Publications by authors named "Amy Lee"

431 Publications

Threat-specific maltreatment exposure: Comparison of measurement models and associations with internalizing, externalizing, and PTSD symptoms.

Child Abuse Negl 2021 Feb 24;115:105010. Epub 2021 Feb 24.

Child HELP Partnership, St. John's University, United States.

Background: Child maltreatment is associated with short- and long-term mental health sequelae. Extant research has demonstrated that exposure characteristics (i.e., severity, frequency, duration, onset) are important in the measurement of maltreatment experiences. Emerging research has highlighted the contributions of these characteristics on symptom outcomes.

Objective: The current study used multiple exposure characteristics of threat-specific types of maltreatment (i.e., physical abuse, sexual abuse, witnessing domestic violence) to examine three distinct measurement models of maltreatment and their relation to symptoms.

Participants And Setting: A racially and ethnically diverse sample of treatment-seeking youth (74 % female) ages 4-17 (N = 348) participated in the study. The majority of the youth (61 %) endorsed experiencing more than one type of threat-specific maltreatment.

Method: Using Structural Equation Modeling, we tested one-factor, three-factor, and bifactor models of maltreatment characteristics, and hypothesized that the bifactor model would yield the best fitting model based on prior studies supporting family violence as an underlying factor for child physical abuse and domestic violence.

Results: The bifactor measurement model fit the data better than the three- and one-factor models. In the bifactor structural model that included symptom outcomes, physical abuse was significantly and positively associated with child internalizing and externalizing symptoms, whereas sexual abuse and witnessing domestic violence were associated with externalizing symptoms and PTSD.

Conclusion: Our findings support the inclusion of multiple exposure characteristics in the measurement of maltreatment and suggest that specific types of threat-specific maltreatment may have distinct associations with mental health sequelae.
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http://dx.doi.org/10.1016/j.chiabu.2021.105010DOI Listing
February 2021

Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1.

Nat Commun 2021 02 22;12(1):1222. Epub 2021 Feb 22.

Arbutus Biopharma Inc, Warminster, PA, USA.

Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.
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http://dx.doi.org/10.1038/s41467-021-21410-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900207PMC
February 2021

The Role of Vitamin B6 in Women's Health.

Authors:
Amy S D Lee

Nurs Clin North Am 2021 03 29;56(1):23-32. Epub 2020 Dec 29.

Capstone College of Nursing, University of Alabama, 650 University Boulevard East, Tuscaloosa, AL 35401, USA. Electronic address:

Vitamin B6, a cofactor in many biochemical reactions in the cells of living organisms, is an essential coenzyme for various catabolic and anabolic processes. Although vitamin B6 deficiency in young healthy women with a balanced diet is thought to be unusual, it can be seen with certain medications, health conditions, and dietary deficits, as well as aging. Vitamin B6 deficiency is associated with a variety of ill health effects, and correction of deficiency is considered beneficial. Women particularly are affected by unique health issues that are part of the array of disorders potentially alleviated through vitamin B6 supplementation.
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http://dx.doi.org/10.1016/j.cnur.2020.10.002DOI Listing
March 2021

The hydroxyquinoline analog YUM70 inhibits GRP78 to induce ER stress-mediated apoptosis in pancreatic cancer.

Cancer Res 2021 Feb 2. Epub 2021 Feb 2.

Medicinal Chemistry, University of Michigan–Ann Arbor

GRP78 (Glucose-regulated protein, 78 kDa) is a key regulator of ER (endoplasmic reticulum) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analog, YUM70, inhibited pancreatic cancer cell growth in vitro and showed in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues. YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress-mediated apoptosis. A YUM70 analog conjugated with BODIPY show co-localization of the compound with GRP78 in the ER. Moreover, a YUM70-PROTAC (PROteolysis TArgeting Chimera) was synthesized to force degradation of GRP78 in pancreatic cancer cells. YUM70 showed a strong synergistic cytotoxicity with topotecan and vorinostat. Together, our study demonstrates that YUM70 is a novel inducer of ER stress with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1540DOI Listing
February 2021

PRimary Care Opioid Use Disorders treatment (PROUD) trial protocol: a pragmatic, cluster-randomized implementation trial in primary care for opioid use disorder treatment.

Addict Sci Clin Pract 2021 01 31;16(1). Epub 2021 Jan 31.

Kaiser Permanente Washington Health Research Institute, 1730 Minor Avenue, Seattle, WA, 98101, USA.

Background: Most people with opioid use disorder (OUD) never receive treatment. Medication treatment of OUD in primary care is recommended as an approach to increase access to care. The PRimary Care Opioid Use Disorders treatment (PROUD) trial tests whether implementation of a collaborative care model (Massachusetts Model) using a nurse care manager (NCM) to support medication treatment of OUD in primary care increases OUD treatment and improves outcomes. Specifically, it tests whether implementation of collaborative care, compared to usual primary care, increases the number of days of medication for OUD (implementation objective) and reduces acute health care utilization (effectiveness objective). The protocol for the PROUD trial is presented here.

