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3i Initiative Weekly Updates
Welcome to the 3i Weekly Update, your source for 3i relevant news and events. Please send all items of interest to Nicole.Frank@hsc.utah.edu by the end of the day on Thursdays.
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10/12 - 10/16- MONDAY, OCTOBER 12, 2020, 2:00 – 3:00 PM - Biochemistry Seminar Series - Smita Patel - "Mechanistic Studies of the Innate Immune Receptor RIG-I"
- MONDAY, OCTOBER 12, 2020, 4:00- 5:00 PM - Department of Pharmaceutics and Pharmaceutical Chemistry Seminar - Dr. Wei Tang - "Remodeling Tumor Microenvironment with Phototheranostics for Advanced Cancer Treatment"
- TUESDAY, OCTOBER 13, 2020, 11:00 AM - 5:00 PM - Annual Bioscience Symposium and Don Summers Memorial Lectures
- THURSDAY, OCTOBER 15TH, 2020, 9:00-10:00 AM - Global Health Affinity Group Meeting
- THURSDAY, OCTOBER 15, 2020, 12:00 – 1:00 PM - Department of Internal Medicine Grand Rounds - Robert Campbell - "Dysregulated Coagulation in COVID-19"
- FRIDAY, OCTOBER 16, 2020, 12:00- 1:00PM - Pathology M&I Seminar Series - Ali Ellebeddy, PhD - “How the germinal center reaction shapes our immune response to influenza vaccination”
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F&A Townhall
The Office of the Vice President for Research is hosting the Second Annual F&A Town Hall on October 20th from 10:00-11:00 am. The town hall is open to all faculty, staff, post-docs, and students, and will consist of a presentation and open Q&A session.
The presentation will cover FY20 Research Awards and Expenditure data and how F&A will be used and distributed in FY21
We encourage all interested members of our Research community to attend. Space is limited, please RSVP HERE.
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Quarterly Reminders
- Please reach out to Julie Kiefer (Associate Director, Science Communications) about any upcoming articles that have been accepted for publication.
- The initiative has the ability to schedule time with Lynn Wong (Health Sciences Foundation Relations Director) to identify which foundations may align with your research interests and can assist in relationship building with these groups. If you are interested in meeting with Lynn, or if you have been approached by a foundation to apply for funding, please let us know.
- If you know of people who want to be added to the 3i listserv, please forward them this link.
- If you would like to be removed from this listserv, please go here.
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3i Funding Opportunities
Current Federal and Private FOAs applicable to the 3is can be found on the U's pivot page. New FOAs announced this week:
- NIAID's September Council Approved Concepts
- RFA-AI-20-064, A Multidisciplinary Approach to Study Vaccine-elicited Immunity and Efficacy against Malaria (U01, Clinical Trial Not Allowed)
- RFA-AI-20-060, Cohort Studies To Improve Our Understanding of Influenza Immunity, Vaccine Response and Effectiveness in Older Adults (65 years and older) (U01, Clinical Trial Not Allowed)
- RFA-AI-20-057, Understanding the Role of the M. Tuberculosis Granuloma in Tuberculosis (TB) Disease and Treatment Outcomes (R01, Clinical Trial Not Allowed)
- RFA-AI-20-055, Understanding Evolutionary Dynamics of Influenza to Inform and Improve Vaccine Strain Selection (R01, Clinical Trial Not Allowed)
- RFA-CA-20-046, Investigation of the Transmission of Kaposi Sarcoma-Associated Herpesvirus (KSHV) (R01 Clinical Trial Optional)
- RFA-MH-20-701, Role of Myeloid Cells in Persistence and Eradication of HIV-1 Reservoirs from the Brain (R01 Clinical Trial Not Allowed)
- Centers for Disease Control and Prevention - ERA Emerging Infections Network - Research for Preventing, Detecting, and Managing Travelers who Acquire Infectious Diseases Abroad Synopsis 1
- National Science Foundation - Innovation: Research Methods
- RFA-HL-21-015, HeartShare: Next-Generation Phenomics to Define Heart Failure Subtypes and Treatment Targets – Clinical Centers (U01 Clinical Trial Not Allowed)
- National Science Foundation - Division of Integrative Organismal Systems Core Programs Synopsis 1
A monthly funding newsletter from PIVOT is sent to 3i investigators on the 2nd Monday of the month. If you have not been receiving the newsletter and would like to be added, please email Nicole.Frank@hsc.utah.edu.
