• An evaluation of the coverage of theoretically based implementation factors in disseminated classroom physical activity programs

      Calvert, Hannah G; Lane, Hannah G; Bejarano, Carolina M; Snow, Kelli; Hoppe, Kate; Alfonsin, Nicole; Turner, Lindsey; Carlson, Jordan A (Oxford University Press, 2018-12-26)
      Classroom-based physical activity (CBPA) is increasingly recommended as a method to support children's physical activity, health, and academic performance. Many adoption-ready programs exist to aid in the implementation of CBPA in schools; yet, implementation rates remain low. The purpose of this study was to evaluate the extent to which resources provided by adoption-ready CBPA programs addressed theory-based implementation contextual factors to support implementation. Existing CBPA programs (N = 37) were identified through Internet searches and all materials (e.g., implementation guides) provided by each program were coded for their inclusion of 51 implementation factors based on the Consolidated Framework for Implementation Research (CFIR). Analyses were conducted to compare inclusion of implementation factors across CFIR Domains and by three program groupings: free (yes/no), research evidence (yes/no), and targeted to teacher only (vs. school). Programs covered a mean of 25.9 per cent (SD = 18.7 per cent) of the 14 Inner Setting implementation factors, 34.2 per cent (SD = 18.0 per cent) of the 6 Characteristics of Individuals implementation factors, and 34.8 per cent (SD = 24.3 per cent) of the 8 Process implementation factors. Programs with research evidence covered more implementation factors than programs without research evidence (43.7 vs. 25.9 per cent; p < .05). Although numerous adoption-ready CBPA programs are available and have many strengths, their inclusion of theory-based factors that support or inhibit implementation is generally low. Consideration of such factors, including organizational climate and teacher-level behavior change, is likely critical to supporting ongoing school-wide implementation of CBPA. Research is needed to develop and test effective strategies for addressing these factors to support more widespread CBPA implementation. © The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.
    • Estimating the incidence of influenza at the state level - Utah, 2016-17 and 2017-18 influenza seasons

      Hughes, M.M.; Carmack, A.E.; McCaffrey, K. (Department of Health and Human Services, 2019)
      What is already known about this topic? Influenza activity can vary widely based on geographic location, and national data on the numbers of persons affected by influenza do not reflect this potential variation. What is added by this report? Application of national methods to estimate the burden of influenza at the state level found that influenza affected 9% and 11% of Utah residents during the 2016-17 and 2017-18 influenza seasons, respectively. What are the implications for public health practice? Local estimation of influenza disease burden can help public health officials, policymakers, and clinicians tailor influenza messaging, planning, and responses for their jurisdictions. State and county health departments might consider adapting these methods to their jurisdictions in future influenza seasons.
    • Contemporary utilization of zone III REBOA for temporary control of pelvic and lower junctional hemorrhage reliably achieves hemodynamic stability in severely injured patients

      Pasley, Jason D.; Brenner, Megan; Pasley, Amelia; Moore, Laura J.; Scalea, Thomas M.; Dubose, Joseph (Orebro University Hospital, 2019-04-25)
      Background: Aortic occlusion is a valuable adjunct for the management of traumatic pelvic and lower extremity junctional hemorrhage. Methods: The American Association for the Surgery of Trauma Aortic Occlusion in Resuscitation for Trauma and Acute Care Surgery registry was reviewed for patients requiring Zone III resuscitative endovascular balloon occlusion of the aorta (REBOA) from eight verified trauma centers. After excluding patients in arrest, demographics, elements of treatment, and outcomes were identified. Results: From November 2013 to December 2016, 30 patients had Zone III REBOA placed. Median age was 41.0 (interquartile range, IQR, 38); median injury severity score was 41.0 (IQR 12). Hypotension (SBP < 90 mm Hg) was present on admission in 30.0% and tachycardia (HR > 100 bpm) in 66.7%. Before REBOA placement, vital signs changed in this cohort with hypotension in 83.3% and tachycardia noted in 90%. Median initial pH was 7.14 (IQR 0.22), and median admission lactate 9.9 mg/dL (IQR 5). Pelvic binders were utilized in 40%. Occlusion balloon devices included Coda™ (70%), ER REBOA™ (13.3%), Reliant™ (10%). After REBOA, hemodynamics improved in 96.7% and stability (BP consistently > 90 mm Hg) was achieved in 86.7%. Median duration of REBOA was 53.0 mins (IQR 112). Median PRBC and FFP requirements were 19.0 units (IQR (17) and 17.0 units (IQR 14), respectively. One amputation unrelated to REBOA utilization was required. Systemic complications included AKI (23.3%) and MODS (10%). REBOA specific complications included groin hematoma (3.3%) and distal thromboembolization (16.7%). Survival to discharge was 56.7%, with in-hospital deaths occurring in the ED 7.7%, OR 23.1%, ICU 69.2%. Conclusions: This review discusses the specifics of the contemporary use of Zone III REBOA placement as well as local and systemic complications for patients in extremis with pelvic/junctional hemorrhage. Further review is required to determine optimal patient selection.
    • Clinical Evaluations Have Low Sensitivity for Identifying Preterm Infants in a Clinical Trial in a Limited Resource Setting.

