Publications by authors named "Courtney Smith"

109 Publications

IGSF1 Does Not Regulate Spermatogenesis or Modify FSH Synthesis in Response to Inhibins or Activins.

J Endocr Soc 2021 Apr 20;5(4):bvab023. Epub 2021 Feb 20.

Department of Anatomy and Cell Biology, McGill University, Montréal, Québec H3A 0C7, Canada.

Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 () gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as an inhibitor of activin type I receptor (ALK4) activity in pituitary gonadotrope cells. If true, loss of IGSF1 should lead to reduced inhibin B action or disinhibition of activin signaling, thereby increasing FSH synthesis. Here, we show that FSH levels and sperm counts are normal in male knockout mice, although testis size is mildly increased. Sperm parameters are also normal in men with IGSF1 deficiency, although their FSH levels may trend higher and their testes are enlarged. Inhibin B retains the ability to suppress FSH synthesis in pituitaries of -knockout mice and IGSF1 does not interact with ALK4 or alter activin A/ALK4 stimulation of FSHβ () subunit transcription or expression. In light of these results, it is unlikely that macroorchidism in IGSF1 deficiency derives from alterations in spermatogenesis or inhibin/activin regulation of FSH.
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http://dx.doi.org/10.1210/jendso/bvab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986638PMC
April 2021

Computational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104-6315;

Kinases play important roles in diverse cellular processes, including signaling, differentiation, proliferation, and metabolism. They are frequently mutated in cancer and are the targets of a large number of specific inhibitors. Surveys of cancer genome atlases reveal that kinase domains, which consist of 300 amino acids, can harbor numerous (150 to 200) single-point mutations across different patients in the same disease. This preponderance of mutations-some activating, some silent-in a known target protein make clinical decisions for enrolling patients in drug trials challenging since the relevance of the target and its drug sensitivity often depend on the mutational status in a given patient. We show through computational studies using molecular dynamics (MD) as well as enhanced sampling simulations that the experimentally determined activation status of a mutated kinase can be predicted effectively by identifying a hydrogen bonding fingerprint in the activation loop and the αC-helix regions, despite the fact that mutations in cancer patients occur throughout the kinase domain. In our study, we find that the predictive power of MD is superior to a purely data-driven machine learning model involving biochemical features that we implemented, even though MD utilized far fewer features (in fact, just one) in an unsupervised setting. Moreover, the MD results provide key insights into convergent mechanisms of activation, primarily involving differential stabilization of a hydrogen bond network that engages residues of the activation loop and αC-helix in the active-like conformation (in >70% of the mutations studied, regardless of the location of the mutation).
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http://dx.doi.org/10.1073/pnas.2019132118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958353PMC
March 2021

A critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy.

Nat Commun 2021 03 3;12(1):1423. Epub 2021 Mar 3.

Department of Biology, The University of Texas at San Antonio, San Antonio, TX, USA.

In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.
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http://dx.doi.org/10.1038/s41467-021-21649-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930276PMC
March 2021

School Closures During COVID-19: Opportunities for Innovation in Meal Service.

Am J Public Health 2020 11 17;110(11):1635-1643. Epub 2020 Sep 17.

Eliza W. Kinsey is with the Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY. Amelie A. Hecht is with the Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. Caroline Glagola Dunn is with the Department of Health Policy and Management, Harvard T. H. Chan School of Public Health, Boston, MA. Ronli Levi and Hilary K. Seligman are with the Department of Medicine and the Center for Vulnerable Populations, University of California, San Francisco. Margaret A. Read, Courtney Smith, and Pamela Niesen are with Share Our Strength, No Kid Hungry Campaign, Washington, DC. Erin R. Hager is with the Department of Pediatrics and the Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore.

