Faculty/ Researcher Works: Recent submissions
Now showing items 21-40 of 2621
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HIV-Associated Neurocognitive Disorders: The Relationship of HIV Infection with Physical and Social ComorbiditiesThe prevalence of HIV (human immunodeficiency virus) associated neurocognitive disorders (HAND) will undoubtedly increase with the improved longevity of HIV-infected persons. HIV infection, itself, as well as multiple physiologic and psychosocial factors can contribute to cognitive impairment and neurologic complications. These comorbidities confound the diagnosis, assessment, and interventions for neurocognitive disorders. In this review, we discuss the role of several key comorbid factors that may contribute significantly to the development and progression of HIV-related neurocognitive impairment, as well as the current status of diagnostic strategies aimed at identifying HIV-infected individuals with impaired cognition and future research priorities and challenges.
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Accurate lattice geometrical parameters and bulk moduli from a semilocal density functionalAccurate prediction of lattice constants is very important in applications of density functional theory. In this work, we assess the efficacy of a non-empirical meta-generalized gradient approximation proposed by Tao and Mo (TM) by calculating the lattice constants as well as bulk moduli of 33 crystalline semiconductors within the TM scheme. We find that the TM functional is able to produce very accurate lattice constants, with a mean absolute error of 0.038 Å, and bulk moduli with a mean absolute error of 3.2 GPa, improving upon commonly-used semilocal density functionals, such as the LSDA, PBE, SOGGA, PBEsol, TPSS, M06L, and SCAN. The high computational efficiency and remarkable agreements with the corresponding experimental values suggest that the TM functional can be a very competitive candidate in electronic structure theory. We attribute the accuracy of the TM functional to be the result of its satisfaction of many exact or nearly-exact conditions related to the exchange-correlation energy and the associated hole, leading to an improved description of the short- as well as intermediate-range van der Waals interactions.
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Activation and polarization of circulating monocytes in severe chronic obstructive pulmonary diseaseBackground: The ability of circulating monocytes to develop into lung macrophages and promote lung tissue damage depends upon their phenotypic pattern of differentiation and activation. Whether this phenotypic pattern varies with COPD severity is unknown. Here we characterize the activation and differentiation status of circulating monocytes in patients with moderate vs. severe COPD. Methods: Blood monocytes were isolated from normal non-smokers (14), current smokers (13), patients with moderate (9), and severe COPD (11). These cells were subjected to analysis by flow cytometry to characterize the expression of activation markers, chemoattractant receptors, and surface markers characteristic of either M1- or M2-type macrophages. Results: Patients with severe COPD had increased numbers of total circulating monocytes and non-classical patrolling monocytes, compared to normal subjects and patients with moderate COPD. In addition, while the percentage of circulating monocytes that expressed an M2-like phenotype was reduced in patients with either moderate or severe disease, the levels of expression of M2 markers on this subpopulation of monocytes in severe COPD was significantly elevated. This was particularly evident for the expression of the chemoattractant receptor CCR5. Conclusions: Blood monocytes in severe COPD patients undergo unexpected pre-differentiation that is largely characteristic of M2-macrophage polarization, leading to the emergence of an unusual M2-like monocyte population with very high levels of CCR5. These results show that circulating monocytes in patients with severe COPD possess a cellular phenotype which may permit greater mobilization to the lung, with a pre-existing bias toward a potentially destructive inflammatory phenotype.
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A novel application of the Staudinger ligation to access neutral cyclic di-nucleotide analog precursors via a divergent methodOur efforts to develop a scalable and divergent synthesis of cyclic di-nucleotide analog precursors have resulted in (1) an orthogonally protected di-amino carbohydrate as well as (2) the novel application of the Staudinger ligation to provide medium-sized macrocycles featuring carbamate or urea linkages.
