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Transcriptional Regulation of NLRC4 Inflammasome by IRF8
Get PDFThe NLRC4 inflammasome is a crucial part of the innate immune response against bacterial infections. We found that NLRC4 inflammasome activation in bone marrow-derived macrophages (BMDMs) is greatly dependent on interferon regulatory factor 8 (IRF8). NLRC4-mediated caspase-1 activation and subsequent production of the inflammasome-dependent cytokines IL-1β and IL-18 and cell death were impaired in IRF8-deficient cells. IRF8 mediated the transcription of genes encoding NAIPs, the receptors for NLRC4 inflammasome, which recognize bacterial flagellin and type III secretion system (T3SS) proteins. IRF8 was critical for host survival following infection with Salmonella Typhimurium or Burkholderia thailandensis. Furthermore, mice deficient in IRF8 were impaired in their ability to produce IL-18 and suffered higher bacterial burdens. Altogether, our data highlights the role of IRF8 as a transcriptional regulator of NAIPs for NLRC4 inflammasome activation
Sex-related differences in perception and discrimination of different speakers: An analysis of the auditory dorsal stream via EEG
Get PDFGrowing evidence that speech perception tasks elicit sensorimotor activity, and that this activity varies due to context, sex, cognitive load, and cognitive ability. However, it is unknown as to whether the sex of the speaker and demands of the task differentially effect males and females during speech perception tasks. This study investigated whether speaker sex and task demands (i.e. passive listening or active discrimination) influence sensorimotor and auditory cortical activity in males and females differently. Raw EEG data were collected from 27 males and 29 females during passive listening to, and discrimination of /ba/ and /da/ syllable pairs spoken by a synthetic female or male speaker. Independent component analysis identified sensorimotor and auditory components characterized by alpha/beta and alpha peaks, respectively. Time- frequency decomposition revealed no significant differences between male and female groups in any testing conditions. Within the male group, stronger mu activity was found in active discrimination conditions compared to passive listening in only the left hemisphere, while females displayed stronger activity in both the left and right hemisphere. Auditory cluster activity revealed males utilizing stronger inhibition after stimulus offset in active discrimination conditions, while females showed stronger activation during stimulus presentation in the same conditions. Both males and females displayed stronger mu activation in response to male speakers compared to female speakers before, during, and after stimulus presentation. Given this, it appears that speaker sex does influence at least anterior dorsal stream activity in a similar fashion for both males and females, but task demands differentially alter anterior and posterior dorsal stream activity in each sex group. These findings may at least partially explain the high variability in findings across neuroimaging studies that feature males and females in the same population
Regulation of CYP3A5 in Pancreatic Ductal Adenocarcinoma
Get PDFCYP3A5 is a drug metabolism enzyme that is polymorphically expressed in normal tissues and expressed in high amounts in some cancers, including pancreatic ductal adenocarcinoma (PDAC). There have been several published studies regarding CYP3A5 regulators, but there is still much to be discovered concerning CYP3A5 regulation in cancer. To further understand the regulation of CYP3A5, a high-throughput screen was performed in the AsPC-1 PDAC cell line. This screen employed small interfering RNA (siRNA) targeting transcription factors and chromatin-associated proteins. We identified siRNA that decreased CYP3A5 mRNA and protein levels in AsPC-1 cells and probed into the potential mechanisms. Taken together, this study brought to light a previously undescribed regulator of CYP3A5 expression
Molecular Mechanisms of Metabolic Reprogramming in Pancreatic Cancer
Get PDFPancreatic cancer ranks as third deadliest cancer worldwide in both men and women. The lack of diagnostic methods, chemo-resistance and invasiveness of the disease diminishes the overall survival rate in patients. Dysregulated glucose metabolism and several molecular determinants including oncogenic signaling pathways play pivotal roles in the development, progression and metastasis of pancreatic cancer. The aberrant glucose metabolism is the most prevalent key factor that influences pancreatic tumorigenesis. The cancer cells of pancreas utilize oxygen for the breakdown of glucose to lactate, which is known as Warburg effect. This phenotype of pancreatic cancer encourages proliferation, growth, migration and invasive phenotypes of cancer cells that worsens the disease. The upstream regulatory molecules responsible for deviant activity of glucose transporters during aberrant glucose metabolism was not very well defined. Thus, identification of new molecular determinants that regulate