      Buchwald, Andrea G; Teguete, Ibrahima; Doumbia, Moussa; Haidara, Fadima C; Coulibaly, Flanon; Diallo, Fatoumata; Sow, Samba O; Blackwelder, William C; Tapia, Milagritos D (SAGE Publications Inc., 2019-06-25)
      Preterm birth is a primary outcome of interest in maternal vaccination trials but determination of gestational age is challenging in limited-resource settings. This study compares the New Ballard Score and fundal height measurements with the current standard of early ultrasound for sensitivity of predicting preterm birth. A trial of maternal influenza vaccination was conducted in Bamako, Mali. The New Ballard Score and fundal height were collected on 4038 infants born in the trial, ultrasound data were available for 1893 of those infants. New Ballard Score and fundal height were compared, consecutively, to all ultrasound results, early ultrasound results from the first trimester, and the date of last menstrual period for estimation of gestational age. Sensitivity of the New Ballard Score for identifying preterm infants was 0.33 compared with early ultrasound and 0.1 compared with the last menstrual period based estimates of gestational age. Sensitivity of low birth weight alone was 0.43 compared with early ultrasound. New Ballard Score estimated gestational age within 1 week of ultrasound more frequently than fundal height (53% compared with 7.6%, respectively) yet New Ballard Score identified few infants as preterm (1.8% vs 5.8% by early ultrasound), and was biased toward categorizing low birth weight infants and infants requiring hospitalization as preterm. New Ballard Score is not an ideal measure for identifying preterm births in low-resource settings. Despite the time and cost of training required for correct measurement of New Ballard Score, measurement of low birth weight alone performed better than New Ballard Score for identifying preterm infants.
    • Targeting HIV/SIV infection of CD4+ T follicular helper (Tfh) Cells: BCL6 inhibition represses HIV infection CD4+ T cells and reduces germinal center hyperplasia in rhesus macaque

      Cai, Y.; Abdel-Mohsen, M.; Watkins, M.; Xue, F.; Ai, Y.; Cheng, H.; Midkiff, C.; Tomescu, C.; Wang, X.; Alvarez, X.; et al. (Mediscript Ltd, 2019-07-01)
    • Bed Sharing in Toddlerhood: Choice Versus Necessity and Provider Guidelines.

      Covington, Lauren B; Armstrong, Bridget; Black, Maureen M (SAGE Publications Inc., 2019-07-24)
    • First-Year Outcomes of Critical Congenital Heart Disease Screening in Maryland.

      Badawi, Deborah; Watson, Johnna; Maschke, Steven; Reid, Lawrence (SAGE Publications Inc., 2019-08-18)
      Objectives. Newborn screening for critical congenital heart disease (CCHD) was added to the Recommended Uniform Screening Panel in 2011, and states have been gradually adding pulse oximetry as point-of-care screening to panels. Few data are available on the effectiveness of pulse oximetry as a mandated screening. This study describes outcomes of the first year of screening in Maryland. Methods. A web-based data collection tool for screening results and outcomes, eScreener Plus, was utilized. Data collected from the start of screening from September 1, 2012, to December 31, 2013, were analyzed. Well-baby nursery data were evaluated separately from neonatal intensive care unit (NICU) data to determine whether setting influenced effectiveness. Results. In the first 15 months of newborn screening for CCHD in Maryland, 4 asymptomatic infants were diagnosed with a critical cardiac condition by newborn screening. Eleven infants passed but were later identified with a primary or secondary target condition. Seventy-one percent of infants with CCHD were identified prenatally or by clinical signs and symptoms. Pulse oximetry screening for CCHD had a specificity of more than 99% in both the well-baby nursery and the NICU. Sensitivity in the well-baby nursery was 10% and 60% in the NICU. Conclusion. Further investigation and interpretation of specific protocols that were used and outcomes of screening is needed for continued refinement of the well-baby algorithm and NICU protocol development. Pulse oximetry screening in newborns provides valuable clinical information, but many infants with CCHD are still not identified with current protocols.
    • Reporting of Drug Benefit in FDA-Approved Prescription Drug Labeling.