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An exploration of some magnetic fundamentals in EuSe using μSREuSe is a simple magnetic system that appears to show many complicated features. Under applied pressure it undergoes a transition from an antiferromagnet (AF) to a ferromagnet (FM). This transition provides a means of testing certain basic fundamentals of magnetic theory and an opportunity to explore the complexities of EuSe. Using the muon-spin rotation and relaxation technique (μSR), EuSe was measured at pressures ranging from ambient to 11 kbar. In ambient-pressure EuSe, muon data reveal two local fields, but show only a single field in the FM state formed under pressure. The μSR measurements appear to show a continuous transition at Tc, contrary to previous Mössbauer results that were interpreted as being evidence of a first-order transition. Values determined for the critical exponent, β, in AF and FM EuSe, differ and therefore appear to be a clear counterexample to the Universality Hypothesis. The values of β also are indicative of EuSe’s being a 2D magnet for pressures up to 11 kbar. The nature and values of the local fields seen by the muons is discussed and analyzed.
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Identification of Novel Inhibitors of DLK Palmitoylation and Signaling by High Content ScreeningAfter axonal insult and injury, Dual leucine-zipper kinase (DLK) conveys retrograde pro-degenerative signals to neuronal cell bodies via its downstream target c-Jun N-terminal kinase (JNK). We recently reported that such signals critically require modification of DLK by the fatty acid palmitate, via a process called palmitoylation. Compounds that inhibit DLK palmitoylation could thus reduce neurodegeneration, but identifying such inhibitors requires a suitable assay. Here we report that DLK subcellular localization in non-neuronal cells is highly palmitoylation-dependent and can thus serve as a proxy readout to identify inhibitors of DLK palmitoylation by High Content Screening (HCS). We optimized an HCS assay based on this readout, which showed highly robust performance in a 96-well format. Using this assay we screened a library of 1200 FDA-approved compounds and found that ketoconazole, the compound that most dramatically affected DLK localization in our primary screen, dose-dependently inhibited DLK palmitoylation in follow-up biochemical assays. Moreover, ketoconazole significantly blunted phosphorylation of c-Jun in primary sensory neurons subjected to trophic deprivation, a well known model of DLK-dependent pro-degenerative signaling. Our HCS platform is thus capable of identifying novel inhibitors of DLK palmitoylation and signalling that may have considerable therapeutic potential.
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Investigating undergraduate students’ ideas about the fate of the UniverseAs astronomers further develop an understanding of the fate of the Universe, it is essential to study students’ ideas on the fate of the Universe so that instructors can communicate the field’s current status more effectively. In this study, we examine undergraduate students’ preinstruction ideas of the fate of the Universe in ten semester-long introductory astronomy course sections (ASTRO 101) at three institutions. We also examine students’ postinstruction ideas about the fate of the Universe in ASTRO 101 over five semester-long course sections at one institution. The data include precourse surveys given during the first week of instruction (N=264), postinstruction exam questions (N=59), and interviews. We find that, preinstruction, more than a quarter of ASTRO 101 students either do not respond or respond with “I don’t know” when asked what the long-term fate of the Universe is. We also find that, though the term was not necessarily used, students tend to describe a “big chill” scenario in the preinstruction surveys, among a wide variety of other scenarios. A fraction of students describe the fate of smaller-scale systems, possibly due to confusion of the hierarchical nature of structure in the Universe. Preinstruction, students mention the Universe’s expansion when describing how astronomers know the fate of the Universe but do not discuss how we know the Universe is expanding or the relationship between expansion and the fate of the Universe. Postinstruction, students’ responses shift toward greater degrees of completeness and correctness.