In 2019, the National School Lunch Program and School Breakfast Program served approximately 15 million breakfasts and 30 million lunches daily at low or no cost to students.Access to these meals has been disrupted as a result of long-term school closures related to the COVID-19 pandemic, potentially decreasing both student nutrient intake and household food security. By the week of March 23, 2020, all states had mandated statewide school closures as a result of the pandemic, and the number of weekly missed breakfasts and lunches served at school reached a peak of approximately 169.6 million; this weekly estimate remained steady through the final week of April.We highlight strategies that states and school districts are using to replace these missed meals, including a case study from Maryland and the US Department of Agriculture waivers that, in many cases, have introduced flexibility to allow for innovation. Also, we explore lessons learned from the pandemic with the goal of informing and strengthening future school nutrition policies for out-of-school time, such as over the summer.
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http://dx.doi.org/10.2105/AJPH.2020.305875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542295PMC
November 2020

Repeated evolution of eye loss in Mexican cavefish: Evidence of similar developmental mechanisms in independently evolved populations.

J Exp Zool B Mol Dev Evol 2020 11 2;334(7-8):423-437. Epub 2020 Jul 2.

Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, Florida.

Evolution in similar environments often leads to convergence of behavioral and anatomical traits. A classic example of convergent trait evolution is the reduced traits that characterize many cave animals: reduction or loss of pigmentation and eyes. While these traits have evolved many times, relatively little is known about whether these traits repeatedly evolve through the same or different molecular and developmental mechanisms. The small freshwater fish, Astyanax mexicanus, provides an opportunity to investigate the repeated evolution of cave traits. A. mexicanus exists as two forms, a sighted, surface-dwelling form and at least 29 populations of a blind, cave-dwelling form that initially develops eyes that subsequently degenerate. We compared eye morphology and the expression of eye regulatory genes in developing surface fish and two independently evolved cavefish populations, Pachón and Molino. We found that many of the previously described molecular and morphological alterations that occur during eye development in Pachón cavefish are also found in Molino cavefish. However, for many of these traits, the Molino cavefish have a less severe phenotype than Pachón cavefish. Further, cave-cave hybrid fish have larger eyes and lenses during early development compared with fish from either parental population, suggesting that some different changes underlie eye loss in these two populations. Together, these data support the hypothesis that these two cavefish populations evolved eye loss independently, yet through some of the same developmental and molecular mechanisms.
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http://dx.doi.org/10.1002/jez.b.22977DOI Listing
November 2020

Traffic jam at the nuclear pore: All roads lead to nucleocytoplasmic transport defects in ALS/FTD.

Neurobiol Dis 2020 07 14;140:104835. Epub 2020 Mar 14.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that specifically affects the function and survival of spinal and cortical motor neurons. ALS shares many genetic, clinical, and pathological characteristics with frontotemporal dementia (FTD), and these diseases are now recognized as presentations of a disease spectrum known as ALS/FTD. The molecular determinants of neuronal loss in ALS/FTD are still debated, but the recent discovery of nucleocytoplasmic transport defects as a common denominator of most if not all forms of ALS/FTD has dramatically changed our understanding of the pathogenic mechanisms of this disease. Loss of nuclear pores and nucleoporin aggregation, altered nuclear morphology, and impaired nuclear transport are some of the most prominent features that have been identified using a variety of animal, cellular, and human models of disease. Here, we review the experimental evidence linking nucleocytoplasmic transport defects to the pathogenesis of ALS/FTD and propose a unifying view on how these defects may lead to a vicious cycle that eventually causes neuronal death.
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http://dx.doi.org/10.1016/j.nbd.2020.104835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253339PMC
July 2020

A Tale of Two Proteins: Betaglycan, IGSF1, and the Continuing Search for the Inhibin B Receptor.

Trends Endocrinol Metab 2020 01 22;31(1):37-45. Epub 2019 Oct 22.

Department of Anatomy and Cell Biology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6.