Methods: PROUD is a hybrid type III cluster-randomized implementation trial in six health care systems. The intervention consists of three implementation strategies: salary for a full-time NCM, training and technical assistance for the NCM, and requiring that three primary care providers have DEA waivers to prescribe buprenorphine. Within each health system, two primary care clinics are randomized: one to the intervention and one to Usual Primary Care. The sample includes all patients age 16-90 who visited the randomized primary care clinics from 3 years before to 2 years after randomization (anticipated to be > 170,000). Quantitative data are derived from existing health system administrative data, electronic medical records, and/or health insurance claims ("electronic health records," [EHRs]). Anonymous staff surveys, stakeholder debriefs, and observations from site visits, trainings and technical assistance provide qualitative data to assess barriers and facilitators to implementation. The outcome for the implementation objective (primary outcome) is a clinic-level measure of the number of patient days of medication treatment of OUD over the 2 years post-randomization. The patient-level outcome for the effectiveness objective (secondary outcome) is days of acute care utilization [e.g. urgent care, emergency department (ED) and/or hospitalizations] over 2 years post-randomization among patients with documented OUD prior to randomization.

Discussion: The PROUD trial provides information for clinical leaders and policy makers regarding potential benefits for patients and health systems of a collaborative care model for management of OUD in primary care, tested in real-world diverse primary care settings. Trial registration # NCT03407638 (February 28, 2018); CTN-0074 https://clinicaltrials.gov/ct2/show/NCT03407638?term=CTN-0074&draw=2&rank=1.
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http://dx.doi.org/10.1186/s13722-021-00218-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849121PMC
January 2021

Modelling the impact of an HIV testing intervention on HIV transmission among men who have sex with men in China.

HIV Med 2021 Jan 28. Epub 2021 Jan 28.

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, UK.

Objectives: An intervention developed through participatory crowdsourcing methods increased HIV self-testing among men who have sex with men [MSM; relative risk (RR) = 1.89]. We estimated the long-term impact of this intervention on HIV transmission among MSM in four cities (Guangzhou, Shenzhen, Jinan and Qingdao).

Methods: A mathematical model of HIV transmission, testing and treatment among MSM in China was parameterized using city-level demographic and sexual behaviour data and calibrated to HIV prevalence, diagnosis and antiretroviral therapy (ART) coverage data. The model was used to project the HIV infections averted over 20 years (2016-2036) from the intervention to increase self-testing, compared with current testing rates.

Results: Running the intervention once would avert < 2.2% infections over 20 years. Repeating the intervention (RR = 1.89) annually would avert 6.4-10.7% of new infections, while further increases in the self-testing rate (hypothetical RR = 3) would avert 11.7-20.7% of new infections.

Conclusions: Repeated annual interventions would give a three- to seven-fold increase in long-term impact compared with a one-off intervention. Other interventions will be needed to more effectively reduce the HIV burden in this population.
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http://dx.doi.org/10.1111/hiv.13063DOI Listing
January 2021

Genetic and Pharmacological Manipulations of Glyoxalase 1 Mediate Ethanol Withdrawal Seizure Susceptibility in Mice.

Brain Sci 2021 Jan 19;11(1). Epub 2021 Jan 19.

Department of Psychiatry, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA.

Central nervous system (CNS) hyperexcitability is a clinically significant feature of acute ethanol withdrawal. There is evidence for a genetic contribution to withdrawal severity, but specific genetic risk factors have not been identified. The gene glyoxalase 1 () has been previously implicated in ethanol consumption in mice, and GLO1 inhibition can attenuate drinking in mice and rats. Here, we investigated whether genetic and pharmacological manipulations of GLO1 activity can also mediate ethanol withdrawal seizure severity in mice. Mice from two transgenic lines overexpressing on different genetic backgrounds (C57BL/6J (B6) and FVB/NJ (FVB)) were tested for handling-induced convulsions (HICs) as a measure of acute ethanol withdrawal. Following an injection of 4 g/kg alcohol, both B6 and FVB mice overexpressing showed increases in HICs compared to wild-type littermates, though only the FVB line showed a statistically significant difference. We also administered daily ethanol injections (2 g/kg + 9 mg/kg 4-methylpyrazole) to wild-type B6 mice for 10 days and tested them for HICs on the 10th day following treatment with either a vehicle or a GLO1 inhibitor (-bromobenzylglutathione cyclopentyl diester (pBBG)). Treatment with pBBG reduced HICs, although this effect was only statistically significant following two 10-day cycles of ethanol exposure and withdrawal. These results provide converging genetic and pharmacological evidence that GLO1 can mediate ethanol withdrawal seizure susceptibility.
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http://dx.doi.org/10.3390/brainsci11010127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835754PMC
January 2021

Whole blood genome-wide transcriptome profiling and metagenomics next-generation sequencing in young infants with suspected sepsis in a low-and middle-income country: A study protocol.

Gates Open Res 2020 26;4:139. Epub 2020 Nov 26.

BC Children's Hospital Research Institute, Vancouver, BC, Canada.