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Impaired non-homologous end joining in human primary alveolar type II cells in emphysemaEmphysema is characterized by alveolar wall destruction induced mainly by cigarette smoke. Oxidative damage of DNA may contribute to the pathophysiology of this disease. We studied the impairment of the non-homologous end joining (NHEJ) repair pathway and DNA damage in alveolar type II (ATII) cells and emphysema development. We isolated primary ATII cells from control smokers, nonsmokers, and patients with emphysema to determine DNA damage and repair. We found higher reactive oxygen species generation and DNA damage in ATII cells obtained from individuals with this disease in comparison with controls. We also observed low phosphorylation of H2AX, which activates DSBs repair signaling, in emphysema. Our results indicate the impairement of NHEJ, as detected by low XLF expression. We also analyzed the role of DJ-1, which has a cytoprotective activity. We detected DJ-1 and XLF interaction in ATII cells in emphysema, which suggests the impairment of their function. Moreover, we found that DJ-1 KO mice are more susceptible to DNA damage induced by cigarette smoke. Our results suggest that oxidative DNA damage and ineffective the DSBs repair via the impaired NHEJ may contribute to ATII cell death in emphysema.
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A Comparison of Request Process and Outcomes in Donation After Cardiac Death and Donation After Brain Death: Results From a National StudyAvailable literature points to healthcare providers’ discomfort with donation after cardiac death (DCD) and their perception of public reluctance toward the procedure. Using a national sample, we report on the communication content of actual DCD and donation after brain death (DBD) approaches by organ procurement organization (OPO) requesters and compare family decision makers’ (FDMs’) experiences of both modalities. We recruited 1601 FDMs using a validated protocol; 347 (21.7%) were of potential DCD donors. Semistructured telephone interviews yielded FDMs’ sociodemographic data, donation attitudes, assessment of approach, final outcomes, and substantiating reasons. Initial analysis consisted of bivariate analyses. Multilevel mixture models compared groups representing authorization outcome and DCD/DBD status. No significant differences in family authorization were found between DCD and DBD cases. Statistically significant associations were found between sociodemographic characteristics and authorization, with white FDMs more likely to authorize DCD or DBD than black FDMs. FDMs of both modalities had similar evaluations of requester skills, topics discussed, satisfaction, and refusal reasons. The findings suggest that the DCD/DBD distinction may not be notable to families. We recommend the use of similar approach strategies and communication skills and the development of education campaigns about the public’s acceptance of DCD.
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Imiquimod Treatment Causes Systemic Disease in Mice Resembling Generalized Pustular Psoriasis in an IL-1 and IL-36 Dependent MannerGeneralized pustular psoriasis (GPP) is a severe form of psoriasis that can be caused by missense mutations in the interleukin-36 (IL-36) receptor antagonist. In addition to neutrophil rich skin inflammation, GPP patients typically also experience anorexia, fever, malaise, and pain. The imiquimod-induced skin inflammation mouse model has rapidly become a popular way to study plaque psoriasis, which typically does not involve symptoms of systemic disease. In this model, neutrophil recruitment to the skin is dependent upon the inflammatory mediators IL-1, via its receptor IL-1R1, and IL-36α. Unexpectedly, we observed that mice also exhibited signs of anorexia (weight loss and decreased food intake), general malaise (decreased activity and loss of interest in building nests), and pain (nose bulging and hunched posture). A scoring system allowing quantitative comparisons of test groups was developed. Female mice were found to develop more severe disease than male mice. Furthermore, mice deficient in both IL-1R1 and IL-36α are nearly disease-free, while mice lacking only one of these inflammatory mediators have less severe disease than wild type mice. Hence, the imiquimod-induced skin inflammation mouse model recapitulates not only plaque psoriasis, but also the more severe symptoms, that is, anorexia, malaise, and pain, seen in GPP.