      Desai, Bansri; Hong, Kyungwan; Powers, John H; Doshi, Peter (Springer Nature, 2019-10-28)
    • Treatment with One Dose of Reltecimod is Superior to Two Doses in Mouse Models of Lethal Infection

      Edgar, Rotem; Tarrio, Margarite L.; Maislin, Greg; Chiguang, Feng; Kaempfer, Raymond; Cross, Alan; Opal, Steven M.; Shirvan, Anat (Springer Science and Business Media LLC, 2019-11-12)
      Soft-tissue bacterial infection can progress to severe sepsis and septic shock as a result of a disproportionate infammatory response, characterized by an excessive release of cytokines and infux of immune cells. Reltecimod (previously known as AB103 or p2TA), a peptide derived from the T-cell receptor CD28, modulates the host immune response by targeting the co-stimulatory pathway, which is essential for the induction of multiple pro-infammatory cytokines. Consequently, reltecimod has demonstrated benefcial efects against diferent bacterial infections, their exotoxins and endotoxins, and ionizing radiation. The dosing regimen of reltecimod was evaluated in three mouse models of infection. The efect of the number of reltecimod doses with respect to survival, cytokine/chemokine levels, and blood leukocyte profles was assessed. Overall, mice treated with a single intravenous dose of reltecimod (5 mg/kg) at 1–2 h after infection showed signifcantly greater survival as compared with saline-treated controls. Mice treated with a second doses demonstrated improved survival compared with saline-treated controls. However, in all models of infection, administration of a single therapeutic dose of reltecimod was superior to two or multiple doses. Further examination showed that the single therapeutic dose of reltecimod was associated with an early (within 24 h) decrease in cytokine/chemokine levels and most circulating leukocyte subpopulations. A second dose of reltecimod did not improve these early positive efects and appeared to attenuate further changes. These results provided insight into the mechanism of action of reltecimod and established a basis for the dosing regimen utilized in clinical trials, where reltecimod is administered as a single dose.
    • The Envelope Residues E152/156/158 of Zika Virus Influence the Early Stages of Virus Infection in Human Cells

      Bos, Sandra; Viranaicken, Wildriss; Frumence, Etienne; Li, Ge; Desprès, Philippe; Zhao, Richard Y.; Gadea, Gilles (MDPI AG, 2019-11-15)
      Emerging infections of mosquito-borne Zika virus (ZIKV) pose an increasing threat to human health, as documented over the recent years in South Pacific islands and the Americas in recent years. To better understand molecular mechanisms underlying the increase in human cases with severe pathologies, we recently demonstrated the functional roles of structural proteins capsid (C), pre-membrane (prM), and envelop (E) of ZIKV epidemic strains with the initiation of viral infection in human cells. Specifically, we found that the C-prM region contributes to permissiveness of human host cells to ZIKV infection and ZIKV-induced cytopathic effects, whereas the E protein is associated with viral attachment and early infection. In the present study, we further characterize ZIKV E proteins by investigating the roles of residues isoleucine 152 (Ile152), threonine 156 (Thr156), and histidine 158 (His158) (i.e., the E-152/156/158 residues), which surround a unique N-glycosylation site (E-154), in permissiveness of human host cells to epidemic ZIKV infection. For comparison purpose, we generated mutant molecular clones of epidemic BeH819015 (BR15) and historical MR766-NIID (MR766) strains that carry each other's E-152/156/158 residues, respectively. We observed that the BR15 mutant containing the E-152/156/158 residues from MR766 was less infectious in A549-Dual™ cells than parental virus. In contrast, the MR766 mutant containing E-152/156/158 residues from BR15 displayed increased infectivity. The observed differences in infectivity were, however, not correlated with changes in viral binding onto host-cells or cellular responses to viral infection. Instead, the E-152/156/158 residues from BR15 were associated with an increased efficiency of viral membrane fusion inside infected cells due to conformational changes of E protein that enhance exposure of the fusion loop. Our data highlight an important contribution of E-152/156/158 residues to the early steps of ZIKV infection in human cells.
    • ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype

