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Regulation of Grxs in Cell Functions and Senescence in the Lens
No full textResearch Appreciation Day Winner - HSC College of Pharmacy, 2024 Pharmaceutical Science Research Award - 2nd PlacePurpose: Glutaredoxins (Grxs), a family of thiol transferases, can reverse protein glutathionylation using glutathione (GSH) as an electron donor. Therefore, it can regulate protein redox state and enzymatic activity. Specifically, Glutaredoxin 1 (Grx1) and Glutaredoxin 2 (Grx2) are predominantly localized in the cytoplasm and mitochondria, respectively. The Grx1/Grx2 double knockout (DKO) mice showed early onset of cataracts and were more sensitive to UV radiation, highlighting the importance of Grx1 and Grx2 in maintaining lens transparency. Lens epithelial cells (LECs) are crucial to lens transparency and functionality. Our current study is to explore novel roles of the Grxs in the lens using the Grx1-/-/Grx2-/- mouse model. Methods: We isolated LECs from the lenses of WT and DKO mice and conducted a range of in vitro experiments to study the effects of Grx depletion on the epithelial morphology, cell proliferation, cell death, and mitochondrial function of LECs. We also did lens tissue sectioning and hematoxylin and eosin (H&E) staining to visualize lens tissue. Results: Loss of Grx1/Grx2 led to stress fiber formation, cytoskeleton reorganization, and higher protein expression of mesenchymal markers (N-cadherin and vimentin) in LECs. The DKO LECs exhibited a lower proliferation rate and cell cycle arrest in comparison with WT LECs. Resistance to apoptosis and elevated levels of β-galactosidase activity of DKO LECs indicated that DKO LECs underwent cell senescence. DKO LECs also displayed compromised mitochondrial function, characterized by decreased ATP production, reduced expression levels of mitochondrial complexes III and IV, and increased proton leak. A compensatory metabolic shift towards glycolysis was observed in DKO LECs, indicating an adaptive response to Grx1 and Grx2 deficiencies. The HE staining data showed that the DKO mouse had aging lens epithelium characterized by less LEC density, remained flat in shape, and aligned less regularly. Conclusions: Our study demonstrates that the Grx1 and Grx2 DKO in LECs results in cytoskeletal reorganization, lower cell proliferation rate, cell cycle arrest, resistance to apoptosis, compromised mitochondrial function, and accelerated senescence. These findings underscore the importance of Grx1 and Grx2 in preventing LECs from undergoing premature aging.NIH and NE
The Evaluation of Elongated Styloid Processes in regard to possible Clinical and Pathological Outcomes - A Case Series
No full textBackground: Eagle’s syndrome (ES) is defined as elongation or ossification of the styloid process that may compress adjacent anatomy, producing variable symptomology. ES is subclassified into Classic ES or Stylocarotid syndrome. Classic ES may present asymptomatically, or with dull, recurring cervicofacial pain, and Stylocarotid syndrome may present with parietal headaches, and presyncope/syncopal episodes. The etiology of the abnormal ossification of the styloid process or stylohyoid ligament is unknown but likely caused by reactive metaplasia/hyperplasia or anatomical variance. Although a styloid process greater than 30mm in length is generally considered elongated, clinical guidelines for measuring styloid process length, and specific histological characterizations for ES have not been formally established. However, elongated styloid processes can be structurally classified as uninterrupted (one unsegmented process), pseudo-articulated (two parts in close proximity), or segmented (three or more parts). Styloid processes may also be classified into four calcification patterns including outlined calcification, partial calcification (multiple bone pieces surrounded by a continuous calcified process), nodular calcification (segmented, bumpy surfaced bone pieces due to thickened calcifications), and complete calcification. However, no clinical correlation has been identified between patient presentation and morphology/calcification pattern.
Case Information:
A 62-year-old deceased Caucasian male (147lbs / 5’6”) with an elongated stylohyoid process was discovered during routine dissection. Medical history was significant for liver and renal disease. Cause of death was reported as “chronic alcoholism”. Social history was significant for off-and-on incarceration for more than 40 years, and chronic alcohol, tobacco, and non-prescription illicit drug use of unknown types, amount, frequency, or duration. No other history was available.