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Inflammation and glucose homeostasis are associated with specific structural features among adults without knee osteoarthritis: a cross-sectional study from the osteoarthritis initiativeBackground: Greater age and body mass index are strong risk factors for osteoarthritis (OA). Older and overweight individuals may be more susceptible to OA because these factors alter tissue turnover in menisci, articular cartilage, and bone via altered glucose homeostasis and inflammation. Understanding the role of inflammation and glucose homeostasis on structural features of early-stage OA may help identify therapeutic targets to delay or prevent the onset of OA among subsets of adults with these features. We examined if serum concentrations of glucose homeostasis (glucose, glycated serum protein [GSP]) or inflammation (C-reactive protein [CRP]) were associated with prevalent knee bone marrow lesions (BMLs) or effusion among adults without knee OA. Methods: We conducted a cross-sectional study using baseline data from the Osteoarthritis Initiative. We selected participants who had no radiographic knee OA but were at high risk for knee OA. Blinded staff conducted assays for CRP, GSP, and glucose. Readers segmented BML volume and effusion using semi-automated programs. Our outcomes were prevalent BML (knee with a BML volume > 1 cm3) and effusion (knee with an effusion volume > 7.5 cm3). We used logistic regression models with CRP, GSP, or glucose concentrations as the predictors. We adjusted for age, sex, body mass index (BMI), and Physical Activity Scale for the Elderly (PASE) scores. Results: We included 343 participants: mean age = 59 ± 9 years, BMI = 27.9 ± 4.5 kg/m2, PASE score = 171 ± 82, and 64% female. Only CRP was associated with BML prevalence (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.09 to 1.87). For effusion, we found an interaction between BMI and CRP: only among adults with a BMI <25 kg/m2 was there a significant trend towards a positive association between CRP and effusion (OR = 1.40, 95% CI = 1.00 to 1.97). We detected a U-shaped relationship between GSP and effusion prevalence. Fasting glucose levels were not significantly associated with the presence of baseline effusion or BML. Conclusions: Among individuals without knee OA, CRP may be related to the presence of BMLs and effusion among normal weight individuals. Abnormal GSP may be associated with effusion. Future studies should explore whether inflammation and glucose homeostasis are predictive of symptomatic knee OA.
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17β-Estradiol regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female miceHistone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17β-estradiol (E2) to enhance object recognition memory consolidation requires histone H3 acetylation in the dorsal hippocampus. However, the extent to which histone acetylation is regulated by E2 in middle-aged females is unknown. The mnemonic benefits of E2 in aging females appear to be greatest in middle age, and so pinpointing the molecular mechanisms through which E2 enhances memory at this age could lead to the development of safer and more effective treatments for maintaining memory function without the side effects of current therapies. Here, we show that dorsal hippocampal infusion of E2 rapidly enhanced object recognition and spatial memory, and increased histone H3 acetylation in the dorsal hippocampus, while also significantly reducing levels of histone deacetylase (HDAC2 and HDAC3) proteins. E2 specifically increased histone H3 acetylation at Bdnf promoters pII and pIV in the dorsal hippocampus of both young and middle-aged mice, despite age-related decreases in pI and pIV acetylation. Furthermore, levels of mature BDNF and pro-BDNF proteins in the dorsal hippocampus were increased by E2 in middle-aged females. Together, these data suggest that the middle-aged female dorsal hippocampus remains epigenetically responsive to E2, and that E2 may enhance memory in middle-aged females via epigenetic regulation of Bdnf.
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Investigating undergraduate students’ ideas about the curvature of the UniverseAs part of a larger project studying undergraduate students’ understanding of cosmology, we explored students’ ideas about the curvature of the Universe. We investigated preinstruction ideas held by introductory astronomy (ASTRO 101) students at three participating universities and postinstruction ideas at one. Through thematic analysis of responses to questions on three survey forms and preinstruction interviews, we found that prior to instruction a significant fraction of students said the Universe is round. Students’ reasoning for this included that the Universe contains round objects, therefore it must also be round, or an incorrect idea that the big bang theory describes an explosion from a central point. We also found that a majority of students think that astronomers use the term curvature to describe properties, such as dimensions, angles, or size, of the Universe or objects in the Universe, or that astronomers use the term curvature to describe the bending of space due to gravity. Students are skeptical that the curvature of the Universe can be measured, to a greater or lesser degree depending on question framing. Postinstruction responses to a multiple-choice exam question and interviews at one university indicate that students are more likely to correctly respond that the Universe as a whole is not curved postinstruction, though the idea that the Universe is round still persists for some students. While we see no evidence that priming with an elliptical or rectangular map of the cosmic microwave background on a postinstruction exam affects responses, students do cite visualizations such as diagrams among the reasons for their responses in preinstruction surveys.