Conducting collaborative and comprehensive epidemiological research on neonatal sepsis in low- and middle-income countries (LMICs) is challenging due to a lack of diagnostic tests. This prospective study protocol aims to obtain epidemiological data on bacterial sepsis in newborns and young infants at Kamuzu Central Hospital in Lilongwe, Malawi. The main goal is to determine if the use of whole blood transcriptome host immune response signatures can help in the identification of infants who have sepsis of bacterial causes. The protocol includes a detailed clinical assessment with vital sign measurements, strict aseptic blood culture protocol with state-of-the-art microbial analyses and RNA-sequencing and metagenomics evaluations of host responses and pathogens, respectively. We also discuss the directions of a brief analysis plan for RNA sequencing data. This study will provide robust epidemiological data for sepsis in neonates and young infants in a setting where sepsis confers an inordinate burden of disease.
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http://dx.doi.org/10.12688/gatesopenres.13172.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783117.2PMC
November 2020

Unusual Combined Orbital Roof and Orbital Floor Fractures in A Pediatric Patient.

Plast Reconstr Surg Glob Open 2020 Dec 21;8(12):e3324. Epub 2020 Dec 21.

Craniofacial Center, Seattle Children's Hospital, Division of Plastic and Craniofacial Surgery, Seattle, Wash.

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http://dx.doi.org/10.1097/GOX.0000000000003324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787296PMC
December 2020

Evolution of Cranioorbital Shape in Nonsyndromic, Muenke, and Saethre-Chotzen Bilateral Coronal Synostosis: A Case-Control Study of 2-Year Outcomes.

Plast Reconstr Surg 2021 Jan;147(1):148-159

From the Craniofacial Image Analysis Lab, Craniofacial Center, Seattle Children's Hospital; and the Division of Plastic Surgery and the Department of Neurological Surgery, University of Washington.

Background: The purpose of this study was to quantify change in cranioorbital morphology from presentation, after fronto-orbital advancement, and at 2-year follow-up.

Methods: Volumetric, linear, and angular analyses were performed on computed tomographic scans of consecutive bilateral coronal synostosis patients. Comparisons were made across three time points, between syndromic and nonsyndromic cases, and against normal controls. Significance was set at p < 0.05.

Results: Twenty-five patients were included: 11 were nonsyndromic, eight had Saethre-Chotzen syndrome, and six had Muenke syndrome. Total cranial volume was comparable to normal, age-matched control subjects before and 2 years after surgery despite an expansion during surgery. Axial and sagittal vector analyses showed advancement and widening of the lower forehead beyond control values with surgery and comparable anterior position, but increased width compared to controls at 2 years. Frontal bossing decreased with a drop in anterior cranial height and advanced lower forehead position. Middle vault height was not normalized and turricephaly persisted at follow-up. Posterior fossa volume remained lower at all three time points compared to control subjects. Supraorbital retrusion relative to anterior corneal position was overcorrected by surgery, with values comparable to those of control subjects at 2 years because of differential growth. There was no difference at 2 years between syndromic and nonsyndromic groups.

Conclusions: Open fronto-orbital advancement successfully remodels the anterior forehead but requires overcorrection to be comparable to normal at 2 years. Although there are differences in syndromic cases at presentation, they do not result in significant morphometric differences on follow-up. Posterior fossa volume remains lower at all time points.

Clinical Question/level Of Evidence: Therapeutic, IV.
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http://dx.doi.org/10.1097/PRS.0000000000007494DOI Listing
January 2021

A Bovine Enteric Infection Model to Analyze Parenteral Vaccine-Induced Mucosal Immunity and Accelerate Vaccine Discovery.

Front Immunol 2020 23;11:586659. Epub 2020 Nov 23.

Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, Saskatoon, SK, Canada.

Mycobacterial diseases of cattle are responsible for considerable production losses worldwide. In addition to their importance in animals, these infections offer a nuanced approach to understanding persistent mycobacterial infection in native host species. ssp. (MAP) is an enteric pathogen that establishes a persistent, asymptomatic infection in the small intestine. Difficulty in reproducing infection in surrogate animal models and limited understanding of mucosal immune responses that control enteric infection in the natural host have been major barriers to MAP vaccine development. We previously developed a reproducible challenge model to establish a consistent MAP infection using surgically isolated intestinal segments prepared in neonatal calves. In the current study, we evaluated whether intestinal segments could be used to screen parenteral vaccines that alter mucosal immune responses to MAP infection. Using Silirum - a commercial MAP bacterin - we demonstrate that intestinal segments provide a platform for assessing vaccine efficacy within a relatively rapid period of 28 days post-infection. Significant differences between vaccinates and non-vaccinates could be detected using quantitative metrics including bacterial burden in intestinal tissue, MAP shedding into the intestinal lumen, and vaccine-induced mucosal immune responses. Comparing vaccine-induced responses in mucosal leukocytes isolated from the site of enteric infection versus blood leukocytes revealed substantial inconsistences between these immune compartments. Moreover, parenteral vaccination with Silirum did not induce equal levels of protection throughout the small intestine. Significant control of MAP infection was observed in the continuous but not the discrete Peyer's patches. Analysis of these regional mucosal immune responses revealed novel correlates of immune protection associated with reduced infection that included an increased frequency of CD335 innate lymphoid cells, and increased expression of and . Thus, intestinal segments provide a novel model to accelerate vaccine screening and discovery by testing vaccines directly in the natural host and provides a unique opportunity to interrogate mucosal immune responses to mycobacterial infections.
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http://dx.doi.org/10.3389/fimmu.2020.586659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719698PMC
November 2020

Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort.