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3i Investigator PublicationsCongratulations to the teams who published this week. If you have a publication that you would like included, please email us.
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Journal of virology, 2020
Syage, AR; Ekiz, HA; Skinner, DD; Stone, C; O'Connell, RM; Lane, TE
Intracranial (i.c.) infection of susceptible C57BL/6 mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) (a member of the Coronaviridae family) results in acute encephalomyelitis and viral persistence associated with an immune-mediated demyelinating disease. The present study was undertaken to better understand the molecular pathways evoked during innate and adaptive immune responses as well as the chronic demyelinating stage of disease in response to JHMV infection of the central nervous system (CNS). Using single cell RNA sequencing analysis (scRNAseq) on flow-sorted CD45-positive cells (CD45+) enriched from brains and spinal cords of experimental mice, we demonstrate the heterogeneity of the immune response as determined by unique molecular signatures and pathways involved in effective anti-viral host defense. Furthermore, we identify potential genes involved in contributing to demyelination as well as remyelination being expressed by both microglia and macrophages. Collectively, these findings emphasize the diversity of the immune response and molecular networks at defined stages following viral infection of the CNS.IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the molecular signatures of immune cells within the CNS at defined times following infection with a neuroadapted murine coronavirus using scRNAseq. This approach has revealed that the immunological landscape is diverse with numerous immune cell subsets expressing distinct mRNA expression profiles that is, in part, dictated by the stage of infection. In addition, these findings reveal new insight into cellular pathways contributing to control of viral replication as well as to neurologic disease.
Read more
Lancet Rheumatol. 2020 Sep 29;:
Authors: Webb BJ, Peltan ID, Jensen P, Hoda D, Hunter B, Silver A, Starr N, Buckel W, Grisel N, Hummel E, Snow G, Morris D, Stenehjem E, Srivastava R, Brown SM
Abstract
Background: A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19.
Methods: We searched for clinical research articles published between Jan 1, 1990, and Aug 20, 2020, on features and diagnostic criteria for secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, cytokine release syndrome, and COVID-19. We compared published clinical data for COVID-19 with clinical features of other hyperinflammatory or cytokine storm syndromes. Based on a framework of conserved clinical characteristics, we developed a six-criterion additive scale for cHIS: fever, macrophage activation (hyperferritinaemia), haematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D-dimer), and cytokinaemia (C-reactive protein, interleukin-6, or triglycerides). We then validated the association of the cHIS scale with in-hospital mortality and need for mechanical ventilation in consecutive patients in the Intermountain Prospective Observational COVID-19 (IPOC) registry who were admitted to hospital with PCR-confirmed COVID-19. We used a multistate model to estimate the temporal implications of cHIS.
Findings: We included 299 patients admitted to hospital with COVID-19 between March 13 and May 5, 2020, in analyses. Unadjusted discrimination of the maximum daily cHIS score was 0·81 (95% CI 0·74-0·88) for in-hospital mortality and 0·92 (0·88-0·96) for mechanical ventilation; these results remained significant in multivariable analysis (odds ratio 1·6 [95% CI 1·2-2·1], p=0·0020, for mortality and 4·3 [3·0-6·0], p<0·0001, for mechanical ventilation). 161 (54%) of 299 patients met two or more cHIS criteria during their hospital admission; these patients had higher risk of mortality than patients with a score of less than 2 (24 [15%] of 138 vs one [1%] of 161) and for mechanical ventilation (73 [45%] vs three [2%]). In the multistate model, using daily cHIS score as a time-dependent variable, the cHIS hazard ratio for worsening from low to moderate oxygen requirement was 1·4 (95% CI 1·2-1·6), from moderate oxygen to high-flow oxygen 2·2 (1·1-4·4), and to mechanical ventilation 4·0 (1·9-8·2).
Interpretation: We proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies.
Funding: Intermountain Research and Medical Foundation.