      Portney, B.A.; Arad, M.; Gupta, A.; Brown, R.A.; Khatri, R.; Lin, P.N.; Hebert, A.M.; Angster, K.H.; Silipino, L.E.; Meltzer, W.A.; et al. (Springer Nature, 2020)
      Cancer stem cells (CSCs) are cells within tumors that maintain the ability to self-renew, drive tumor growth, and contribute to therapeutic resistance and cancer recurrence. In this study, we investigate the role of Zinc finger and SCAN domain containing 4 (ZSCAN4) in human head and neck squamous cell carcinoma (HNSCC). The murine Zscan4 is involved in telomere maintenance and genomic stability of mouse embryonic stem cells. Our data indicate that the human ZSCAN4 is enriched for, marks and is co-expressed with CSC markers in HNSCC. We show that transient ZSCAN4 induction for just 2 days increases CSC frequency both in vitro and in vivo and leads to upregulation of pluripotency and CSC factors. Importantly, we define for the first time the role of ZSCAN4 in altering the epigenetic profile and regulating the chromatin state. Our data show that ZSCAN4 leads to a functional histone 3 hyperacetylation at the promoters of OCT3/4 and NANOG, leading to an upregulation of CSC factors. Consistently, ZSCAN4 depletion leads to downregulation of CSC markers, decreased ability to form tumorspheres and severely affects tumor growth. Our study suggests that ZSCAN4 plays an important role in the maintenance of the CSC phenotype, indicating it is a potential therapeutic target in HNSCC. Copyright 2020, The Author(s).
    • Histone demethylase JMJD1A promotes expression of DNA repair factors and radio-resistance of prostate cancer cells

      Fan, L.; Xu, S.; Zhang, F.; Cui, X.; Clark, D.J.; Yang, A.; Hussain, A.; Rassool, F.; Qi, J. (Springer Nature, 2020)
      The DNA damage response (DDR) pathway is a promising target for anticancer therapies. The androgen receptor and myeloblastosis transcription factors have been reported to regulate expression of an overlapping set of DDR genes in prostate cancer cells. Here, we found that histone demethylase JMJD1A regulates expression of a different set of DDR genes largely through c-Myc. Inhibition of JMJD1A delayed the resolution of γ-H2AX foci, reduced the formation of foci containing ubiquitin, 53BP1, BRCA1 or Rad51, and inhibited the reporter activity of double-strand break (DSB) repair. Mechanistically, JMJD1A regulated expression of DDR genes by increasing not only the level but also the chromatin recruitment of c-Myc through H3K9 demethylation. Further, we found that ubiquitin ligase HUWE1 induced the K27-/K29-linked noncanonical ubiquitination of JMJD1A at lysine-918. Ablation of the JMJD1A noncanonical ubiquitination lowered DDR gene expression, impaired DSB repair, and sensitized response of prostate cells to irradiation, topoisomerase inhibitors or PARP inhibitors. Thus, development of agents that target JMJD1A or its noncanonical ubiquitination may sensitize the response of prostate cancer to radiotherapy and possibly also genotoxic therapy. Copyright 2020, The Author(s).
    • Re-annotation of the Theileria parva genome refines 53% of the proteome and uncovers essential components of N-glycosylation, a conserved pathway in many organisms

      Tretina, K.; Pelle, R.; Silva, J.C. (Springer Nature, 2020)
      BACKGROUND: The apicomplexan parasite Theileria parva causes a livestock disease called East coast fever (ECF), with millions of animals at risk in sub-Saharan East and Southern Africa, the geographic distribution of T. parva. Over a million bovines die each year of ECF, with a tremendous economic burden to pastoralists in endemic countries. Comprehensive, accurate parasite genome annotation can facilitate the discovery of novel chemotherapeutic targets for disease treatment, as well as elucidate the biology of the parasite. However, genome annotation remains a significant challenge because of limitations in the quality and quantity of the data being used to inform the location and function of protein-coding genes and, when RNA data are used, the underlying biological complexity of the processes involved in gene expression. Here, we apply our recently published RNAseq dataset derived from the schizont life-cycle stage of T. parva to update structural and functional gene annotations across the entire nuclear genome. RESULTS: The re-annotation effort lead to evidence-supported updates in over half of all protein-coding sequence (CDS) predictions, including exon changes, gene merges and gene splitting, an increase in average CDS length of approximately 50 base pairs, and the identification of 128 new genes. Among the new genes identified were those involved in N-glycosylation, a process previously thought not to exist in this organism and a potentially new chemotherapeutic target pathway for treating ECF. Alternatively-spliced genes were identified, and antisense and multi-gene family transcription were extensively characterized. CONCLUSIONS: The process of re-annotation led to novel insights into the organization and expression profiles of protein-coding sequences in this parasite, and uncovered a minimal N-glycosylation pathway that changes our current understanding of the evolution of this post-translational modification in apicomplexan parasites.
    • Attitudes and Perceptions Toward Authorized Deception: A Pilot Comparison of Healthy Controls and Fibromyalgia Patients