The styloid processes of the patient were imaged in-situ using a 3D C-arm X-ray machine. Furthermore, bilateral styloid processes were collected from the patient and seven other anatomical donors (6 M/1 F, age range 61-76) by detaching them from the base of the temporal bone and excising portions of the hyoid bone to maintain the stylohyoid ligament intact. Calipers were used to measure the length of the styloid processes and their calcifications. The primary donor exhibited elongated, asymmetrical processes (31.9 mm left, 37.8 mm right). Significant variation in styloid process lengths were observed in this sample (mean length 28.5 mm; standard deviation 13.5 mm; range 14.5-68.3 mm). Generally, the styloid processes demonstrated bilateral asymmetry across the sample. This asymmetry was notably pronounced in one donor with a significantly elongated styloid process (20.5 mm left, 68.3 mm right), co-occurrent with thyroid cartilage calcification.
Conclusions: There is presently no consistent diagnostic measure of an elongated stylohyoid process available for providers to assess patient risk for Eagle’s Syndrome or its future progression. In this study, styloid length was found to be a continuous variable with no clear “cutoff” between elongated and normal lengths at 30mm. Furthermore, the lack of histological evidence detailing the condition's progression hinders diagnostic measures and risk assessment. We recommend further studies perform histologic analysis to better understand the progression of elongated styloid processes. Based on additional samples, a standardized diagnostic measurement can be created to improve treatment regimens and health risk screenings
Stress Due to Inflation: Changes over Time, Correlates, and Coping Strategies among Working-Age Adults in the United States
Get PDFBACKGROUND: During the COVID-19 pandemic, the annual US inflation rate increased from 1.2% in July 2020 to 8% in July 2022. It has since declined to 3.4% (December 2023). This study examined the prevalence of stress due to inflation during a period when it declined from 8.2% in September 2022 to 3% in June 2023 and its association with demographic and social determinants of health (SDOH). METHODS: We conducted a cross-sectional analysis of the online Household Pulse Survey (HPS), which surveils the experiences of US households. Beginning September 2022, HPS initiated data collection on stress due to inflation" through a question on how stressful the increase in prices in the last 2 months has been. Participants could respond: very, moderately, a little, or not stressful. We analyzed data on working-age adults (18-64 years) who responded to the above question of stress due to inflation during 14-26 September 2022 (N = 32,579) and 7-19 June 2023 (N = 36,229). We used replicate weights in chi-squared tests and ordinal logistic regression analyses controlling for gender, age, race and ethnicity, COVID-19, COVID-19 vaccination, health insurance, and SDOH, including education, lost employment income, poverty status, marital status, food affordability, and region. RESULTS: The prevalence of stress due to inflation (price increases being very or moderately stressful) significantly increased from 76.9% in September 2022 to 78.9% in June 2023. The odds of stress due to inflation were higher for individuals with the following characteristics: female, transgender, having income below 400% of the federal poverty line, having lost employment income, not being able to afford food, had long or acute COVID-19, and did not have a COVID-19 vaccine. CONCLUSIONS: More than three quarters of working-age adults in the US experienced stress due to inflation. Despite a declining national inflation rate in recent months, stress due to inflation has significantly increased among working-age adults. Inflation-related stress warrants further research and policy attention."The project described was supported by the National Institute of General Medical Sciences, 5U54GM104942-07 (R.C.W) and NIH/1OT2OD032581-02 (U.S). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH
Prospective Molecular Targets for Natural Killer Cell Immunotherapy against Glioblastoma Multiforme
No full textGlioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor and has a dismal overall survival rate. To date, no GBM therapy has yielded successful results in survival for patients beyond baseline surgical resection, radiation, and chemotherapy. Immunotherapy has taken the oncology world by storm in recent years and there has been movement from researchers to implement the immunotherapy revolution into GBM treatment. Natural killer (NK) cell-based immunotherapies are a rising candidate to treat GBM from multiple therapeutic vantage points: monoclonal antibody therapy targeting tumor-associated antigens (TAAs), immune checkpoint inhibitors, CAR-NK cell therapy, Bi-specific killer cell engagers (BiKEs), and more. NK therapies often focus on tumor antigens for targeting. Here, we reviewed some common targets analyzed in the fight for GBM immunotherapy relevant to NK cells: EGFR, HER2, CD155, and IL-13Ralpha2. We further propose investigating the Lectin-like Transcript 1 (LLT1) and cell surface proliferating cell nuclear antigen (csPCNA) as targets for NK cell-based immunotherapy.This work is supported by a grant (#RP210046) from the Cancer Prevention and Research Institute of Texas and by the NIH T32 Neurobiology of Aging and Alzheimer's Disease (Award #2T32AG020494-21)
Locomotor and discriminative stimulus effects of NBOH hallucinogens in rodents