Front Immunol 2020 30;11:578801. Epub 2020 Nov 30.

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.

Background: Vaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts.

Methods: We applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres.

Results: Using both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response.

Conclusion: This study provides further evidence that baseline cellular and molecular characteristics of an individual's immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets.
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http://dx.doi.org/10.3389/fimmu.2020.578801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734088PMC
November 2020

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life.

Front Immunol 2020 20;11:578505. Epub 2020 Oct 20.

Department of Pathology, Boston Children's Hospital, Boston, MA, United States.

Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn's immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases.
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http://dx.doi.org/10.3389/fimmu.2020.578505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732455PMC
October 2020

Identification of novel targets of azithromycin activity against grown in physiologically relevant media.

Proc Natl Acad Sci U S A 2020 12 14;117(52):33519-33529. Epub 2020 Dec 14.

Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;

causes severe multidrug-resistant infections that often lead to bacteremia and sepsis. Physiologically relevant conditions can increase the susceptibility of pathogens to antibiotics, such as azithromycin (AZM). When compared to minimal-inhibitory concentrations (MICs) in laboratory media, AZM had a 16-fold lower MIC in tissue culture medium with 5% Mueller Hinton broth (MHB) and a 64-fold lower MIC in this tissue culture medium with 20% human serum. AZM also demonstrated increased synergy in combination with synthetic host-defense peptides DJK-5 and IDR-1018 under host-like conditions and in a murine abscess model. To mechanistically study the altered effects of AZM under physiologically relevant conditions, global transcriptional analysis was performed on with and without effective concentrations of AZM. This revealed that the operon, mediating arabinosaminylation of lipopolysaccharides and related regulatory systems, was down-regulated in host-like media when compared to MHB. Inactivation of genes within the operon led to increased susceptibility of to AZM and great increases in synergy between AZM and other antimicrobial agents, indicating that dysregulation of the operon might explain increased AZM uptake and synergy in host-like media. Furthermore, genes involved in central and energy metabolism and ribosome biogenesis were dysregulated more in physiologically relevant conditions treated with AZM, likely due to general changes in cell physiology as a result of the increased effectiveness of AZM in these conditions. These data suggest that, in addition to the operon, there are multiple factors in host-like environments that are responsible for observed changes in susceptibility.
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http://dx.doi.org/10.1073/pnas.2007626117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777150PMC
December 2020

Costs of using evidence-based implementation strategies for behavioral health integration in a large primary care system.

Health Serv Res 2020 Dec;55(6):913-923

Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.

Objective: To describe the cost of using evidence-based implementation strategies for sustained behavioral health integration (BHI) involving population-based screening, assessment, and identification at 25 primary care sites of Kaiser Permanente Washington (2015-2018).

Data Sources/study Setting: Project records, surveys, Bureau of Labor Statistics compensation data.

Study Design: Labor and nonlabor costs incurred by three implementation strategies: practice coaching, electronic health records clinical decision support, and performance feedback.

Data Collection/extraction Methods: Personnel time spent on these strategies was estimated for five broad roles: (a) project leaders and administrative support, (b) practice coaches, (c) clinical decision support programmers, (d) performance metric programmers, and (e) primary care local implementation team members.

Principal Finding: Implementation involved 286 persons, 18 131 person-hours, costing $1 587 139 or $5 per primary care visit with screening or $38 per primary care visit identifying depression, suicidal thoughts and/or alcohol or substance use disorders, in a single year. The majority of person-hours was devoted to project leadership (35%) and practice coaches (34%), and 36% of costs were for the first three sites.

Conclusions: When spread across patients screened in a single year, BHI implementation costs were well within the range for commonly used diagnostic assessments in primary care (eg, laboratory tests). This suggests that implementation costs alone should not be a substantial barrier to population-based BHI.
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http://dx.doi.org/10.1111/1475-6773.13592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704468PMC
December 2020

Systems Biology Methods Applied to Blood and Tissue for a Comprehensive Analysis of Immune Response to Hepatitis B Vaccine in Adults.

Front Immunol 2020 4;11:580373. Epub 2020 Nov 4.

Vaccine Evaluation Center, BC Children's Hospital Research Institute, Vancouver, BC, Canada.

Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches-NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design.
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http://dx.doi.org/10.3389/fimmu.2020.580373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672042PMC
November 2020

Development of a robust crystallization platform for immune receptor TREM2 using a crystallization chaperone strategy.

Protein Expr Purif 2021 Mar 20;179:105796. Epub 2020 Nov 20.

