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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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10/30- 11/6- FRIDAY, OCTOBER 30, 2020, 11:45- 1:00 PM - BIOENGINEERING ELEVATED SEMINAR SERIES - Dr. Dennis E. Discher - "Convergent science approaches to Solid Tumors: From Mechano-Genetic Variation to a Macrophage Checkpoint"
- FRIDAY, OCTOBER 30, 2020, 12:00- 2:30 PM - Dialogue on Disparities
- THURSDAY, NOVEMBER 5, 2020, 4:00- 5:00 PM - SBS Seminar Series - Dr. Jason Shepherd - “Viral Origins of Memory”
- FRIDAY, NOVEMBER 6, 2020, 12:00- 1:00 PM - November 3i COVID 19 Flash Talks
- FRIDAY, NOVEMBER 6, 2020, 11:45- 1:00 PM - BIOENGINEERING ELEVATED SEMINAR SERIES - Dr. Vetria L. Byrd - "Building Data Visualization Capacity: A Byrd’s Eye View"
- MONDAY, NOVEMBER 9, 2020, 2:00-3:00 PM - Biochemistry Seminar Series -Roshanak Irannejad - "The Role of Transporters in Regulating GPCR Signaling"
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- University of Utah 3i Global Health Symposium - WEDNESDAY, NOVEMBER 11, 2020, 12:00 PM -5:00 PM
- Vitae 2020 - THURSDAY, DECEMBER 10, 2020, 3:00 - 5:00 PM
- 3i Initiative Spring 2021 Symposium - FRIDAY, ARPIL 30, 2021, 8:00 AM -5:00 PM
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- 3i/UU Core expansion - Please fill out this survey on 3i/UU Core expansion to help prioritize services offered.
- 3i Initiative Graduate Fellowships in Emerging Microbial Threats and Inflammation - Applications are being accepted now. The deadline to apply is December 1st.
- Open Postdoctoral Research Position - The Puri Lab at the University of Utah seeks to hire a postdoctoral research associate to work on a funded project studying the biosynthesis of natural products made by underexplored bacteria. The ideal candidate will have a Ph.D. in Biochemistry, Chemistry, Microbiology, or a related field, and experience with protein expression, purification, and enzymology. Interested applicants should contact Aaron Puri directly (a.puri@utah.edu) with a cover letter, CV, and contact information for 3 references.
- School of Medicine Seed Grant Reviewers - The School of Medicine recently released a call for proposals for the School of Medicine Research Incentive Seed Grant Program. We are asking for faculty volunteers to serve on our review committee. The anticipated review period for this year’s grant applications will be December 11-January 4, with a review session to be held the week of January 11. If you are willing to assist please contact Abby Rooney.
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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:
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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Pigment Cell Melanoma Res. 2020 Oct 23;:
Authors: Parkman GL, Kircher DA, Stehn CM, McMahon M, Holmen SL
Abstract
Cutaneous melanoma is the most lethal form of skin cancer and is a complex, heterogeneous disease in terms of its etiology, histopathology, and genetics. Genetically engineered mouse (GEM) models provide an important platform for investigations of specific hypotheses, and as such, there are multiple different mouse models that have been employed to answer crucial questions underlying the biology of melanoma. Each of these models has advantages and limitations. The National Institutes of Health (NIH) has proposed a multi-dimensional initiative that includes sex as an additional biological variable in basic and preclinical research in order to eliminate bias in data analysis.
PMID: 33098202 [PubMed - as supplied by publisher]
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Chronic Obstr Pulm Dis. 2020 Oct;7(4):370-381
Authors: Burkes RM, Ceppe AS, Couper DJ, Comellas AP, Wells JM, Peters SP, Criner GJ, Kanner RE, Paine R, Christenson SA, Cooper CB, Barjaktarevic IZ, Krishnan JA, Labaki WW, Han MK, Curtis JL, Hansel NN, Wise RA, Drummond MB, SPIROMICS collaborators
Abstract
Ratrionale: The antimicrobial peptide cathelicidin, also known in humans as LL-37, is a defensin secreted by immune and airway epithelial cells. Deficiencies in this peptide may contribute to adverse pulmonary outcomes in chronic obstructive pulmonary disease (COPD).
