground: Hypertension, a leading global health concern, poses significant risks to vital organs such as the heart, brain, and kidneys. Effective management remains a challenge, especially in countries like India, where cardiovascular diseases are a major contributor to mortality. This study aimed to evaluate the drug utilization patterns of antihypertensive drugs and associated prescribing practices in a tertiary care teaching hospital.
Methods: A hospital-based cross-sectional descriptive study was conducted from January to October 2023 in the Departments of Medicine and Cardiology. The study included patients diagnosed with hypertension aged 18 years or older. Data on prescribed antihypertensive drugs, including drug type, dosage and comorbidities, were collected and analyzed.
Results: A total of 230 prescriptions were analyzed, with 75.59% of patients receiving monotherapy. Amlodipine was the most commonly prescribed drug, used in 87.5% of monotherapy cases. Combination therapies were prescribed to 24.41% of patients, with the most common combinations being Amlodipine + Atenolol and Losartan + Hydrochlorothiazide + Amlodipine. Diabetes mellitus was the most frequent comorbidity observed, affecting 60 patients. A significant portion of prescriptions (59%) was written using brand names, and 41% were written using generic names.
Conclusion: Future research should focus on enhancing patient adherence, optimizing treatment regimens, and continuously monitoring prescribing patterns to improve hypertension management and reduce associated health burdens
Epigenomic and metabolic drivers of intestinal development
No full textEmbryonic intestinal development is a dynamic process where tissue undergoes drastic transitory changes from morphological and physiological changes, to chromatin restructuring for intestinal specification, to metabolic shifts for supporting growing tissue. My research focuses on two critical themes regulating embryonic intestinal development: Epigenomic and Metabolic. During early endoderm development, cells exhibit cellular plasticity with the ability to acquire cell fate of multiple endodermal lineages. Lineage-inducing transcription factors (TF) drive tissue-specific transcriptomes, leading to distinct cell types, with the loss of cellular plasticity as tissue matures. However, transcriptional mechanisms governing organ specification and cell fate are poorly understood. We provide evidence that loss of intestinal lineage-inducing TF CDX2 in the developing endoderm at E9.5, using Shh-cre, leads to underdeveloped intestine with cells exhibiting foregut-like cellular identity. This phenomenon is conserved across species with the induction of esophageal and stomach cell fates upon CDX2 loss in human intestinal organoid cultures (HIO). By temporal mapping of Cdx2 knockout in the developing intestine, we highlight the loss of intestine’s ability to transform in esophageal lineages by E9.5; between E9.5-E13.5 CDX2 loss leads to gastric lineage, while intestine’s window of CDX2-restricted plasticity is entirely lost by E15.5. Enhancers bound by CDX2 in the developing endoderm, identified using CDX2 ChIP-seq at E13 and E17, regulate genes involved in gut tube development and are enriched for patterning transcription factor motifs. In contrast, enhancers bound by CDX2 in adult epithelium regulate genes involved in metabolic processes and are enriched for mature intestinal transcription factors. This dynamic binding of CDX2 along development is conserved across species, as we identify different regions regulated by CDX2 in early specified hindgut when compared to adult human intestinal cultures, with similar relationships suggesting patterning roles for CDX2 early in development, and mature intestine-specific physiological functions in the adult tissue. In a temporal survey of developing intestinal chromatin assayed using ATAC-seq, we find that CDX2’s differential binding and intestine’s cellular plasticity coincide with dynamic chromatin restructuring during villus formation. Villogenesis is a transition point in intestinal development, when early embryonic enhancer chromatin condenses while mature intestinal enhancers gain accessibility. We highlight temporal CDX2 bound enhancers highly overlap with dynamic chromatin accessibility. Additionally, in human intestinal cultures, in presence of Wnt/FGF signaling CDX2 binds at enhancers specifying intestinal cell fate, however in absence of Wnt/FGF CDX2 fails to impart intestinal cell fate and loses its ability to bind at intestine-specifying enhancers. These results indicate that CDX2 requires additional factors to drive the intestinal transcriptome, and chromatin accessibility strongly correlates with dynamic CDX2 binding. Enhancer regions with transcriptionally active histone H3k27ac modifications, that become inactive after human hindgut specification, are