glucose metabolic pathway would provide promising therapeutic outcomes. Our lab has established the role of MUC13 protein in pancreatic cancer development. Another interesting molecule, Protein Kinase D1 has been reported to play essential role in hypoxic metabolism in squamous cell carcinoma, and glucose uptake in cardiac hypertrophy. Also, it has been extensively studied in our research group, and has been suggested by some other groups to have an essential role in pancreatic cancer. However, its role in regulating glucose metabolism in pancreatic cancer remains elusive. In this dissertation, we investigated that MUC13 and PKD1 proteins are involved in abrupt glucose metabolism in pancreatic cancer cells. We have demonstrated that targeted overexpression of these oncogenes upregulates key oncogenic signaling components involved in aberrant glucose metabolism in pancreatic cancer cells. We also investigated a natural agent Steviol that restored glucose metabolism in pancreatic cancer cells via repression of MUC13 and PKD1 expression. MUC13 is a transmembrane glycoprotein which has an elevated expression in pancreatic cancer. Due to the presence of a cytoplasmic domain, it confers kinase activity and regulates many signaling processes. Therefore, we investigated the effect of MUC13 in metabolic reconditioning of pancreatic cancer. As a result, it was observed that presence of MUC13 in pancreatic cancer upregulated glucose uptake and lactate secretion. This in turn led to more aggressive behavior of the tumor, as evidenced by enhanced proliferation, migration and invasive characteristics of the cells as compared to MUC13 null cells. Interestingly, we observed the interaction of MUC13 with Glut-1 protein, which influences glucose uptake in cancer cells. This was confirmed through various assays such as: immunoprecipitation, immunofluorescence, co-capping and proximity ligation assay. The interpretation of inhibitor results envisaged the role of NFҡB pathway during the molecular interactions of MUC13 and Glut-1. To understand the clinical importance of this mechanism, we evaluated this interaction in tumor samples from the patients with pancreatic disease in advanced stages. Our findings fortified the mechanistic role of MUC13 in rewiring of aberrant glucose metabolism. Altogether, we believed that MUC13 has clinical implication as a key molecule that might be responsible for dysregulated glucose metabolism. As discussed earlier about the paucity of associated proteins related to dysregulated glucose metabolism, we further investigated the possible key players with kinase domain for association and activation with other signaling molecules.
Protein Kinase D1 (PKD1), a Ser/Thr kinase has been shown to be involved in progression of pancreatic cancer. In this study, we established PKD1 as a novel molecular target and its involvement in regulating aberrant glucose metabolism in pancreatic cancer. We observed that PKD1 was overexpressed in pancreatic cancer tissues compared to normal human tissues. We also found constitutive expression of PKD1 in various pancreatic cancer cells as compared to normal pancreatic ductal epithelial cells. The overexpression of PKD1 in low PKD1 expressing pancreatic cancer cells enhanced tumorigenic characteristics. We observed that specific knockdown of PKD1 inhibited key oncogenic signaling components in pancreatic cancer cells suggesting its oncogenic role in pancreatic cancer. Additionally, during the PKD1 overexpression, cells displayed increased glucose consumption and lactate production. This suggested role of PKD1 in metabolic reprogramming in pancreatic cancer. Also, we observed that PKD1 stimulates the glucose uptake through mTORC1, a component of mTOR signaling pathway. Additionally, the knockdown of PKD1 promoted the chemosensitivity of cells towards gemcitabine and 2DG (2-deoxyglucose). Overall, these results indicated a significant function of PKD1 in rewiring of glucose metabolism in pancreatic cancer. It was mandating to target and counteract the aberrant glucose metabolism along with the proteins identified in our previous results. In this perspective herein, we proposed steviol, a natural sweetener from plant origin to assess its inhibitory action towards dysregulated glucose metabolism and its associated proteins (MUC13 and PKD1). The reason behind steviol selection for this approach includes that it mimics the glucose molecule that facilitates enhanced uptake of drug (steviol) within the cells and on the other side, it provides glucose homeostasis to adjacent normal cells. These features made steviol as dual functional drug by overtaking other natural drugs for promising results. The exposure of steviol inhibited the proliferative (IC50: 10mM) and clonogenic abilities of pancreatic cancer cells. It also suppressed the cell migration and cell invasion capabilities of pancreatic cancer cells. Further, steviol caused the selective inhibition of intracellular glucose intake and lactate accumulation in a concentration dependent manner. The selective inhibition of MUC13 and PKD1 (upstream key proteins of glucose