Objectives: Using clinical and biological samples from the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we assessed the associations of plasma cathelicidin levels with cross-sectional and longitudinal COPD outcomes.
Methods: A total of 1609 SPIROMICS participants with COPD and available plasma samples were analyzed. Cathelicidin was modeled dichotomously (lowest quartile [< 50 ng/ml] versus highest 75% [≥ 50 ng/ml]) and continuously per 10 ng/ml. Fixed-effect multilevel regression analyses were used to assess associations between cathelicidin and cross-sectional as well as longitudinal lung function. The associations between cathelicidin and participant-reported retrospective and prospective COPD exacerbations were assessed via logistic regression.
Measurements and Main Results: Cathelicidin < 50 ng/ml (N=383) was associated with female sex, black race, and lower body mass index (BMI).At baseline,cathelicidin < 50 ng/ml was independently associated with 3.55% lower % predicted forced expiratory volume in 1 second (FEV1)(95% confidence interval [CI] -6.22% to -0.88% predicted; p=0.01), while every 10 ng/ml lower cathelicidin was independently associated with 0.65% lower % predicted FEV1 (95% CI -1.01% to -0.28% predicted; p< 0.001). No independent associations with longitudinal lung function decline or participant-reported COPD exacerbations were observed.
Conclusions: Reduced cathelicidin is associated with lower lung function at baseline. Plasma cathelicidin may potentially identify COPD patients at increased risk for more severe lung disease.
PMID: 33108110 [PubMed - as supplied by publisher]
J Exp Med. 2021 Feb 01;218(2):
Authors: Wirasinha RC, Davies AR, Srivastava M, Sheridan JM, Sng XYX, Delmonte OM, Dobbs K, Loh KL, Miosge LA, Lee CE, Chand R, Chan A, Yap JY, Keller MD, Chen K, Rossjohn J, La Gruta NL, Vinuesa CG, Reid HH, Lionakis MS, Notarangelo LD, Gray DHD, Goodnow CC, Cook MC, Daley SR
Abstract
NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that is partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IκB function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100.
PMID: 33107914 [PubMed - as supplied by publisher]
Nat Metab. 2020 Oct 26;:
Authors: Zhang Y, Taufalele PV, Cochran JD, Robillard-Frayne I, Marx JM, Soto J, Rauckhorst AJ, Tayyari F, Pewa AD, Gray LR, Teesch LM, Puchalska P, Funari TR, McGlauflin R, Zimmerman K, Kutschke WJ, Cassier T, Hitchcock S, Lin K, Kato KM, Stueve JL, Haff L, Weiss RM, Cox JE, Rutter J, Taylor EB, Crawford PA, Lewandowski ED, Des Rosiers C, Abel ED
Abstract
In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1-/-) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1-/- hearts. Although concurrent short-term KDs did not rescue cMPC1-/- hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function.
PMID: 33106689 [PubMed - as supplied by publisher]
Exp Neurol. 2020 04;326:113196
Authors: Clarkson C, Smeal RM, Hasenoehrl MG, White JA, Rubio ME, Wilcox KS
Abstract
The persistent unresponsiveness of many of the acquired epilepsies to traditional antiseizure medications has motivated the search for prophylactic drug therapies that could reduce the incidence of epilepsy in this at risk population. These studies are based on the idea of a period of epileptogenesis that can follow a wide variety of brain injuries. Epileptogenesis is hypothesized to involve changes in the brain not initially associated with seizures, but which result finally in seizure prone networks. Understanding these changes will provide crucial clues for the development of prophylactic drugs. Using the repeated low-dose kainate rat model of epilepsy, we have studied the period of epileptogenesis following status epilepticus, verifying the latent period with continuous EEG monitoring. Focusing on ultrastructural properties of the tripartite synapse in the CA1 region of hippocampus we found increased astrocyte ensheathment around both the presynaptic and postsynaptic elements, reduced synaptic AMPA receptor subunit and perisynaptic astrocyte GLT-1 expression, and increased number of docked vesicles at the presynaptic terminal. These findings were associated with an increase in frequency of the mEPSCs observed in patch clamp recordings of CA1 pyramidal cells. The results suggest a complex set of changes, some of which have been associated with increasingly excitable networks such as increased vesicles and mEPSC frequency, and some associated with compensatory mechanisms, such as increased astrocyte ensheathment. The diversity of ultrastructural and electrophysiological changes observed during epileptogeneiss suggests that potential drug targets for this period should be broadened to include all components of the tripartite synapse.