No full textDespite the efforts of the Drug Enforcement Administration to safeguard the public from hazardous analogs of synthetic hallucinogens, these compounds have increasingly been observed in the illicit drug market. Four novel compounds were found to be similar in structure to the previously described 25X-NBOMe synthetic hallucinogens. These four compounds, 25B-NBOH, 25C-NBOH, 25E-NBOH, and 25I-NBOH were evaluated for their ability to modify spontaneous locomotor activity in mice to obtain dose range and time-course information and were then tested for discriminative stimulus effects similar to the prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM). All four test compounds decreased locomotor activity. The locomotor depressant effects were similar in magnitude and potency to DOM, but less potent than the 25X-NBOMe compounds in previous reports. 25B-NBOH, 25C-NBOH, and 25E-NBOH fully substituted (>/=80%) in DOM-trained rats, whereas 25I-NBOH failed to fully substitute for DOM even at doses that suppressed responding. The discriminative stimulus effects were more potent than those of DOM and the 25X-NBOMe compounds. These findings suggest that three of the four test compounds are most likely to be used as recreational hallucinogens in a similar manner to DOM and the 25X-NBOMe compounds, whereas 25I-NBOH may be less liable to illicit use.This study was supported by NIH N01DA-18-8908 and N01DA-23-8908
Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2
No full textAcylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved cocrystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial-mesenchymal transition.Promega kindly provided constructs for NanoBRET measurements of CDKL2, AAK1, and BMP2K. The kinome tree in Figure 2 was prepared using the TREEspot kinase interaction mapping software at http://treespot.discoverx.com. We acknowledge the UNC Department of Chemistry Mass Spectrometry Core Laboratory for assisting with mass spectrometry analyses. We thank the beamline scientists at the Swiss Light Source (PSI) for their great support during data collection. The SGC is a registered charity (no. 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, the Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute, EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking, Janssen, Merck KGaA (aka EMD in Canada and USA), Pfizer, the São Paulo Research Foundation-FAPESP, and Takeda. Research reported in this publication was supported in part by NC Biotechnology Center Institutional Support grant 2018-IDG-1030 and NIH U24DK116204. Ultanir lab was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2037), the UK Medical Research Council (CC2037), the Wellcome Trust (CC2037), and the Loulou Foundation Project Grant. For Open Access, the authors have applied a CC-BY public copyright license to any Author Accepted Manuscript version
COVID-19 clinical trial participation and awareness in Texas
No full textThe COVID-19 pandemic required the rapid development of COVID-19 vaccines and treatments, necessitating quick yet representative clinical trial enrollment to evaluate these preventive measures. However, misinformation around the COVID-19 pandemic and general concerns about clinical trial participation in the U.S. hindered clinical trial enrollment. This study assessed awareness of, willingness to participate in, and enrollment in COVID-19 vaccine and treatment clinical trials in Texas. A quota sample of 1,089 Texas residents was collected online from June - July 2022. Respondents were asked if they were aware of, willing to participate in, and had enrolled in clinical trials for COVID-19 vaccines or treatments. Overall, 45.8% of respondents reported being aware of clinical trials for COVID-19 treatments or vaccines, but only 21.7% knew how to enroll and only 13.2% had enrolled in a COVID-19 clinical trial. Respondents with bachelor's or graduate degrees were more likely to be aware of clinical trials, more likely to have enrolled in trials, and more willing to participate in treatment trials. Women were less willing to participate and less likely to have enrolled in COVID-19 clinical trials than men. Respondents aged 55 years and older were more willing to participate, but less likely to have enrolled in COVID-19 clinical trials than 18-to-24-year-olds. Common reasons given for not participating in clinical trials included concerns that COVID-19 treatments may not be safe, government distrust, and uncertainty about what clinical trial participation would entail. Substantial progress is needed to build community awareness and increase enrollment in clinical trials.This study was funded by the National Institutes of Health (NIH) Agreement [1OT2HL156812] as part of the NIH Community Engagement Alliance (CEAL), PI: Vishwanatha. The funding agency had no role in the design of the study or in the writing of the manuscript
Tractography as a method for mapping brain connectivity
No full textPurpose. Mapping the brain and its complex connectivity has proved a challenging feat for neuroscience, though with the development of diffusion tensor imaging and tractography, we are one step closer to understanding brain anatomical connections. This method utilizes diffusion-weighted magnetic resonance imaging, which takes advantage of the Brownian motion of water molecules, to produce a diffusion tensor. In the white matter of the brain, diffusion varies in direction due to cellular membranes and myelin, and the diffusion tensor measures this anisotropic diffusivity to indicate possible tissue orientation. The generalized q-sampling imaging tractography method, developed by Frank Yeh in 2010, uses the diffusion tensor to approximate the course of white matter tracts and can be used to determine the exact location and termination of white matter bundles to assess connectivity between