enriched for foregut transcription factor motifs.This indicates that genomic regions where foregut transcription factors bind become inactive once intestinal cell fate is established. Furthermore, we analyze forestomach enhancer regions, identified using ATAC-seq from forestomach tissue at post-natal Day 1, for chromatin accessibility in temporally developing intestinal epithelium, assayed using ATAC-seq. We highlight that the foregut enhancer regions are accessible in the developing intestine at E11, which then progressively lose permissive chromatin and are mostly inaccessible by E16. However, in the absence of CDX2, foregut enhancers remain accessible in intestine at E16, permitting ectopic foregut cellular identity to establish in intestine. Our study highlights an unexplored mechanism of chromatin regulation of organ specification and cellular plasticity. To further decipher mechanisms regulating intestinal development, we investigate the role of transcription factor Yin-Yang1 (Yy1) and metabolism during intestinal development. While, CDX2 is a transcription factor that is appreciated to be involved in intestinal development, the role of YY1 in intestinal development has not been elucidated before. Although, we explore the mechanisms governed by CDX2 and YY1 independently, we highlight that during villogenesis both YY1 and CDX2 regulated processes are critical for intestinal development. During late gestation, structures called villi extend into the intestinal lumen, significantly increasing the surface area of the intestinal epithelium to prepare the gut for the neonatal diet. Incomplete development of the intestine is a most common gastrointestinal complication in neonates, but the causes remain unclear. We provide evidence that YY1 is critical for intestinal villus development. YY1 loss in the developing endoderm has no apparent consequences until late gestation, after which the intestine differentiates poorly and exhibits severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration may function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the greatly unappreciated role of metabolic regulation during organogenesis, and suggests its possible contribution to the pathogenesis of neonatal gastrointestinal disorders.Ph.D.Includes bibliographical referencesby Namit Kuma
Quantitative temporal in vivo proteomics deciphers the transition of virus-driven myeloid cells into M2 macrophages
No full textMyeloid cells play a central role in the context of viral eradication, yet precisely how these cells differentiate throughout the course of acute infections is poorly understood. In this study, we have developed a novel quantitative temporal in vivo proteomics (QTiPs) platform to capture proteomic signatures of temporally transitioning virus-driven myeloid cells directly in situ, thus taking into consideration host–virus interactions throughout the course of an infection. QTiPs, in combination with phenotypic, functional, and metabolic analyses, elucidated a pivotal role for inflammatory CD11b+, Ly6G–, Ly6Chigh-low cells in antiviral immune response and viral clearance. Most importantly, the time-resolved QTiPs data set showed the transition of CD11b+, Ly6G–, Ly6Chigh-low cells into M2-like macrophages, which displayed increased antigen-presentation capacities and bioenergetic demands late in infection. We elucidated the pivotal role of myeloid cells in virus clearance and show how these cells phenotypically, functionally, and metabolically undergo a timely transition from inflammatory to M2-like macrophages in vivo. With respect to the growing appreciation for in vivo examination of viral–host interactions and for the role of myeloid cells, this study elucidates the use of quantitative proteomics to reveal the role and response of distinct immune cell populations throughout the course of virus infection
A Study on Socio-Economic and Psychological Causes of Suicide Among Youths in India
No full textOver the last few years, the number of suicide cases in India has increased at a significant level, thereby influencing the youth in a negative way. There are several reasons that can be considered as potential causes of suicide that, include depression, financial loss, poor academic performance, and many more. These reasons influence the mind of young individuals that then becomes the reason for suicide attempts. Each year, there are almost 8 lakh people that lose their lives due to the reason of suicide. This study focuses on the increase in the suicide rates over a certain time period in India. The rate of mortality is considered high and the intervention studies have remained minimal
Growth selection induced residual stresses and fracture behavior of as-deposited thermal barrier coatings