PMID: 31935368 [PubMed - indexed for MEDLINE]
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Science. 2020 10 09;370(6513):
Authors: Christensen DE, Ganser-Pornillos BK, Johnson JS, Pornillos O, Sundquist WI
Abstract
During the first half of the viral life cycle, HIV-1 reverse transcribes its RNA genome and integrates the double-stranded DNA copy into a host cell chromosome. Despite progress in characterizing and inhibiting these processes, in situ mechanistic and structural studies remain challenging. This is because these operations are executed by individual viral preintegration complexes deep within cells. We therefore reconstituted and imaged the early stages of HIV-1 replication in a cell-free system. HIV-1 cores released from permeabilized virions supported efficient, capsid-dependent endogenous reverse transcription to produce double-stranded DNA genomes, which sometimes looped out from ruptured capsid walls. Concerted integration of both viral DNA ends into a target plasmid then proceeded in a cell extract-dependent reaction. This reconstituted system uncovers the role of the capsid in templating replication.
PMID: 33033190 [PubMed - indexed for MEDLINE]
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Adv Exp Med Biol. 2020;1273:197-208
Authors: Cole AP, Hoffmeyer E, Chetty SL, Cruz-Cruz J, Hamrick F, Youssef O, Cheshier S, Mitra SS
Abstract
Microglia are the brain resident phagocytes that act as the primary form of the immune defense in the central nervous system. These cells originate from primitive macrophages that arise from the yolk sac. Advances in imaging and single-cell RNA-seq technologies provided new insights into the complexity of microglia biology.Microglia play an essential role in the brain development and maintenance of brain homeostasis. They are also crucial in injury repair in the central nervous system. The tumor microenvironment is complex and includes neoplastic cells as well as varieties of host and infiltrating immune cells. Microglia are part of the glioma microenvironment and play a critical part in initiating and maintaining tumor growth and spread. Microglia can also act as effector cells in treatments against gliomas. In this chapter, we summarize the current knowledge of how and where microglia are generated. We also discuss their functions during brain development, injury repair, and homeostasis. Moreover, we discuss the role of microglia in the tumor microenvironment of gliomas and highlight their therapeutic implications.
PMID: 33119883 [PubMed - as supplied by publisher]
J Thromb Haemost. 2020 Oct 29;:
Authors: Campbell RA, Boilard E, Rondina MT
Abstract
There is an urgent need to understand the underlying mechanisms contributing to thrombotic and inflammatory complications during COVID-19. Data from independent groups have identified that platelets are hyperreactive during COVID-19. Platelet hyperreactivity is accompanied by changes in platelet gene expression, and enhanced interactions between platelets and leukocytes. In some patients, SARS-CoV-2 mRNA has been detected in platelets. Together, this suggests that SARS-CoV-2 may interact with platelets. However, controversy remains on which receptors mediate SARS-CoV-2 platelet interactions. Most, but not all, transcriptomic and proteomic analyses fail to observe the putative SARS-CoV-2 receptor, angiotensin converting enzyme-2, or the cellular serine protease necessary for viral entry, TMPRSS2, on platelets and megakaryocytes. Interestingly, platelets express other known SARS-CoV-2 receptors, which induce similar patterns of activation to those observed when platelets are incubated with SARS-CoV-2. This Forum Article explores these findings, and discusses ongoing areas of controversy and uncertainty with regards to SARS-CoV-2 platelet interactions.
