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Library Holiday Hours
No full textThe TMC Library will observe the following schedule for the winter holidays.
Regular library hours resume on Saturday, January 3rd, 2026. Happy Holidays
Identification of a Translatable Animal Model for Dry Eye Disease Using Comparative Analysis of Tear Proteins Across Species
No full textPurpose: This study aimed to assess the similarity of tear proteins between experimental animals and humans to identify the most translational animal model for dry eye disease (DED).
Methods: Eleven species were selected for a structural and physicochemical comparison of healthy human tear fluid proteins involved in DED. Amino acid sequences were compared using BLAST. Protein primary structure, isoelectric point (pI) and grand average of hydropathicity (GRAVY) were determined using ExPASy and compared with humans.
Results: Among non-primate mammals, the cat (69.7 %) and pig (68.7 %) showed the highest protein sequence similarity to humans. The ruminants and cat showed amino acid content changes for the highest number of proteins (≥3/15). The pig, rabbit, dog and rodents had the closest global pI values to humans, while the cat showed the highest protein number (9/15) with pI values far from humans. GRAVY values for the pig and dog were the closest to humans. Tear-soluble factor study revealed that the pig was the only species with high similarity for all proteins (\u3e60 %). Amino acid content was similar for most species compared to humans, except mouse for IL-6 and rodents and pig for IL-8. The pI and GRAVY values varied across species, though the pig and sheep were the only ones with similar pI to humans for four out of five factors.
Conclusion: The pig exhibited the highest similarity to humans in tear protein analysis among non-primate mammals, suggesting that the porcine model may be the most translational for DED research
A Whole-Brain Voxel-Based Analysis of Structural Abnormalities in PTSD: An Enigma-PGC Study
No full textBackground: Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.
Methods: T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).
Results: PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges\u27 g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges\u27 g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (p corrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (p corrected = .001).
Conclusions: PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology
Functional Vision Assessment Over 4 Years in USH2A Using the Veteran Affairs Low-Vision Visual Functioning Questionnaire
No full textPurpose: The purpose of this study was to evaluate the validity of the Veterans Affairs Low Vision Visual Functioning Questionnaire (VALVVFQ-48) functional vision scores (FVS) in patients with USH2A-associated retinal degeneration. In addition, to correlate the change in the VALVVFQ-48 FVS with the change in visual function (VF) measurements.
Methods: The VALVVFQ-48 was administered verbally to participants ≥18 years of age at baseline, and after 2 and 4 years. Associations among changes in FVS and changes in VF measures were assessed using the Spearman correlation coefficients. Mixed effects regression models with a random intercept were used to estimate annual rates of change of FVS and their responsiveness to change in VF measurements.
Results: All domain scores (except visual motor) showed significant decline over 4 years. Changes in the VALVVFQ-48 domain scores were negligibly to strongly correlated with changes in clinical measures of vision function over 4 years (|r| = 0.02 to 0.61). All domains showed evidence of responsiveness to changes in some VF measures, particularly the visual field. Participants with improvement and worsening in FVS beyond the coefficient of repeatability (CoR) ranged between 17% and 46% across all domains. Ceiling effects at baseline precluded accurate calculation of change over time in 19% to 36% of participants in 3 domains.
Conclusions: The VALVVFQ-48 may not be a sensitive measure for evaluating longitudinal outcomes in all persons with USH2A-associated retinal degeneration
Association of Preoperative Nocturnal Hypoxaemia Nadir and Fentanyl Ventilatory Sensitivity in Children With Obstructive Sleep Apnoea Undergoing General Anaesthesia: A Multicentre Clinical Cohort Study
No full textBackground: Obstructive sleep apnoea (OSA) has been thought to increase the risk of respiratory depression from opioids. The primary aim of this study was to assess whether preoperative hypoxaemia by sleep study pulse oximetry imparts greater opioid sensitivity.
Methods: A multicentre observational cohort study with in-cohort dose randomisation was performed in children 2-8 yr of age with OSA undergoing adenotonsillectomy. Ninety patients were assigned to one of two Spo2 cohorts by preoperative sleep study Spo2 nadir of \u3c or ≥85% to receive fentanyl 1.0 or 1.5 μg kg-1 (maximum 25 μg) after sevoflurane induction. The primary outcome was the extent of opioid-induced central ventilatory depression over time by Spo2 status as defined by the differences in tidal volume, respiratory rate, end-tidal CO2, and minute ventilation for 10 min after fentanyl administration when compared with pre-fentanyl baseline values. Secondary outcomes included assessment of body mass index, fentanyl dose, sex, age, and race on opioid-induced central ventilatory depression. Intention-to-treat and per protocol analysis were performed.
Results: Ninety patients underwent in-cohort randomisation (Spo2 \u3c 85%; n=47 and Spo2 ≥85%; n=43). Final per protocol analysis included 73 subjects, fentanyl 1.0 μg kg-1 (Spo2 \u3c 85%; n=36 and Spo2 ≥85%; n=37) and 15 subjects, fentanyl 1.5 μg kg-1 (Spo2 \u3c 85%; n=9 and Spo2 ≥85%; n=6). Multivariable mixed effect model for the primary outcomes (tidal volume, respiratory rate, end-tidal CO2, and minute ventilation) from baseline to 10 min (as % change per minute) were not different between groups by Spo2 nadir (\u3c or ≥85%) and fentanyl dose for the intention-to-treat and per protocol analyses.