Department of Computational and Structural Sciences, Merck & Co., Inc., West Point, PA, USA.

TREM2 has been identified by genomic analysis as a potential and novel target for the treatment of Alzheimer's disease. To enable structure-based screening of potential small molecule therapeutics, we sought to develop a robust crystallization platform for the TREM2 Ig-like domain. A systematic set of constructs containing the structural chaperone, maltose binding protein (MBP), fused to the Ig domain of TREM2, were evaluated in parallel expression and purification, followed by crystallization studies. Using protein crystallization and high-resolution diffraction as a readout, a MBP-TREM2 Ig fusion construct was identified that generates reproducible protein crystals diffracting at 2.0 Å, which makes it suitable for soaking of potential ligands. Importantly, analysis of crystal packing interfaces indicates that most of the surface of the TREM2 Ig domain is available for small molecule binding. A proof of concept co-crystallization study with a small library of fragments validated potential utility of this system for the discovery of new TREM2 therapeutics.
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http://dx.doi.org/10.1016/j.pep.2020.105796DOI Listing
March 2021

A phosphorylation-regulated eIF3d translation switch mediates cellular adaptation to metabolic stress.

Science 2020 11;370(6518):853-856

Department of Biology, Brandeis University, Waltham, MA 02453, USA.

Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by the induction of distinct gene programs tailored to each stress. Although the mechanisms driving repression of general protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here, we found that the noncanonical 5' cap-binding protein eIF3d was activated in response to metabolic stress in human cells. Activation required reduced CK2-mediated phosphorylation near the eIF3d cap-binding pocket. eIF3d controls a gene program enriched in factors important for glucose homeostasis, including members of the mammalian target of rapamycin (mTOR) pathway. eIF3d-directed translation adaptation was essential for cell survival during chronic glucose deprivation. Thus, this mechanism of translation reprogramming regulates the cellular response to metabolic stress.
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http://dx.doi.org/10.1126/science.abb0993DOI Listing
November 2020

Medicolegal issues in abusive head trauma for the pediatric neurosurgeon.

Neurosurg Focus 2020 11;49(5):E23

1Department of Neurological Surgery, University of Washington; and.

The purpose of this article is to serve as a rational guide for the pediatric neurosurgeon in navigating common medicolegal issues that arise in the management of abusive head trauma (AHT). Many of these issues may be unfamiliar or unpleasant to surgeons focused on addressing disease. The authors begin with a brief history on the origins of the diagnosis of AHT and the controversy surrounding it, highlighting some of the facets of the diagnosis that make it particularly unique in pediatric neurosurgery. They then review some special medical considerations in these patients through the perspective of the neurosurgeon and provide several examples as illustration. The authors discuss how to appropriately document these cases in the medical record for expected legal review, and last, they provide an overview of the legal process through which the neurosurgeon may be called to provide testimony.
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http://dx.doi.org/10.3171/2020.8.FOCUS20599DOI Listing
November 2020

Transgenic Expression of Rescues Vision and Retinal Morphology in a Mouse Model of Congenital Stationary Night Blindness 2A (CSNB2A).

Transl Vis Sci Technol 2020 10 14;9(11):19. Epub 2020 Oct 14.

Department of Medical Genetics, and Department of Surgery, Alberta Children's Hospital Research Institute, and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Purpose: Congenital stationary night blindness 2A (CSNB2A) is a genetic retinal disorder characterized by poor visual acuity, nystagmus, strabismus, and other signs of retinal dysfunction resulting from mutations in the gene coding for the pore-forming subunit of the calcium channel Ca1.4. Mouse models of CSNB2A have shown that mutations causing the disease deleteriously affect photoreceptors and their synapses with second-order neurons. This study was undertaken to evaluate whether transgenic expression of could rescue morphology and visual function in a -KO model of CSNB2A.

Methods: Strategic creation, breeding and use of transgenic mouse lines allowed for Cre-driven retina-specific expression of in a CSNB2A model. Transgene expression and retinal morphology were investigated with immunohistochemistry in retinal wholemounts or cross-sections. Visual function was assessed by optokinetic response (OKR) analysis and electroretinography (ERG).

Results: Mosaic, prenatal expression of in the otherwise -KO retina was sufficient to rescue some visual function. Immunohistochemical analyses demonstrated wild-type-like photoreceptor and synaptic morphology in sections with transgenic expression of .

Conclusions: This report describes a novel system for Cre-inducible expression of in a -KO mouse model of CSNB2A and provides preclinical evidence for the potential use of gene therapy in the treatment of CSNB2A.

Translational Relevance: These data have relevance in the treatment of CSNB2A and in understanding how photoreceptor integration might be achieved in retinas in which photoreceptors have been lost, such as retinitis pigmentosa, age-related macular degeneration, and other degenerative conditions.
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http://dx.doi.org/10.1167/tvst.9.11.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571326PMC
October 2020

Issues of consent and assent in pediatric neurosurgery.

Childs Nerv Syst 2021 Jan 17;37(1):33-37. Epub 2020 Oct 17.