PMID: 33119197 [PubMed - as supplied by publisher]
Mol Genet Genomic Med. 2020 Oct 29;:e1532
Authors: Cannon-Albright LA, Teerlink CC, Stevens J, Snow AK, Thompson BA, Bell R, Nguyen KN, Sargent NR, Kohlmann WK, Neklason DW, Tavtigian SV
Abstract
PURPOSE: While familial aggregation of colorectal cancer (CRC) is recognized, the majority of the germline predisposition factors remain unidentified, and many high-risk CRC pedigrees remain unexplained by known risk variants. Fanconi Anemia genes have been recognized to be associated with cancer risk. Notably, FANCM (OMIM 609644) variants have been reported to confer risk for CRC and breast cancer.
METHODS: Exome sequencing of CRC-affected cousins in a set of 47 independent extended high-risk CRC pedigrees identified a candidate set of rare, shared variants. Variants were tested for association with risk in 744 Utah CRC cases and 1525 controls, and for segregation with CRC in affected relatives.
RESULTS: A FANCM stopgain variant was observed in two CRC-affected cousin pairs, each from an independent Utah high-risk pedigree, and yielded a nonsignificant, but elevated OR = 2.05 in a set of Utah cases and controls. Segregation of the variant to other related CRC-affected cases was observed in the two extended pedigrees.
CONCLUSION: A rare stopgain variant in FANCM (rs144567652) that is recognized as a breast cancer predisposition variant, and that has previously been proposed, but not confirmed, as a CRC predisposition variant, is validated here as a risk factor for familial CRC.
PMID: 33118316 [PubMed - as supplied by publisher]
Front Immunol. 2020 Oct 7;11:575200
Authors: Rogers SW, Myers EJ, Gahring LC
Abstract
Nicotine acts as a potent modulator of normal cellular responses through the nicotinic acetylcholine receptor subtype alpha7. In a mouse genetic model of alpha7 receptor dysfunction, alpha7E260A:G, 85 percent of 18 month-old mice exhibit an age-associated spontaneous loosening or complete loss of 3rd molars that was not present in the control mice. The adjacent soft tissues appeared largely unaffected. Further analysis including micro-CT revealed evidence of bone loss surrounding the 3rd molars with areas of cavitation and/or sponge-like (cancellous) bone remodeling in the mandible. The mandible microbiome was examined using 16S-rRNA sequencing. The results show the alpha7E260A:G oral microbiome included increased landscape complexity indicative of dysbiosis, and a significant increase of some bacteria, particularly Staphylococcus. These results suggest that normal alpha7 function plays a relevant role in maintaining normal gene expression and oral microbiome stasis. Consequently, this mouse model suggests there are consequences to ongoing alpha7 receptor dysfunction and oral health, as can occur from chronic exposure to nicotine as expected from electronic nicotine delivery systems (ENDS or "vaping"), that may not be seen until older age.
PMID: 33117372 [PubMed - in process]
Int J Chron Obstruct Pulmon Dis. 2020;15:2467-2476
Authors: Stott-Miller M, Müllerová H, Miller B, Tabberer M, El Baou C, Keeley T, Martinez FJ, Han M, Dransfield M, Hansel NN, Cooper CB, Woodruff P, Ortega VE, Comellas AP, Paine Iii R, Kanner RE, Anderson W, Drummond MB, Kim V, Tal-Singer R, Lazaar AL
Abstract
Background: Chronic cough and phlegm are frequently reported chronic obstructive pulmonary disease (COPD) symptoms. Prior research classified chronic mucus hypersecretion (CMH) based on the presence of these symptoms for ≥3 months, called chronic bronchitis (CB) if respiratory infection symptoms were present for 1-2 years (Medical Research Council [MRC] definition). We explored whether the COPD Assessment Test (CAT), a simple measure developed for routine clinical use, captures CMH populations and outcomes similarly to MRC and St. George's Respiratory Questionnaire (SGRQ) definitions.