Inhibins are gonadal hormones that suppress follicle-stimulating hormone (FSH) synthesis by pituitary gonadotrope cells. The structurally related activins stimulate FSH by signaling through complexes of type I and type II receptors. Two models of inhibin action were proposed in 2000. First, inhibins function as competitive receptor antagonists, binding activin type II receptors with high affinity in the presence of the TGF-β type III coreceptor, betaglycan. Second, immunoglobulin superfamily, member 1 (IGSF1, then called p120) was proposed to mediate inhibin B antagonism of activin signaling via its type I receptor. These ideas have been challenged over the past few years. Rather than playing a role in inhibin action, IGSF1 is involved in the central control of the thyroid gland. Betaglycan binds inhibin A and inhibin B with high affinity, but only functions as an obligate inhibin A coreceptor in murine gonadotropes. There is likely to be a distinct, but currently unidentified coreceptor for inhibin B.
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http://dx.doi.org/10.1016/j.tem.2019.08.014DOI Listing
January 2020

Individual Sea Urchin Coelomocytes Undergo Somatic Immune Gene Diversification.

Front Immunol 2019 6;10:1298. Epub 2019 Jun 6.

Department of Biological Sciences, The George Washington University, Washington, DC, United States.

The adaptive immune response in jawed vertebrates is marked by the ability to diversify somatically specific immune receptor genes. Somatic recombination and hypermutation of gene segments are used to generate extensive repertoires of T and B cell receptors. In contrast, jawless vertebrates utilize a distinct diversification system based on copy choice to assemble their variable lymphocyte receptors. To date, very little evidence for somatic immune gene diversification has been reported in invertebrate species. Here we show that the ( ; formerly ) immune effector gene family members from individual coelomocytes from purple sea urchins undergo somatic diversification by means of gene deletions, duplications, and acquisitions of single nucleotide polymorphisms. While sperm cells from an individual sea urchin have identical gene repertoires, single cells from two distinct coelomocyte subpopulations from the same sea urchin exhibit significant variation in the gene repertoires. Moreover, the highly diverse gene sequences derived from single coelomocytes are all in-frame, suggesting that an unknown mechanism(s) driving these somatic changes involve stringent selection or correction processes for expression of productive transcripts. Together, our findings infer somatic immune gene diversification strategy in an invertebrate.
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http://dx.doi.org/10.3389/fimmu.2019.01298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563789PMC
October 2020

The Axial Organ and the Pharynx Are Sites of Hematopoiesis in the Sea Urchin.

Front Immunol 2019 25;10:870. Epub 2019 Apr 25.

Department of Biological Sciences, George Washington University, Washington, DC, United States.

The location of coelomocyte proliferation in adult sea urchins is unknown and speculations since the early 1800s have been based on microanatomy and tracer uptake studies. In adult sea urchins () with down-regulated immune systems, coelomocyte numbers increase in response to immune challenge, and whether some or all of these cells are newly proliferated is not known. The gene regulatory network that encodes transcription factors that control hematopoiesis in embryonic and larval sea urchins has not been investigated in adults. Hence, to identify the hematopoietic tissue in adult sea urchins, cell proliferation, expression of phagocyte specific genes, and expression of genes encoding transcription factors that function in the conserved regulatory network that controls hematopoiesis in embryonic and larval sea urchins were investigated for several tissues. Cell proliferation was induced in adult sea urchins either by immune challenge through injection of heat-killed or by cell depletion through aspiration of coelomic fluid. In response to either of these stimuli, newly proliferated coelomocytes constitute only about 10% of the cells in the coelomic fluid. In tissues, newly proliferated cells and cells that express SpTransformer proteins (formerly Sp185/333) that are markers for phagocytes are present in the axial organ, gonad, pharynx, esophagus, and gut with no differences among tissues. The expression level of genes encoding transcription factors that regulate hematopoiesis show that both the axial organ and the pharynx have elevated expression compared to coelomocytes, esophagus, gut, and gonad. Similarly, an RNAseq dataset shows similar results for the axial organ and pharynx, but also suggests that the axial organ may be a site for removal and recycling of cells in the coelomic cavity. Results presented here are consistent with previous speculations that the axial organ may be a site of coelomocyte proliferation and that it may also be a center for cellular removal and recycling. A second site, the pharynx, may also have hematopoietic activity, a tissue that has been assumed to function only as part of the intestinal tract.
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http://dx.doi.org/10.3389/fimmu.2019.00870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494969PMC
July 2020

Infection as a Predictor of Low Aerobic Capacity in Ugandan Children.