Department of Neurological Surgery, University of Washington, 325 Ninth Ave., Seattle, WA, 98104, USA.

Background: Consent and assent are important concepts to understand in the care of pediatric neurosurgery patients. Recently it has been recommended that although pediatric patients generally do not have the legal capacity to make medical decisions, they be encouraged to be involved in their own care. Given the paucity of information on this topic in the neurosurgery community, the objective is to provide pediatric neurosurgeons with recommendations on how to involve their patients in medical decision-making.

Methods: We review the essential elements and current guidelines of consent and assent for pediatric patients using illustrative neurosurgical case vignettes.

Results: The pediatric population ranges widely in cognitive and psychological development making the process of consent and assent quite complex. The role of the child or adolescent in medical decision-making, issues associated with obtaining assent or dissent, and informed refusal of treatment are considered.

Conclusion: The process of obtaining consent and assent represents a critical yet often overlooked aspect to care of pediatric neurosurgical patients. The pediatric neurosurgeon must be able to distill immensely complex and high-risk procedures into simple, understandable terms. Furthermore, they must recognize when the child's dissent or refusal to treatment is acceptable. In general, allowing children to be involved in their neurosurgical care is empowering and gives them both identity and agency, which is the vital first step to a successful neurosurgical intervention.
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http://dx.doi.org/10.1007/s00381-020-04907-wDOI Listing
January 2021

Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Ca1.4 Ca channels.

J Biol Chem 2020 Dec 8;295(50):17215-17226. Epub 2020 Oct 8.

Departments of Molecular Physiology and Biophysics, Otolaryngology Head-Neck Surgery, and Neurology, Iowa Neuroscience Institute, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa USA

Voltage-gated Ca1 and Ca2 Ca channels are comprised of a pore-forming α subunit (Ca1.1-1.4, Ca2.1-2.3) and auxiliary β (β) and αδ (αδ-1-4) subunits. The properties of these channels vary with distinct combinations of Ca subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Ca subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Ca1.4 channels typical of those in human retina: Ca1.4 splice variants with or without exon 47 (Ca1.4+ex47 and Ca1.4Δex47, respectively), and the auxiliary subunits, β and αδ-4. We find that IT caused both Ca1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β and αδ-4 but not in those with β and αδ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Ca1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β and αδ-4. Our results reveal complex actions of IT in modifying the properties of Ca1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.
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http://dx.doi.org/10.1074/jbc.RA120.014138DOI Listing
December 2020

Remote Application and Use of Real-Time Continuous Glucose Monitoring by Adults with Type 2 Diabetes in a Virtual Diabetes Clinic.

Diabetes Technol Ther 2021 Feb 5;23(2):128-132. Epub 2020 Nov 5.

Onduo, Newton, Massachusetts, USA.

The Onduo Virtual Diabetes Clinic (VDC) for people with type 2 diabetes (T2D) combines a mobile app, remote lifestyle coaching, connected devices, and live video consultations with board-certified endocrinologists. Adults with T2D ( = 594) who were evaluated by a VDC endocrinologist, remotely prescribed and mailed a real-time continuous glucose monitoring (rtCGM) device and used ≥1 sensor completed a CGM satisfaction questionnaire. The CGM satisfaction score was 4.5 0.8 out of 5. Most respondents (94.7%) agreed/strongly agreed that they were comfortable inserting the sensor remotely and that rtCGM use improved understanding of the impact of eating (97.0%), increased diabetes knowledge (95.7%), and helped improve diabetes control when not wearing the sensor (79.4%). HbA1c ( = 372) decreased from 7.7% 1.6% to 7.1% 1.2% ( < 0.001; 10.2 months). These data suggest that it is feasible to provide rtCGM directly to individuals with T2D through a VDC without in-office training. Intermittent use of rtCGM was well-received by adults with T2D and was associated with improvement in HbA1c.
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http://dx.doi.org/10.1089/dia.2020.0396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868574PMC
February 2021

Rapid Magnetic Resonance Imaging of the Spine in Neonates with Spinal Dysraphism.

World Neurosurg 2020 Dec 19;144:e648-e659. Epub 2020 Sep 19.

Department of Radiology, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, Washington, USA.

Background: The use of nonsedated T2-weighted Half-Fourier Acquisition Single-shot Turbo spin Echo magnetic resonance imaging (MRI) sequences in screening for spinal cord syrinx in neonates with spinal dysraphism has not been reported in the literature. We sought to review our experience using T2-weighted Half-Fourier Acquisition Single-shot Turbo spin Echo imaging of the spine (i.e., rapid spine MRI) in nonsedated neonates for detecting spinal cord syrinx in neonates with spinal dysraphism.

Methods: We performed a retrospective search of our radiology database for neonates with spinal dysraphism who had rapid spine MRI between May 2017 and February 2020. The images were reviewed in conjunction with clinical findings and standard spine imaging, when available.