PMID: 33015645 [PubMed - as supplied by publisher]
J Aerosol Sci. 2021 Jan;151:
Authors: Kaur K, Overacker D, Ghandehari H, Reilly C, Paine R, Kelly KE
Abstract
In vitro studies are the first step toward understanding the biological effects of particulate matter. As a more realistic exposure strategy than submerged culture approaches, air-liquid interface (ALI) in vitro exposure systems are gaining interest. One challenge with ALI systems is determining accurate particle mass deposition. Although a few commercially available ALI systems are equipped with online mass deposition monitoring, most studies use indirect methods to estimate mass doses. These different indirect methods may contribute to inconsistencies in the results from in vitro studies of aerosolized nanoparticles. This study explored the effectiveness of using a commercially available Quartz Crystal Microbalance (QCM) to estimate the real-time, particle-mass deposition inside an electrostatic, parallel-flow, ALI system. The QCM system required minor modifications, including custom-designed and fabricated headers. Three QCM systems were simultaneously placed in three of the six wells in the ALI exposure chamber to evaluate the uniformity of particle deposition. The measurements from fluorescein dosimetry and QCM revealed an uneven deposition between these six wells. The performance of the QCM system was also evaluated using two different methods. First, using fluorescein deposition in one well, depositions in three other wells were estimated, which was then compared to the actual QCM readings. Second, using the QCM measured deposition in one well, the deposition in three other wells was estimated and compared to deposition measured by fluorescein dosimetry. For both methods, the expected and actual deposition yields a linear fit with the slope ~1. This good fit suggests that QCM systems can be used to measure real-time mass deposition in an electrostatic ALI system.
PMID: 33012843 [PubMed]
Blood. 2020 09 10;136(11):1317-1329
Authors: Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben C, Petrey AC, Tolley ND, Guo L, Cody M, Weyrich AS, Yost CC, Rondina MT, Campbell RA
Abstract
There is an urgent need to understand the pathogenesis of coronavirus disease 2019 (COVID-19). In particular, thrombotic complications in patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis, with the major difference being increased risk of thrombosis rather than bleeding. However, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters platelet function to contribute to the pathophysiology of COVID-19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2. RNA sequencing demonstrated distinct changes in the gene-expression profile of circulating platelets of COVID-19 patients. Pathway analysis revealed differential gene-expression changes in pathways associated with protein ubiquitination, antigen presentation, and mitochondrial dysfunction. The receptor for SARS-CoV-2 binding, angiotensin-converting enzyme 2 (ACE2), was not detected by messenger RNA (mRNA) or protein in platelets. Surprisingly, mRNA from the SARS-CoV-2 N1 gene was detected in platelets from 2 of 25 COVID-19 patients, suggesting that platelets may take-up SARS-COV-2 mRNA independent of ACE2. Resting platelets from COVID-19 patients had increased P-selectin expression basally and upon activation. Circulating platelet-neutrophil, -monocyte, and -T-cell aggregates were all significantly elevated in COVID-19 patients compared with healthy donors. Furthermore, platelets from COVID-19 patients aggregated faster and showed increased spreading on both fibrinogen and collagen. The increase in platelet activation and aggregation could partially be attributed to increased MAPK pathway activation and thromboxane generation. These findings demonstrate that SARS-CoV-2 infection is associated with platelet hyperreactivity, which may contribute to COVID-19 pathophysiology.
PMID: 32573711 [PubMed - indexed for MEDLINE]
Am J Physiol Regul Integr Comp Physiol. 2020 07 01;319(1):R33-R42
Authors: Jarrett CL, Shields KL, Broxterman RM, Hydren JR, Park SH, Gifford JR, Richardson RS
Abstract
Cerebral blood flow (CBF) is commonly inferred from blood velocity measurements in the middle cerebral artery (MCA), using nonimaging, transcranial Doppler ultrasound (TCD). However, both blood velocity and vessel diameter are critical components required to accurately determine blood flow, and there is mounting evidence that the MCA is vasoactive. Therefore, the aim of this study was to employ imaging TCD (ITCD), utilizing color flow images and pulse wave velocity, as a novel approach to measure both MCA diameter and blood velocity to accurately quantify changes in MCA blood flow. ITCD was performed at rest in 13 healthy participants (7 men/6 women; 28 ± 5 yr) with pharmaceutically induced vasodilation [nitroglycerin (NTG), 0.8 mg] and without (CON). Measurements were taken for 2 min before and for 5 min following NTG or sham delivery (CON). There was more than a fivefold, significant, fall in MCA blood velocity in response to NTG (∆-4.95 ± 4.6 cm/s) compared to negligible fluctuation in CON (∆-0.88 ± 4.7 cm/s) (P < 0.001). MCA diameter increased significantly in response to NTG (∆0.09 ± 0.04 cm) compared with the basal variation in CON (∆0.00 ± 0.04 cm) (P = 0.018). Interestingly, the product of the NTG-induced fall in MCA blood velocity and increase in diameter was a significant increase in MCA blood flow following NTG (∆144 ± 159 ml/min) compared with CON (∆-5 ± 130 ml/min) (P = 0.005). These juxtaposed findings highlight the importance of measuring both MCA blood velocity and diameter when assessing CBF and document ITCD as a novel approach to achieve this goal.