      Goo, S.J.; Frangos, E.; Colloca, L. (Oxford University Press, 2020)
      Objective: Little is known about the perceptions and attitudes of participants who volunteer in studies involving authorized deception. Thus, this cross-sectional pilot study measured, for the first time, the perceptions about participation in an authorized-deception placebo analgesia study in chronic pain patients with fibromyalgia and assessed whether their perceptions differed from healthy controls. Methods: An anonymous survey with questions about trust in research and willingness to participate in future research involving deception was mailed to participants in both groups after completion of the parent study. Statistical analyses were performed using the Mann-Whitney U and chi-square tests (31 controls and 16 fibromyalgia patients were included in the analyses). Results: The majority of participants expressed little or no concern about the deception, still trusted the scientific process, and found the debriefing procedure helpful and worthwhile. Group differences were found in willingness to 1) participate in the parent study had the deceptive element been disclosed in advance (controls = definitely, fibromyalgia patients = probably, U = 341.5, P = 0.01) and 2) participate in future studies (controls = definitely, fibromyalgia patients = probably, U = 373, P < 0.001). Conclusions: Despite slightly less favorable responses of fibromyalgia patients and the relatively small size of the study, these findings suggest that attitudes and perceptions about participating in an authorized placebo study remain positive in both healthy and chronic pain populations.
    • Review of Emerging Pharmacotherapy for the Treatment of Coronavirus Disease 2019

      Barlow, A.; Landolf, K.M.; Yeung, S.Y.A.; Heavner, J.J.; Claassen, C.W.; Heavner, M.S. (Wiley-Blackwell, 2020)
      The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID‐19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit (ICU) admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacological management of patients with COVID‐19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immune modulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS‐CoV‐2. Critically ill patients with COVID‐19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID‐19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.
    • National Institutes of Health (NIH) grant awards: does past performance predict future success?

      Prasad, J.M.; Shipley, M.T.; Rogers, T.B.; Puche, A.C. (Palgrave Macmillan Ltd., 2020)
      The NIH is the major federal biomedical research funding agency within the United States, and NIH funding has become a priority in institutional decisions on faculty recruitment, salary, promotion, and tenure. The implicit assumption is that well-funded investigators will maintain their funding success; however, our analysis of NIH awardees from 2000 to 2015 suggests that regardless of how well funded an investigator is, their research portfolio exhibits "regression to the mean," matching the typical NIH funding profile within just 10-15 years. Thus, outperformance in past funding is not a strong predictor of future outperformance in funding success. This study indicates that faculty performance should not be solely judged upon grant success but should include other institutional mission priorities such as provision of clinical care, education, and service to community/profession. Copyright 2020, The Author(s).
    • Cost Analysis of Treating Pediatric Supracondylar Humerus Fractures in Community Hospitals Compared With a Tertiary Care Hospital

      Shasti, M.; Li, T.P.; Case, A.L.; Hariharan, A.R.; Jauregui, J.J.; Abzug, J.M. (Wolters Kluwer Health, 2020)
      OBJECTIVE: In the current healthcare environment, providing cost-efficient care is of paramount importance. One emerging strategy is to use community hospitals (CHs) rather than tertiary care hospitals (TCHs) for some procedures. This study assesses the costs of performing closed reduction percutaneous pinning (CRPP) of pediatric supracondylar humerus fractures (SCHFs) at a CH compared with a TCH. METHODS: A retrospective review of 133 consecutive SCHFs treated with CRPP at a CH versus a TCH over a 6-year period was performed. Total encounter and subcategorized costs were compared between the procedures done at a CH versus those done at a TCH. RESULTS: Performing CRPP for a SCHF at a CH compared with a TCH saved 44% in costs (P < 0.001). Cost reduction of 51% was attributable to operating room costs, 19% to anesthesia-related costs, 16% to imaging-related costs, and 7% to supplies. DISCUSSION: Performing CRPP for a SCHF at a CH compared with a TCH results in a 44% decrease in direct cost, driven largely by surgical, anesthesia, and radiology-related savings.
    • Detecting geospatial patterns of Plasmodium falciparum parasite migration in Cambodia using optimized estimated effective migration surfaces