No full textThis study explored the impact of microstructure and residual stresses on the fracture behavior of as-deposited thermal barrier coatings (TBCs). Two distinct air plasma sprayed TBCs, Coating A (conventional lamellar porous) and Coating B (dense vertically cracked), were investigated. Coating A involved coarser but less dense powders as feedstock and a lower substrate temperature during deposition. Further, Coating A had (Formula presented.) times higher randomly oriented porosities, finer grains, lower hardness, and elastic stiffness. Strikingly, however, the fracture strength was higher for the porous as-deposited Coating A. The answer to this apparent contradiction emerged from the intergranular residual stresses. These were measured using both X-ray diffraction and high-resolution-electron backscattered diffraction. Coating B, deposited at a higher substrate temperature, had clear growth selection of (Formula presented.) oriented grains. These also had more out-of-plane normal and shear residual stresses. The growth selection induced residual stresses appeared responsible for the decohesion of Coating B from the substrate and, correspondingly, lower fracture strength. © 2024 The American Ceramic Society.</p
Pathway-Driven Peptide–Bioglass Nanocomposites as the Dynamic and Self-Healable Matrix
No full textPeptide hydrogels have recently emerged as potential biomaterials for designing synthetic scaffolds in tissue engineering. We demonstrate pathway-controlled self-assembly of peptide amphiphile 1 to furnish kinetically controlled nanofibers (1NF) and thermodynamically stable twisted helical bundles (1TB). These supramolecular nanostructures with varied persistence lengths promote in situ mineralization to yield templated bioactive glass composites, 1NFBG and 1TBBG – resorbable, mesoporous, and degradable biomaterials as bone scaffolds. The structural features of the hydrogel composites are investigated extensively with microscopic characterization, energy-dispersive X-ray spectroscopy, Raman spectroscopy, and XPS to conclude 1TBBG as the superior material with higher percentage of open network structures as obtained from ratios of nonbridging and bridging oxygen. The hydrogel composites show excellent dynamic and self-healing behavior from rheological studies, especially the elastic modulus of 1TBBG being almost comparable to natural bone. Upon incubation in simulated body fluid, the bioglass composites illustrate tunable bioactive response mediated by the structural and topological control to induce the deposition of multiphasic calcium phosphate along with octacalcium phosphate and carbonate hydroxyapatite. Finally, such spatiotemporal composites facilitate stiffness-controlled osteoblast cellular interactions to support U2OS subsistence in the hydrogel matrix, highlighting their potential as a substrate for osteoblast growth for prolonged culture periods and in 3D bone tissue modeling
Adelante: A Journal of Student Research and Creative Work (Vol. 1, no. 1)
No full textThe goal of Adelante: A Journal of Student Research and Creative Work is to showcase the breadth and diversity of Chico State undergraduate and graduate student research and creative work. The idea for the journal grew out of our desire to provide examples of student work that demonstrate a wide array of methods, styles, and diverse voices. We hope the journal inspires more students to engage in research and to pursue opportunities to present and publish their work in this journal and beyond. The student journal is edited by graduate students wishing to learn about the peer-review process, editing, and publishing academic research. We determined the structure and scope of this first journal. In addition to establishing a competitive, peer-review process to select and publish a small number of high-quality finished papers, we also wanted to include shorter pieces that allowed all student researchers to publicly share at least some part of their work. For this reason, we encouraged students to submit abstracts that captured their research and creative work. All of our authors had an opportunity to work with us to edit and format their work. In addition to the completed papers and abstracts, we expanded the journal to include student author photos and biographies. We also thought it was important to recognize and highlight the amazing faculty who provide the opportunities and mentoring necessary to ensure our students' success. We included their photos and biographies, too. Finally, we developed and included in the journal a research and writing resource guide to share with students beginning or continuing their research journeys. We are pleased with this first edition. We believe it does meet our goal of showcasing our students' research and creative endeavors and the dedicated faculty who support them. In future editions, we hope to expand the journal to provide even more opportunities for students to showcase their excellent work