Results: Thirty studies (in 29 neonates) fulfilled our inclusion criteria. Of the 26 neonates with myelomeningocele, 5 of them (19%) had spinal cord syrinx identified on neonatal rapid spine MRI. An additional 2 patients developed syrinx by 2 years of age. Potential pitfalls identified in interpreting rapid spine MRI include motion artifacts and distinguishing a severe holocord syrinx from a truncated spinal cord.

Conclusions: Rapid spine MRI acquired without sedation or anesthesia may be used as a screening technique to detect spinal cord syrinx in neonates with spinal dysraphism.
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http://dx.doi.org/10.1016/j.wneu.2020.09.013DOI Listing
December 2020

A dual role for Ca1.4 Ca channels in the molecular and structural organization of the rod photoreceptor synapse.

Elife 2020 09 17;9. Epub 2020 Sep 17.

Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, United States.

Synapses are fundamental information processing units that rely on voltage-gated Ca (Ca) channels to trigger Ca-dependent neurotransmitter release. Ca channels also play Ca-independent roles in other biological contexts, but whether they do so in axon terminals is unknown. Here, we addressed this unknown with respect to the requirement for Ca1.4 L-type channels for the formation of rod photoreceptor synapses in the retina. Using a mouse strain expressing a non-conducting mutant form of Ca1.4, we report that the Ca1.4 protein, but not its Ca conductance, is required for the molecular assembly of rod synapses; however, Ca1.4 Ca signals are needed for the appropriate recruitment of postsynaptic partners. Our results support a model in which presynaptic Ca channels serve both as organizers of synaptic building blocks and as sources of Ca ions in building the first synapse of the visual pathway and perhaps more broadly in the nervous system.
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http://dx.doi.org/10.7554/eLife.62184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561352PMC
September 2020

Interactions between genetics and environment shape Camelina seed oil composition.

BMC Plant Biol 2020 Sep 14;20(1):423. Epub 2020 Sep 14.

Department of Biology, Washington University in St. Louis, St. Louis, MO, 63130, USA.

Background: Camelina sativa (gold-of-pleasure) is a traditional European oilseed crop and emerging biofuel source with high levels of desirable fatty acids. A twentieth century germplasm bottleneck depleted genetic diversity in the crop, leading to recent interest in using wild relatives for crop improvement. However, little is known about seed oil content and genetic diversity in wild Camelina species.

Results: We used gas chromatography, environmental niche assessment, and genotyping-by-sequencing to assess seed fatty acid composition, environmental distributions, and population structure in C. sativa and four congeners, with a primary focus on the crop's wild progenitor, C. microcarpa. Fatty acid composition differed significantly between Camelina species, which occur in largely non-overlapping environments. The crop progenitor comprises three genetic subpopulations with discrete fatty acid compositions. Environment, subpopulation, and population-by-environment interactions were all important predictors for seed oil in these wild populations. A complementary growth chamber experiment using C. sativa confirmed that growing conditions can dramatically affect both oil quantity and fatty acid composition in Camelina.

Conclusions: Genetics, environmental conditions, and genotype-by-environment interactions all contribute to fatty acid variation in Camelina species. These insights suggest careful breeding may overcome the unfavorable FA compositions in oilseed crops that are predicted with warming climates.
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http://dx.doi.org/10.1186/s12870-020-02641-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490867PMC
September 2020

A Retrospective Evaluation of Airway Anatomy in Young Children and Implications for One-Lung Ventilation.

J Cardiothorac Vasc Anesth 2020 Aug 12. Epub 2020 Aug 12.

Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC.

Objective: One-lung ventilation (OLV) in children remains a niche practice with few studies to guide best practices. The objective of this study was to describe lower airway anatomy relevant to establishment of OLV in young children.

Design: Retrospective, observational study using pre-existing studies in the electronic health record.

Setting: Single institution, academic medical center, tertiary-care hospital.

Participants: Pediatric patients <8 years old.

Interventions: None.

Measurements And Main Results: Chest computed tomographic scans of 111 children 4 days to 8 years of age were reviewed. Measurements were taken from the thyroid isthmus to the carina, carina to first lobar branch on the left and right, diameter of the trachea at the carina, and diameter of the left and right mainstem bronchi. Dimensions were correlated with the outer diameter of endotracheal tubes and bronchial blockers. The left mainstem bronchus is consistently smaller than the right. Lung isolation using a mainstem technique on the left should use an endotracheal tube a half size smaller than would be used for tracheal intubation. The length from the carina to the first lobar branch on the left is consistently 3 times longer than on the right. Further, age-delineated bronchial diameters suggest that the clinician should transition from a 5F to a 7F Arndt bronchial blocker at 3-to-4 years of age.

Conclusion: A more detailed and accurate understanding of pediatric lower airway anatomy may assist the clinician in successfully performing OLV in young children.
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http://dx.doi.org/10.1053/j.jvca.2020.08.015DOI Listing
August 2020

Cannabis use, other drug use, and risk of subsequent acute care in primary care patients.

Drug Alcohol Depend 2020 11 8;216:108227. Epub 2020 Aug 8.