metabolism) that caused the disruption of glucose intake in cancer cells, was observed during steviol treatment. Secondly, steviol interfered with translation-initiation machinery, causing destabilization of the cellular functionality. The impairment of cellular translation process had promoted G1 cell cycle arrest in cells due to the lack of G1-S transition proteins during drug exposure. Collectively, all these events engendered the cellular integrity and directed towards activation of apoptosis. In conclusion, we evaluated the role of MUC13 and PKD1 in aberrant glucose metabolism leading to growth and aggressive metastatic phenotypes of pancreatic cancer. We also demonstrated efficacy of steviol to repress aberrant glucose metabolism via suppression of MUC13 and PKD1 proteins
Prioritizing Resources for Third-Year Medical Students
Get PDFPrioritizing Resources for Third Year Medical Students To assess the effectiveness of using library surveys as a means of prioritizing resources for collection development. In the third year of medical undergraduate education, students are undergoing their core clinical rotations. During this period, exams in the core areas must be passed and therefore, access to relevant library resources is vital for successful completion. As part of their curriculum, students were able to accumulate additional points toward their final average by completing a survey, which assessed how library resources and availability, or lack thereof, affected their performance during this critical year. Since survey results have been previously collected for the purposes of quality improvement by the medical school, use of this data received IRB exemption. Short answer or Likert scale responses were thematically or quantitatively analyzed for those resources that students considered most beneficial. A modified version of Ose’s method for coding open-ended questions from web-based surveys was used for the analysis. Based on survey results, a final resource list conforming to a limited library budget, was generated and prioritized. After engagement of the medical school’s Learning Resources Committee, the requested resources were submitted for approval. The next group of third year medical students will determine the effectiveness of the newly acquired resources when a similar survey is deployed toward the end of the academic year
Shaping an Institutional Workplace Wellness Program to Fit an Academic Health Science Center Library
Get PDFObjective: In 2018, The University of Mississippi Medical Center (UMMC) established the Office of Wellbeing as an umbrella structure to enhance the physical health, emotional wellbeing, and professional fulfillment of faculty, staff, and students. The UMMC Office of Wellbeing sponsors workshops, lectures, and classes on a variety of wellness topics. Wellness events are held primarily in the clinical areas of the large academic medical center campus during the noon hour. Attending these events can be challenging for library faculty and staff that are juggling busy work schedules, responsibilities, and duties. The aim is to improve accessibility and participation in wellness activities.
Methods: A Rowland Medical Library (RML) faculty member was selected to be a “Wellness Champion”. The role of a Wellness Champion is to support the Office of Wellbeing’s initiatives of creating a healthy work culture in their own department or division. The RML Wellness Champion initiated quarterly wellness sessions for library faculty and staff in the library classroom at a convenient, scheduled time.
Results: To integrate the institutional wellness mission and improve participation of library faculty and staff, wellness sessions are scheduled quarterly in the library. The sessions focus on one of five target areas identified by the Office of Wellbeing: physical health and fitness, emotional/mental wellness, social wellness, intellectual/professional wellness, and financial wellness.
Conclusions: Feedback on the wellness sessions from library faculty and staff has been overwhelmingly positive. Bringing the sessions to the library makes it easier for RML employees to benefit from institutional wellness initiatives. Scheduling wellness events at the department level could serve as a model at the institution for other departments to replicate
Overview of Credit-Bearing Library-Sponsored Courses for Health Sciences Students
Get PDFObjective: This research project aims to present an overview of credit-bearing library-sponsored courses offered by librarians at Association of Academic Health Sciences Libraries (AAHSL) member institutions during the 2017-2018 academic year.
Methods: The research team gathered information about credit-bearing library-sponsored courses offered during the 2017-2018 academic year through a national survey, and gathered additional data using semistructured interviews. The cross-sectional survey investigated prevalence, content covered, credits offered, barriers, and other details about credit-bearing library courses. Information gleaned from interviews was thematically analyzed using qualitative methodologies.