      Shetty, A.C.; O'Connor, T.D.; Takala-Harrison, S. (BioMed Central Ltd., 2020)
      Background: Understanding the genetic structure of natural populations provides insight into the demographic and adaptive processes that have affected those populations. Such information, particularly when integrated with geospatial data, can have translational applications for a variety of fields, including public health. Estimated effective migration surfaces (EEMS) is an approach that allows visualization of the spatial patterns in genomic data to understand population structure and migration. In this study, we developed a workflow to optimize the resolution of spatial grids used to generate EEMS migration maps and applied this optimized workflow to estimate migration of Plasmodium falciparum in Cambodia and bordering regions of Thailand and Vietnam. Methods: The optimal density of EEMS grids was determined based on a new workflow created using density clustering to define genomic clusters and the spatial distance between genomic clusters. Topological skeletons were used to capture the spatial distribution for each genomic cluster and to determine the EEMS grid density; i.e., both genomic and spatial clustering were used to guide the optimization of EEMS grids. Model accuracy for migration estimates using the optimized workflow was tested and compared to grid resolutions selected without the optimized workflow. As a test case, the optimized workflow was applied to genomic data generated from P. falciparum sampled in Cambodia and bordering regions, and migration maps were compared to estimates of malaria endemicity, as well as geographic properties of the study area, as a means of validating observed migration patterns. Results: Optimized grids displayed both high model accuracy and reduced computing time compared to grid densities selected in an unguided manner. In addition, EEMS migration maps generated for P. falciparum using the optimized grid corresponded to estimates of malaria endemicity and geographic properties of the study region that might be expected to impact malaria parasite migration, supporting the validity of the observed migration patterns. Conclusions: Optimized grids reduce spatial uncertainty in the EEMS contours that can result from user-defined parameters, such as the resolution of the spatial grid used in the model. This workflow will be useful to a broad range of EEMS users as it can be applied to analyses involving other organisms of interest and geographic areas. Copyright 2020 The Author(s).
    • Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy

      Wang, L.; Xu, M.; Bryant, J.L. (BioMed Central Ltd., 2020)
      Background: In the past 30 years, incidences of non-alcoholic fatty liver disease (NAFLD) has risen by 30%. However, there is still no clear mechanism or accurate method of anticipating liver failure. Here we reveal the phase transitions of liquid crystalline qualities in hepatic lipid droplets (HLDs) as a novel method of anticipating prognosis. Methods: NAFLD was induced by feeding C57BL/6J mice on a high-fat (HiF) diet. These NAFLD livers were then evaluated under polarized microscopy, X-ray diffraction and small-angle scattering, lipid component chromatography analysis and protein expression analysis. Optically active HLDs from mouse model and patient samples were both then confirmed to have liquid crystal characteristics. Liver MAP1LC3A expression was then evaluated to determine the role of autophagy in liquid crystal HLD (LC-HLD) formation. Results: Unlike the normal diet cohort, HiF diet mice developed NAFLD livers containing HLDs exhibiting Maltese cross birefringence, phase transition, and fluidity signature to liquid crystals. These LC-HLDs transitioned to anisotropic crystal at 0 °C and remain crystalline. Temperature increase to 42 °C causes both liquid crystal and crystal HLDs to convert to isotropic droplet form. These isotropic HLDs successfully transition to anisotropic LC with fast temperature decrease and anisotropic crystal with slow temperature decrease. These findings were duplicated in patient liver. Patient LC-HLDs with no inner optical activity were discovered, hinting at lipid saturation as the mechanism through which HLD acquire LC characteristics. Downregulation of MAP1LC3A in conjunction with increased LC-HLD also implicated autophagy in NAFLD LC-HLD formation. Conclusions: Increasing concentrations of amphiphilic lipids in HLDs favors organization into alternating hydrophilic and hydrophobic layers, which present as LC-HLDs. Thus, evaluating the extent of liquid crystallization with phase transition in HLDs of NAFLD patients may reveal disease severity and predict impending liver damage. Copyright 2020 The Author(s).
    • COVID-19 and the RAAS-a potential role for angiotensin II?

      Busse, L.W.; Chow, J.H.; McCurdy, M.T. (Springer Nature, 2020)