Kaiser Permanente Washington Health Research Institute, 1730 Minor Ave, Suite 1600, Seattle, WA, 98101-1466, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, 1959 NE Pacific Street, Box 356560, Room BB1644, Seattle, WA, 98195-6560, USA. Electronic address:

Background: Cannabis and other drug use is associated with adverse health events, but little is known about the association of routine clinical screening for cannabis or other drug use and acute care utilization. This study evaluated whether self-reported frequency of cannabis or other drug use was associated with subsequent acute care.

Method: This retrospective cohort study used EHR and claims data from 8 sites in Washington State that implemented annual substance use screening. Eligible adult primary care patients (N = 47,447) completed screens for cannabis (N = 45,647) and/or other drug use, including illegal drug use and prescription medication misuse, (N = 45,255) from 3/3/15-10/1/2016. Separate single-item screens assessed frequency of past-year cannabis and other drug use: never, less than monthly, monthly, weekly, daily/almost daily. An indicator of acute care utilization measured any urgent care, emergency department visits, or hospitalizations ≤19 months after screening. Adjusted Cox proportional hazards models estimated risk of acute care.

Results: Patients were predominantly non-Hispanic White. Those reporting cannabis use less than monthly (Hazard Ratio [HR] = 1.12, 95 % CI = 1.03-1.21) or daily (HR = 1.24; 1.10-1.39) had greater risk of acute care during follow-up than those reporting no use. Patients reporting other drug use less than monthly (HR = 1.34; 1.13-1.59), weekly (HR = 2.21; 1.46-3.35), or daily (HR = 2.53; 1.86-3.45) had greater risk of acute care than those reporting no other drug use.

Conclusion: Population-based screening for cannabis and other drug use in primary care may have utility for understanding risk of subsequent acute care. It is unclear whether findings will generalize to U.S. states with broader racial/ethnic diversity.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896808PMC
November 2020

Systems Biology Approaches to Understanding the Human Immune System.

Front Immunol 2020 30;11:1683. Epub 2020 Jul 30.

Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada.

Systems biology is an approach to interrogate complex biological systems through large-scale quantification of numerous biomolecules. The immune system involves >1,500 genes/proteins in many interconnected pathways and processes, and a systems-level approach is critical in broadening our understanding of the immune response to vaccination. Changes in molecular pathways can be detected using high-throughput omics datasets (e.g., transcriptomics, proteomics, and metabolomics) by using methods such as pathway enrichment, network analysis, machine learning, etc. Importantly, integration of multiple datasets is becoming key to revealing novel biological insights. In this perspective article, we highlight the use of protein-protein interaction (PPI) networks as a multi-omics integration approach to unravel information flow and mechanisms during complex biological events, with a focus on the immune system. This involves a combination of tools, including: , a database of curated interactions between genes and protein products involved in the innate immunity; , a visualization and analysis platform for InnateDB interactions; and , a tool to integrate metabolite data into PPI networks. The application of these systems techniques is demonstrated for a variety of biological questions, including: the developmental trajectory of neonates during the first week of life, mechanisms in host-pathogen interaction, disease prognosis, biomarker discovery, and drug discovery and repurposing. Overall, systems biology analyses of omics data have been applied to a variety of immunology-related questions, and here we demonstrate the numerous ways in which PPI network analysis can be a powerful tool in contributing to our understanding of the immune system and the study of vaccines.
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http://dx.doi.org/10.3389/fimmu.2020.01683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406790PMC
July 2020

Characterization of immune responses and the lung transcriptome in a murine model of IL-33 challenge.

Biochim Biophys Acta Mol Basis Dis 2020 12 22;1866(12):165950. Epub 2020 Aug 22.

Manitoba Centre for Proteomics and Systems Biology, Department of Internal Medicine, University of Manitoba, Winnipeg, Canada; Department of Immunology, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada. Electronic address:

IL-33 induces airway inflammation and hyper-responsiveness in respiratory diseases. Although defined as a therapeutic target, there are limited studies that have comprehensively investigated IL-33-mediated responses in the lungs in vivo. In this study, we characterized immunological and physiological responses induced by intranasal IL-33 challenge, in a mouse model. We identified specific cytokines, IL-4, IL-5, IL-6, IL-10, IP-10 and MIP1-α, that are increased in bronchoalveolar lavage and lung tissues by IL-33. Using transcriptomics (RNA-Seq) we demonstrated that 2279 transcripts were up-regulated and 1378 downregulated (≥ 2-fold, p < 0.01) in lung tissues, in response to IL-33. Bioinformatic interrogation of the RNA-Seq data was used to predict biological pathways and upstream regulators involved in IL-33-mediated responses. We showed that the mRNA and protein of STAT4, a predicted upstream regulator of IL-33-induced transcripts, was significantly enhanced in the lungs following IL-33 challenge. Overall, this study provides specific IL-33-induced molecular targets and endpoints that can be used as a resource for in vivo studies, e.g. in preclinical murine models examining novel interventions to target downstream effects of IL-33.
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http://dx.doi.org/10.1016/j.bbadis.2020.165950DOI Listing
December 2020