PMID: 32401627 [PubMed - indexed for MEDLINE]
Ann N Y Acad Sci. 2020 06;1469(1):52-64
Authors: Adler FR, Green AM, Şekercioğlu ÇH
Abstract
By involving the public, citizen science runs against the grain of an idealized science that leaves out the human element, and thus provides new opportunities for ecological research and society. We classify the goals of citizen science in ecology and environment into four broad categories: (1) scientific, (2) participant benefits, (3) community, and (4) policy. Although none of these goals have been well studied, we review the literature showing that these projects are most effective in tracking ecological trends over large swaths of space and time, and discuss the challenges of recruiting, training, retaining, and educating participants, maintaining and disseminating high-quality data, and connecting with the larger community and policy. Biomedical studies, where patients participate in their own treatment in randomized trials, provide an interesting comparison with citizen science in ecology, sharing challenges in recruitment and involvement of nonscientists and ethical conduct of research. Future study will help address the ethical difficulties and enhance ways for citizen science in ecology and the environment to complement scientific discovery, involve and educate the public, and guide policy founded in science and the local community.
PMID: 32216157 [PubMed - indexed for MEDLINE]
J Child Neurol. 2019 12;34(14):928-936
Authors: Gregerson CHY, Bakian AV, Wilkes J, Knighton AJ, Nkoy F, Sweney M, Filloux FM, Bonkowsky JL
Abstract
OBJECTIVE: The purpose of our study was to assess whether race/ethnicity was associated with seizure remission in pediatric epilepsy.
METHODS: This was a retrospective population-based cohort study of children who were evaluated for new-onset epilepsy in the clinic, emergency department, and/or hospital by a pediatric neurologist in an integrated health care delivery system. Children were between ages 6 months and 15 years at their initial presentation of epilepsy. The cohort, identified through an electronic database, was assembled over 6 years, with no less than 5 years of follow-up. All children were evaluated for race, ethnicity, insurance type, and socioeconomic background. Patient outcome was determined at the conclusion of the study period and categorized according to their epilepsy control as either drug resistant (pharmacoresistant and intractable) or drug responsive (controlled, probable remission, and terminal remission).
RESULTS: In the final cohort of 776 patients, 63% were drug responsive (control or seizure remission). After controlling for confounding socioeconomic and demographic factors, children of Hispanic ethnicity experienced reduced likelihood (hazard) of drug-responsive epilepsy (hazard ratio 0.6, P < .001), and had longer median time to remission (8 years; 95% CI 5.9-9.6 years) compared to white non-Hispanic patients (5.6 years; 95% CI 4.9-6.1 years). Among Hispanic patients, higher health care costs were associated with reduced likelihood of drug responsiveness.
SIGNIFICANCE: We found that Hispanic ethnicity is associated with a reduced likelihood of achieving seizure control and remission. This study suggests that factors associated with the race/ethnicity of patients contributes to their likelihood of achieving seizure freedom.
PMID: 31502509 [PubMed - indexed for MEDLINE]
High Alt Med Biol. 2019 12;20(4):331-336
Authors: Trunk AD, Rondina MT, Kaplan DA
Abstract
Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is a prevalent disorder that confers substantial cardiovascular morbidity and, in serious cases, death. VTE has a complex and incompletely understood etiopathogenesis with genetic, acquired, and environmental risk factors. As the focus of this review, one environmental risk factor, which may interact with other risk factors such as hereditary and/or acquired thrombophilias, is travel to high altitude (HA), although current evidence is limited. As guidelines do not directly address this topic, we will discuss the epidemiology of HA-VTE, review the putative mechanisms for thrombosis at HA, and discuss our clinical approach to both risk stratification and counseling, including specific pharmacologic and nonpharmacologic recommendations for patients with elevated VTE risk before they travel to HA.