Results: The survey was completed by 40 of 150 U.S. AAHSL institutions, resulting in a 27% survey completion rate. During the 2017-2018 academic year, 17 institutions (42.5% of survey respondents) reported that they offered library-sponsored courses to students for academic credit, 8 institutions (20%) reported that they did not offer such courses but planned to in the future, and 15 institutions (37.5%) reported that they did not offer such courses and do not plan to. Interviews were conducted with 16 of the institutions that reported offering library sponsored courses, only 3 of which met our definition. Other details obtained through the semi-structured interviews -such as the credit-granting process, tuition distribution, assignments, grading format, and course evolution - will be presented.
Conclusions: While many librarians are teaching credit-bearing courses, most of these are not library-sponsored courses. The main barrier to teaching credit-bearing library-sponsored courses is the lack of a central entity to grant course credit and offer the course to multiple disciplines
Implementation of Pharmacogenomics into Electronic Health Record and Clinical Decision Support
Get PDFThe advent of electronic health records (EHR) and clinical decision support (CDS) has brought numerous changes in the healthcare field and has improved how patients receive care. The field of pharmacogenomics has made many breakthrough discoveries in the last few decades and these new advances have immensely reduced the cost of genetic testing. As advances have been made, researchers have discovered that individuals may respond to a medication differently due to genetic variants. There is a shift in the medical field from a one size fits all model to a personalized medicine model based on genetic information. Institutions have started to incorporate genetic information in their EHR and CDS systems to aid clinicians in the prescribing process. The rate of implementation is uneven among the institutions across the United States. Healthcare institutions have encountered some challenges associated with implementing pharmacogenomic data into CDS and EHR system. These challenges include lack of clinician education about pharmacogenomic data, poor user interface, and lack of resources for additional information for these alerts. If these challenges are overcome, there is great potential for pharmacogenomic CDS systems to help improve patient care and reduce adverse drug events
Investigation of Narrow Spectrum Targets in Antibacterial Drug Discovery
Get PDFBackground: Significant concerns are associated with the use of broad-spectrum antibacterial agents, including collateral eradication of beneficial bacteria from the human microbiome, the onset of antibacterial-associated infections, and continued emergence of antibacterial drug resistance. As such, a critical need for novel and selective antibacterial targets exists. The investigation of two such targets, each pertaining to the highly concerning infections caused by streptococcal species and Clostridioides difficile, are presented herein. Bacterial topoisomerase I represents a potentially promising narrow-spectrum target as studies have arisen demonstrating its essentiality in bacterial species lacking the only other type IA topoisomerase (topoisomerase III). Additionally, recent studies demonstrating the essentiality of the fabK gene expressing enoyl-ACP reductase II (FabK) in C. difficile indicate its significant potential as a narrow-spectrum target. Presented here are data characterizing and validating both the TopoI and FabK enzymes as novel antibacterial targets via the implementation of an array of drug discovery techniques, including structural studies, biochemical assay development and application, and inhibitor screening and testing. Methods: An assortment of drug discovery techniques were employed for the targeting of SmTopoI and CdFabK, including different protein expression and purification techniques; X-ray crystallography; various biophysical and biochemical techniques for target characterization, validation, and drug screening; and different lead development and optimization studies. Results: The respective genes for SmTopoI and CdFabK have been cloned, and the expression and purification of various constructs of each target have been carried out and optimized for further analysis. The crystal structure of SmTopoI_N65 has been determined to 2.06 Å and diffracting CdFabK crystals (3.5 Å) have been attained. A high-throughput plate-based biochemical fluorescence kinetic assay has been optimized for screening against the CdFabK enzyme. Furthermore, activity and modality of inhibition assessment of small-molecule inhibitors of the CdFabK enzyme have been conducted, including phenylimidazole and benzothiazole compounds. Phenylimidazole analogues have been found to display micromolar inhibitory activity against CdFabK, and a benzothiazole analogue has been found to display nanomolar inhibitory activity against the target. Conclusions: The SmTopoI and CdFabK enzymes present potentially novel, narrow- spectrum antibacterial drug targets, and substantial progress has been made toward the rational targeting of these two enzymes. Of particular note, the first structure of a Topo I fragment from a gram-positive organism, S. mutans, has been determined. Enzymology and inhibitor studies have been conducted supporting the druggability of CdFabK and indicating the potential for selective inhibition of CdFabK