Methods: We identified CMH in the SPIROMICS COPD cohort using (a) MRC definitions, (b) SGRQ questions for cough and phlegm (both as most/several days a week), and (c) CAT cough and phlegm questions. We determined optimal cut-points for CAT items and described exacerbation frequencies for different CMH definitions. Moderate exacerbations required a new prescription for antibiotics/oral corticosteroids or emergency department visit; severe exacerbations required hospitalization. Results were stratified by smoking status.
Results: In a population of 1431 participants (57% male; mean FEV1% predicted 61%), 47% and 49% of evaluable participants had SGRQ- or CAT-defined CMH, respectively. A cut-point of ≥2 for cough and phlegm items defined CMH in CAT. Among SGRQ-CMH+ participants, 80% were also defined as CMH+ by the CAT. CMH+ participants were more likely to be current smokers. A higher exacerbation frequency was observed for presence of CMH+ versus CMH- in the year prior to baseline for all CMH definitions; this trend continued across 3 years of follow-up, regardless of smoking status.
Conclusion: Items from the CAT identified SGRQ-defined CMH, a frequent COPD trait that correlated with exacerbation frequency. The CAT is a short, simple questionnaire and a potentially valuable tool for telemedicine or real-world trials. CAT-based CMH is a novel approach for identifying clinically important characteristics in COPD that can be ascertained in these settings.
PMID: 33116463 [PubMed - in process]
Future Oncol. 2020 Oct 29;:
Authors: Chien SH, Morreall D, Patil V, Rasmussen KM, Li C, Yong CM, Burningham Z, Masaquel A, Halloran M, De Long-Sieg E, Schulz M, Sauer BC, Halwani AS
Abstract
Aim: To describe practices and outcomes in veterans with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Using Veteran Affairs Cancer Registry System and electronic health record data, we identified relapsed/refractory diffuse large B-cell lymphoma patients completing second-line treatment (2L) in 2000-2016. Treatments were classified as aggressive/nonaggressive. Analyses included descriptive statistics and the Kaplan-Meier estimation of progression-free survival and overall survival. Results: Two hundred and seventy patients received 2L. During median 9.7-month follow-up starting from 2L, 470 regimens were observed, averaging 2.7 regimens/patient: 219 aggressive, 251 nonaggressive. One hundred and twenty-one patients proceeded to third-line, 50 to fourth-line and 18 to fifth-line treatment. Median progression-free survival in 2L was 5.2 months. Median overall survival was 9.5 months. Forty-four patients (16.3%) proceeded to bone marrow transplant. Conclusion: More effective, less toxic treatments are needed and should be initiated earlier in treatment trajectory.
PMID: 33115291 [PubMed - as supplied by publisher]
J Antibiot (Tokyo). 2020 05;73(5):290-298
Authors: Miller BW, Torres JP, Tun JO, Flores MS, Forteza I, Rosenberg G, Haygood MG, Schmidt EW, Concepcion GP
Abstract
The emergence of antibiotic resistance necessitates not only the identification of new compounds with antimicrobial properties, but also new strategies and combination therapies to circumvent this growing problem. Here, we report synergistic activity against methicillin-resistant Staphylococcus aureus (MRSA) of the β-lactam antibiotic oxacillin combined with 7,8-dideoxygriseorhodin C in vitro. Ongoing efforts to identify antibiotics from marine mollusk-associated bacteria resulted in the isolation of 7,8-dideoxygriseorhodin C from a Streptomyces sp. strain cultivated from a marine gastropod tissue homogenate. Despite the long history of 7,8-dideoxygriseorhodin C in the literature, the absolute configuration has never been previously reported. A comparison of measured and calculated ECD spectra resolved the configuration of the spiroketal carbon C6, and 2D ROESY NMR spectroscopy established the absolute configuration as 6s,6aS. The compound is selective against Gram-positive bacteria including MRSA and Enterococcus faecium with an MIC range of 0.125-0.5 μg ml-1. Moreover, the compound synergizes with oxacillin against MRSA as observed in the antimicrobial microdilution and time-kill assays. Simultaneous treatment of the compound with oxacillin resulted in an approximately tenfold decrease in MIC with a combination index of <0.5, indicating synergistic anti-MRSA activity.
PMID: 31992865 [PubMed - indexed for MEDLINE]
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