PMID: 31479310 [PubMed - indexed for MEDLINE]
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J Bone Joint Surg Am. 2020 Oct 21;:
Authors: Shaw JD, Brodke DS, Williams DL, Ashton NN
Abstract
BACKGROUND: Bacterial biofilms pose a challenge in treating implant-associated infections. Biofilms provide bacteria with protection against antimicrobial agents and the immune response and often are invisible to the naked eye. As a biofilm-disclosing agent, methylene blue (MB) has shown promise, but lacks rigorous in vitro evaluation. The purposes of the present study were to assess MB as a biofilm-disclosing agent in vitro for common biofilm-forming organisms and to determine performance characteristics across implant materials and healthy tissue types.
METHODS: Staphylococcus aureus (ATCC 6538) and Pseudomonas aeruginosa (ATCC 27853) biofilms were grown on culture for 2 days in CDC biofilm reactors on titanium, cobalt chromium, polyethylene, and polyether ether ketone (PEEK) coupons. Biofilms were stained with MB solutions of either 0.005% or 0.01% and then were washed with normal saline solution. Digital photographs were obtained to compare the visual sensitivity of the blue dye at these dilutions. Scanning electron microscopy (SEM) was performed to confirm the absence or presence of biofilm on MB-stained areas. Uninoculated controls were also assessed. Healthy adult sheep tissues were also stained to determine the staining characteristics of the host tissue. ImageJ was used to determine the relative blue intensity of stained implants and tissues compared with standard curves.
RESULTS: S. aureus and P. aeruginosa biofilms stained avidly on titanium, cobalt chromium, polyethylene, and PEEK coupons. There was visible dose-dependent staining based on dye concentration. MB was visible only where biofilms were present as confirmed by SEM. MB did not stain uninoculated controls. Articular cartilage and meniscus demonstrated appreciable staining; bone, tendon, muscle, nerve, and fat did not. Bacterial biofilms demonstrated both dose-dependent and species-specific staining.
CONCLUSIONS: MB is an effective disclosing agent for S. aureus and P. aeruginosa biofilms in vitro. MB did not stain implant materials, nor did it stain most healthy tissues in vitro. MB may allow surgeons to see biofilms and may allow for enhanced debridement once visualized.
PMID: 33027087 [PubMed - as supplied by publisher]
Ann Hum Genet. 2020 Oct 07;:
Authors: Teerlink CC, Jurynec MJ, Hernandez R, Stevens J, Hughes DC, Brunker CP, Rowe K, Grunwald DJ, Facelli JC, Cannon-Albright LA
Abstract
Osteoporosis is a common skeletal disorder characterized by deterioration of bone tissue. The set of genetic factors contributing to osteoporosis is not completely specified. High-risk osteoporosis pedigrees were analyzed to identify genes that may confer susceptibility to disease. Candidate predisposition variants were identified initially by whole exome sequencing of affected-relative pairs, approximately cousins, from 10 pedigrees. Variants were filtered on the basis of population frequency, concordance between pairs of cousins, affecting a gene associated with osteoporosis, and likelihood to have functionally damaging, pathogenic consequences. Subsequently, variants were tested for segregation in 68 additional relatives of the index carriers. A rare variant in MEGF6 (rs755467862) showed strong evidence of segregation with the disease phenotype. Predicted protein folding indicated the variant (Cys200Tyr) may disrupt structure of an EGF-like calcium-binding domain of MEGF6. Functional analyses demonstrated that complete loss of the paralogous genes megf6a and megf6b in zebrafish resulted in significant delay of cartilage and bone formation. Segregation analyses, in silico protein structure modeling, and functional assays support a role for MEGF6 in predisposition to osteoporosis.
PMID: 33026655 [PubMed - as supplied by publisher]
J Neuroinflammation. 2020 Oct 06;17(1):291
Authors: Sanchez JMS, Doty DJ, DePaula-Silva AB, Brown DG, Bell R, Klag KA, Truong A, Libbey JE, Round JL, Fujinami RS
Abstract
BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field.