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Scorpion-inspired Needle Design for Insertion in Soft Tissue MaterialsThe goal of this project is to develop a bioinspired biopsy needle that takes inspiration from the structure of a scorpion stinger to reduce tissue damage and limit the needle path deflection for more accurate results. Our scorpion-inspired needle showed an 8.38% reduction in force, 29.37% reduction in tissue damage, and a 19.64% reduction in deflection in comparison to the standard biopsy needle used today.
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Get Help Finding a Digital Copy: A pandemic response becomes the new normalOur large, urban research university serves a sizeable, diverse community and is open to all. Library building closures in the early stages of the pandemic challenged us to maintain a comparable degree of openness and access virtually. We saw an opportunity to enhance our virtual reference services and keep the library "open" even when our buildings were closed. Since access to our physical collections was suddenly cut off, we established a new Get Help Finding a Digital Copy service that connected patrons to librarians working from home who could help them find digital copies of inaccessible physical items. Our crisis response became part of our permanent virtual reference services and ultimately improved the user experience of our library catalog. This poster will describe the service and present data illustrating how we meet patron needs and keep staff-patron relationships engaged during times of potential disconnection and disengagement. Learning Outcomes: Participants will learn how to enhance traditional email reference services by adding a focus on finding digital copies of inaccessible or inconveniently accessible physical materials. Participants will identify ways of deploying virtual reference technologies already in use at many libraries to facilitate access to their resources, even when buildings are closed, or patrons and staff are at a distance. Participants will learn techniques for helping virtual reference staff adapt to increased request volume and remote work conditions.
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The Rural Opioid Initiative Consortium description: providing evidence to Understand the Fourth Wave of the Opioid CrisisObjective: To characterize and address the opioid crisis disproportionately impacting rural U.S. regions. Methods: The Rural Opioid Initiative (ROI) is a two-phase project to collect and harmonize quantitative and qualitative data and develop tailored interventions to address rural opioid use. The baseline quantitative survey data from people who use drugs (PWUD) characterizes the current opioid epidemic (2018–2020) in eight geographically diverse regions. Results: Among 3,084 PWUD, 92% reported ever injecting drugs, 86% reported using opioids (most often heroin) and 74% reported using methamphetamine to get high in the past 30 days; 53% experienced homelessness in the prior 6 months; and 49% had ever overdosed. Syringe service program use varied by region and 53% had ever received an overdose kit or naloxone prescription. Less than half (48%) ever received medication for opioid use disorder (MOUD). Conclusions: The ROI combines data across eight rural regions to better understand drug use including drivers and potential interventions in rural areas with limited resources. Baseline ROI data demonstrate extensive overlap between opioid and methamphetamine use, high homelessness rates, inadequate access to MOUD, and other unmet needs among PWUD in the rural U.S. By combining data across studies, the ROI provides much greater statistical power to address research questions and better understand the syndemic of infectious diseases and drug use in rural settings including unmet treatment needs.