Conclusions: Single-dose fentanyl ventilatory effects in paediatric OSA patients during sevoflurane anaesthesia were not associated with preoperative nocturnal hypoxaemia nadir. Fentanyl dosing in children with OSA should not be determined by sleep study Spo2 nadir
Quality of Life in Young Adults With Type 1 Diabetes
No full textIntroduction: Challenges of young adulthood with type 1 diabetes (T1D) include transitioning to adult care, increased T1D self-management responsibilities, and normal developmental transitions. Recognizing patterns of health-related quality of life (HRQOL) across a demographically and clinically broad range of young adults with T1D may help identify who needs additional support as they transfer to adult healthcare. We hypothesized that young adults from specific demographic and clinical groups would report lower HRQOL.
Methods: At baseline of a behavioral RCT (≤2 months after last pediatric T1D clinic visit), 100 young adults (Mage=19.9 ± 1.3, MA1c=8.8 ± 2.0 %) self-reported demographics and HRQOL; A1c was analyzed via point of care or dried blood spot. ANOVAs and t-tests were used to compare HRQOL by demographic (gender, race/ethnicity, insurance, school enrollment) and clinical variables (device use, A1c).
Results: Diabetes-specific HRQOL differed significantly by gender and school enrollment; females and young adults enrolled in school reported higher HRQOL. There were no significant differences in HRQOL across race/ethnicity, insurance type, and diabetes technology use.
Conclusion: Monitoring HRQOL may be helpful to identify diabetes-specific psychosocial needs during the transition from pediatric to adult healthcare. Patterns suggest males and those not in school may benefit from additional support
Dinaciclib Improves Treatment Response in Chemoresistant Hepatoblastoma
No full textChemoresistant hepatoblastoma (HB) is associated with poor outcomes. Cyclin-dependent kinases (CDKs) are potential therapeutic targets because of their critical role in cell growth and chemoresistance. To evaluate the efficacy of CDK inhibition, HB cell lines were treated with dinaciclib and evaluated with cytotoxic, cell-death reversal, and immunoblotting assays. A HB patient-derived xenograft (PDX) model was treated with placebo, vincristine + irinotecan (VI), dinaciclib, or VI + dinaciclib to evaluate tumor growth and response to therapy. We found that dinaciclib had a marked effect on HB cell viability, induced PARP cleavage, and decreased CDK9 protein expression in vitro. Overexpression of CDK9 increased resistance to dinaciclib. Dinaciclib induced cytotoxicity through a mitochondrial-mediated apoptotic pathway with reversal of cell death observed with co-treatment of cells with an apoptosis inhibitor, Z-VAD. In our PDX model, treatment with VI + dinaciclib resulted in decreased tumor volume, viability and HB cell proliferation. Given these findings, combination treatment with VI and dinaciclib should be investigated further as a treatment for chemoresistant HB
High Tumor CD161 Expression Predicts a Survival Advantage and Marks a Th1-Skewed Microenvironment
No full textCD8+CD161+ T-cells exhibit augmented memory and cytolytic properties, mediating enhanced immunity in murine tumor models and improved survival in human non-small cell lung cancer. This T-cell subset might serve as a biomarker of positive response to therapy or even be isolated to augment current immunotherapeutic approaches yet limited knowledge of CD161 expression in human cancers restricts practical application. Here we bioinformatically tested the hypothesis that CD161 expression may be associated with positive outcomes in human cancers and investigated mechanisms underlying any observed advantages. Using TCGA-PANCAN dataset, we analyzed expression of CD161 in over 10,000 human tumors, correlating expression levels with survival. CD161 expression was highly correlated and largely co-expressed with CD8, indicating that observed benefits could be attributed to CD8+CD161+ T-cells. While patients with high CD161 expression exhibited a clear survival advantage over those with low expression, this survival advantage was highly dependent on co-expression of CD11c, indicating a reliance on dendritic cells (DC). To further explore the mechanism by which high CD161 expression confers a survival advantage in cancer, we analyzed available scRNA-sequencing data derived from 31 melanoma tumors. Tumors exhibiting high CD8+CD161+ infiltration also exhibited greater expression of cDC1 and TH1 transcription factors along with higher levels of inflammatory cytokine transcripts. CD8+CD161+ cells themselves displayed enhanced cytotoxicity markers and reduced exhaustion markers compared to CD8+CD161neg T-cells. The data suggest that CD161 could serve as a biomarker for positive outcomes and that DC play a critical in vivo role in the propagation of CD161+ T-cell responses
Antibiofilm Properties of 4-Hydroxy-3-Methyl-2-Alkenylquinoline, a Novel Burkholderia-Derived Alkaloid
No full textBiofilms are an important colonization mechanism employed by several microbial species to better establish themselves and monopolize the acquisition of resources across different environs. Some bacteria have evolved specialized metabolites that, when secreted, disrupt the formation and stability of biofilms generated by competing heterospecies, providing the producing organism with an ecological advantage. Soil-derived species are probable candidates for the identification of such compounds, given the intense level of competition that occurs within the terrestrial ecosystem. The MS14 strain of Burkholderia contaminans isolated from soil in Mississippi has previously been shown to produce antimicrobial compounds like occidiofungin and ornibactin. In this report, we demonstrate that this strain also produces 4-hydroxy-3-methyl-2-alkenylquinoline (HMAQ-7), an alkaloid-based metabolite structurally similar to others produced by Burkholderia. HMAQ-7 was isolated and purified in sufficient quantities to enable the elucidation of its covalent structure and the evaluation of its biological effects. The compound was found to possess a unique ability to inhibit biofilm biosynthesis in several species, including opportunistic pathogens like Staphylococcus haemolyticus and within saliva-derived multispecies biofilms. HMAQ-7 also demonstrated an ability to modulate additional cellular behaviors in Bacillus subtilis, including motility and sporulation, suggesting that this molecule is important to the interspecies dynamics present across many diverse microenvironments