and within different brain regions. Despite limitations that decrease the accuracy of white matter tracking, tractography remains the only method to visualize white matter trajectories in vivo and non-invasively. Though commonly used for human diffusion-weighted images, here we verify tractography as a method to visualize and measure white matter trajectories in the rat brain. Methods. A male 3-month Sprague Dawley rat was used to acquire DWI images that were analyzed using DSI Studio. The DWI was superimposed with the corresponding T2W image and regions of interest (ROIs) were drawn in the corpus callosum and were applied via the built-in Waxholm Space rat atlas. Fiber tracking was seeded from the ROI, and fractional anisotropy, quantitative anisotropy, isotropy, mean diffusivity, axial diffusivity, and radial diffusivity was calculated at each ROI by DSI software. Results. Tractography of the corpus callosum was easily visualized using both drawn and atlas-applied ROIs. Fiber tractography from both ROIs included fibers from the internal and external capsules to ensure the integrity of all corpus callosum fibers. Diffusion metrics were not drastically different between the two seeding methods. Conclusion. This study presents tractography as a tool for visualizing white matter tracts and quantifying different diffusion metrics. Using both hand-drawn regions and regions from the rat atlas, white matter tracts in diseased brains can be compared to controls to measure several aspects of pathology, such as edema, axonal integrity, and axonal density. One application includes the imaging and quantification of both acute and chronic stroke, which exhibit different pathologies that can be visualized and measured with diffusion metrics, allowing for more precise targets of therapy. The use of tractography in adjunct with other established methods can improve the understanding of disease and assist in the development of better treatment
PINK1 knockout rats show premotor cognitive deficits measured through a complex maze
Get PDFCognitive decline in Parkinson's disease (PD) is a critical premotor sign that may occur in approximately 40% of PD patients up to 10 years prior to clinical recognition and diagnosis. Delineating the mechanisms and specific behavioral signs of cognitive decline associated with PD prior to motor impairment is a critical unmet need. Rodent PD models that have an impairment in a cognitive phenotype for a time period sufficiently long enough prior to motor decline can be useful to establish viable candidate mechanisms. Arguably, the methods used to evaluate cognitive decline in rodent models should emulate methods used in the assessment of humans to optimize translation. Premotor cognitive decline in human PD can potentially be examined in the genetically altered PINK1(-/-) rat model, which exhibits a protracted onset of motor decline in most studies. To increase translation to cognitive assessment in human PD, we used a modified non-water multiple T-maze, which assesses attention, cognitive flexibility, and working memory similarly to the Trail Making Test (TMT) in humans. Similar to the deficiencies revealed in TMT test outcomes in human PD, 4-month-old PINK1(-/-) rats made more errors and took longer to complete the maze, despite a hyperkinetic phenotype, compared to wild-type rats. Thus, we have identified a potential methodological tool with cross-species translation to evaluate executive functioning in an established PD rat model.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. IS was supported by the National Institute on Aging Training (Grant T32 AG 020494). This study was funded in part by the Department of Defense Parkinson's Disease Research Program (Award W81XWH-19-1-0757) to MS, an Institute for Healthy Aging Intramural Award at the University of North Texas granted to MS and VN, and an HSC Presidential Endowment to the Chair of Pharmacology and Neuroscience to DS
Case report: rapid development and progression of duodenal varices without significant change in existing esophagogastric varices
No full textBackground: Duodenal varices (DV) are a rare complication of portal hypertension, leaving the topic relatively unexplored. There are some reports describing the presence of and potential treatments for DV, but little is known about their progression. Below we present an interesting case of a patient with portal hypertension who developed and had rapid progression of DV without any progression of her existing esophageal varices (EV). Case Information: The patient had an esophagogastroduodenoscopy (EGD) which showed non bleeding grade 1 esophageal varices and no other abnormal findings.2 years later, the patient underwent an EGD which showed non bleeding grade 1 varices found in the lower third of the esophagus. Further inspection revealed large non bleeding varices in the second portion of her duodenum. Conclusions: Although rarer than EV, bleeding from DV is often difficult to diagnose and even harder to control, leading to mortality rates up to 40% for initial bleeding. Otherwise, there is little data comparing the pathophysiology and outcomes of EV and DV. We hypothesize that the rapid development and progression of DV without any significant change in EV may be related to 1) increased flow toward the duodenum and away from the esophagus, 2) increased propensity for duodenal anastomoses to dilate, or 3) anatomical variants not previously identified or studied. As our understanding of DV grows, diagnostic and therapeutic algorithms may need to be adjusted to account for ectopic varices other than EV and to more effectively allocate beta blocker prophylaxis in patients with portal hypertension