METHODS: We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb).
RESULTS: We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases.
CONCLUSIONS: Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.
PMID: 33023618 [PubMed - in process]
Leukemia. 2020 06;34(6):1679-1683
Authors: Than H, Pomicter AD, Yan D, Beaver LP, Eiring AM, Heaton WL, Senina A, Clair PM, Shacham S, Mason CC, Hare TO, Deininger MW
PMID: 31980730 [PubMed - indexed for MEDLINE]
Gigascience. 2020 01 01;9(1):
Authors: Waller TC, Berg JA, Lex A, Chapman BE, Rutter J
Abstract
BACKGROUND: Metabolic networks represent all chemical reactions that occur between molecular metabolites in an organism's cells. They offer biological context in which to integrate, analyze, and interpret omic measurements, but their large scale and extensive connectivity present unique challenges. While it is practical to simplify these networks by placing constraints on compartments and hubs, it is unclear how these simplifications alter the structure of metabolic networks and the interpretation of metabolomic experiments.
RESULTS: We curated and adapted the latest systemic model of human metabolism and developed customizable tools to define metabolic networks with and without compartmentalization in subcellular organelles and with or without inclusion of prolific metabolite hubs. Compartmentalization made networks larger, less dense, and more modular, whereas hubs made networks larger, more dense, and less modular. When present, these hubs also dominated shortest paths in the network, yet their exclusion exposed the subtler prominence of other metabolites that are typically more relevant to metabolomic experiments. We applied the non-compartmental network without metabolite hubs in a retrospective, exploratory analysis of metabolomic measurements from 5 studies on human tissues. Network clusters identified individual reactions that might experience differential regulation between experimental conditions, several of which were not apparent in the original publications.
CONCLUSIONS: Exclusion of specific metabolite hubs exposes modularity in both compartmental and non-compartmental metabolic networks, improving detection of relevant clusters in omic measurements. Better computational detection of metabolic network clusters in large data sets has potential to identify differential regulation of individual genes, transcripts, and proteins.
PMID: 31972021 [PubMed - indexed for MEDLINE]
Eur Respir J. 2019 10;54(4):
Authors: Arjomandi M, Zeng S, Barjaktarevic I, Barr RG, Bleecker ER, Bowler RP, Buhr RG, Criner GJ, Comellas AP, Cooper CB, Couper DJ, Curtis JL, Dransfield MT, Han MK, Hansel NN, Hoffman EA, Kaner RJ, Kanner RE, Krishnan JA, Paine R, Peters SP, Rennard SI, Woodruff PG, SPIROMICS Investigators
Abstract
The characteristics that predict progression to overt chronic obstructive pulmonary disease (COPD) in smokers without spirometric airflow obstruction are not clearly defined.We conducted a post hoc analysis of 849 current and former smokers (≥20 pack-years) with preserved spirometry from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed-effect linear modelling.Among these subjects with normal forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio, CT-measured residual volume (RVCT) to total lung capacity (TLCCT) ratio varied widely, from 21% to 59%. Over 2.5±0.7 years of follow-up, subjects with higher RVCT/TLCCT had a greater differential rate of decline in FEV1/FVC; those in the upper RVCT/TLCCT tertile had a 0.66% (95% CI 0.06%-1.27%) faster rate of decline per year compared with those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former versus current) or smoking burden (pack-years). Accordingly, subjects with higher RVCT/TLCCT were more likely to develop spirometric COPD (OR 5.7 (95% CI 2.4-13.2) in upper versus lower RVCT/TLCCT tertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RVCT/TLCCT retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction.
PMID: 31439683 [PubMed - indexed for MEDLINE]
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Blood Adv. 2020 Oct 13;4(19):4864-4868
Authors: Luetkens T, Metcalf R, Planelles V, Zheng Y, Larragoite ET, Spivak ES, Spivak AM, Steinbach M, Blaylock RC, Avila SV, Hankey KG, Martins TB, Slev PR, Mannuel HD, Sajadi M, Rapoport AP, Atanackovic D
PMID: 33031540 [PubMed - as supplied by publisher]
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