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Molecular Framework of Mouse Endothelial Cell Dysfunction during Inflammation: A Proteomics ApproachA key aspect of cytokine-induced changes as observed in sepsis is the dysregulated activation of endothelial cells (ECs), initiating a cascade of inflammatory signaling leading to leukocyte adhesion/migration and organ damage. The therapeutic targeting of ECs has been hampered by concerns regarding organ-specific EC heterogeneity and their response to inflammation. Using in vitro and in silico analysis, we present a comprehensive analysis of the proteomic changes in mouse lung, liver and kidney ECs following exposure to a clinically relevant cocktail of proinflammatory cytokines. Mouse lung, liver and kidney ECs were incubated with TNF-α/IL-1β/IFN-γ for 4 or 24 h to model the cytokine-induced changes. Quantitative label-free global proteomics and bioinformatic analysis performed on the ECs provide a molecular framework for the EC response to inflammatory stimuli over time and organ-specific differences. Gene Ontology and PANTHER analysis suggest why some organs are more susceptible to inflammation early on, and show that, as inflammation progresses, some protein expression patterns become more uniform while additional organ-specific proteins are expressed. These findings provide an in-depth understanding of the molecular changes involved in the EC response to inflammation and can support the development of drugs targeting ECs within different organs. Data are available via ProteomeXchange (identifier PXD031804).
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Editorial: Insights in cardiovascular therapeutics: 2021 – cell death, cardiovascular injuries, and novel targets of cardiovascular therapeuticsWith the effort and support of the authors, editorial office, and editorial team, the Frontiers in Cardiovascular Medicine, Cardiovascular Therapeutics Section-Research Topic “Insights in Cardiovascular Therapeutics: 2021” has achieved great success and is attracting interest from the cardiovascular community. Here, we spotlight 12 studies published in our section that related to cell death and cardiovascular injuries, as well as some recent advances in the field that have tremendous potential in cardiovascular therapy. In addition, these highlights may serve as the foundation for some new developments in our Cardiovascular Therapeutics areas. In 2022, we will keep working to create a fantastic platform for cardiologists, translational cardiovascular scientists, and cardiovascular pharmacological scientists to share new results and data in clinical cardiology and translational cardiovascular therapeutics.
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Predictive Factors of Research Productivity among Ophthalmology Residents: A Benchmark AnalysisIntroduction: Positive and negative associations between prior publications and future research productivity is described in other fields, but no such analysis exists for ophthalmology. We conducted a study to determine characteristics of residents exhibiting research productivity during residency. Methods: Using San Francisco Match and Program Web sites, a roster of ophthalmology residents in 2019 to 2020 was compiled, and publication data was collected via PubMed and Google Scholar on a random sample of 100 third-year residents. Results: The median number of publications generated by ophthalmology residents before residency is 2 (range 0–13). Thirty-seven, 23, and 40 residents had zero, one, and two or more papers published during residency, respectively, with a median of 1 (range 0–14). On univariate analysis, compared with residents who published zero or one paper, those who published ≥ 2 were more likely to have more preresidency publications (odds ratio [OR] 1.30; p = 0.005), attend a top-25 ranked residency program by multiple metrics including Doximity reputation (OR 4.92; p < 0.001), and have attended a top-25 ranked medical school program by U.S. News and World Report (OR 3.24; p = 0.03). However, on adjusted analyses, the only factor that remained significant for predicting publications in residency was whether the residency program attended was top 25 ranked (OR 3.54; p = 0.009). Discussion/Conclusion: With the advent of the United States Medical Licensing Examination Step 1 pass/fail system, greater emphasis will be placed on other metrics, including research. This is the first benchmark analysis examining factors predictive of publication productivity in ophthalmology residents. Our study suggests that the residency program attended, not the medical school attended or prior publication history, plays an influential role in the number of publications produced during residency, highlighting the importance of factors to support research on the institutional level, such as mentorship and funding, rather than historical factors in research productivity by the resident.
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Management of Decompensated Cirrhosis in the Surgical ICU: an American Association for the Surgery of Trauma Critical Care Committee Clinical Consensus DocumentManagement of decompensated cirrhosis (DC) can be challenging for the surgical intensivist. Management of DC is often complicated by ascites, coagulopathy, hepatic encephalopathy, gastrointestinal bleeding, hepatorenal syndrome, and difficulty assessing volume status. This Clinical Consensus Document created by the American Association for the Surgery of Trauma Critical Care Committee reviews practical clinical questions about the critical care management of patients with DC to facilitate best practices by the bedside provider.