Am J Trop Med Hyg 2019 06;100(6):1498-1506

Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Using the 20-meter shuttle run test (20mSRT) as a morbidity metric, we assessed whether infection was associated with decreased aerobic capacity in Ugandan children across a range of altitudes, either at low (∼600 m) or high (∼1,000 m) altitudes. A total of 305 children were recruited from six schools within the Buliisa District, Lake Albert, Uganda. A subset ( = 96) of these had been previously assessed and treated for schistosomiasis ± malaria 2 weeks prior. Fitness scores on the 20mSRT were translated into VO2max using a standardized equation. Unadjusted and multivariable-adjusted analyses were performed using VO2max as the primary outcome. Analysis of fitness scores from 304 children, inclusive of the subset follow-up cohort, revealed a median VO2max of 45.4 mL kg min (interquartile range: 42.9-48.0 mL kg min). Children residing at high altitudes demonstrated increased aerobic capacities (46.3 versus 44.8 mL kg min, = 0.031). The prevalence of stunting, wasting, egg patent infection, malaria, giardiasis, anemia, and fecal occult blood were 36.7%, 16.1%, 44.3%, 65.2%, 21.4%, 50.6%, and 41.2%, respectively. Median VO2max was elevated in those previously treated, compared with those newly recruited (46.3 versus 44 mL kg min, < 0.001). Multivariable-adjusted analysis revealed a strong negative association between egg patent infection and VO2max at low altitude (beta coefficient: -3.96, 95% CI: -6.56 to -137, = 0.004). This is the first study to document a negative association between infection and aerobic capacity at low altitudes using the 20mSRT.
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http://dx.doi.org/10.4269/ajtmh.18-0922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553905PMC
June 2019

Methods for collection, handling, and analysis of sea urchin coelomocytes.

Methods Cell Biol 2019 9;150:357-389. Epub 2019 Jan 9.

Stem Cell Institute, School of Medicine, and the Hopkins Marine Station, Stanford University, Stanford, CA, United States.

Sea urchin coelomocytes can be collected in large numbers from adult sea urchins of the species, Strongylocentrotus purpuratus, which typically has 12-40mL of coelomic fluid. Coelomocytes are used for analysis of immune reactions and immune gene expression in addition to basic functions of cells, in particular for understanding structure and modifications of the cytoskeleton in phagocytes. The methods described here include coelomocyte isolation, blocking the clotting reaction, establishing and maintaining primary cultures, separation of different types of coelomocytes into fractions, processing live coelomocytes for light microscopy, fixation and staining for light and electron microscopy, analysis of coelomocyte populations by flow cytometry, and sorting single cells for more detailed follow-up analyses including transcriptomics or genomic characteristics. These methods are provided to make working with coelomocytes accessible to researchers who are unfamiliar with these cells and perhaps to aid others who have worked extensively with invertebrate cells.
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http://dx.doi.org/10.1016/bs.mcb.2018.11.009DOI Listing
June 2019

Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents.

Angew Chem Int Ed Engl 2019 02 30;58(8):2454-2458. Epub 2019 Jan 30.

Department of Chemistry, Scripps Research, North Torrey Pines Road, La Jolla, CA, 92037, USA.

This work bridges a gap in the cross-coupling of aliphatic redox-active esters with aryl zinc reagents. Previously limited to primary, secondary, and specialized tertiary centers, a new protocol has been devised to enable the coupling of general tertiary systems using nickel catalysis. The scope of this operationally simple method is broad, and it can be used to simplify the synthesis of medicinally relevant motifs bearing quaternary centers.
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http://dx.doi.org/10.1002/anie.201814524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391118PMC
February 2019

HDAC1 overexpression enhances β-cell proliferation by down-regulating Cdkn1b/p27.

Biochem J 2018 12 19;475(24):3997-4010. Epub 2018 Dec 19.

Nutrition, Dietetics and Food Science Department, College of Life Sciences, Brigham Young University, Provo, UT 84602, U.S.A.

The homeobox transcription factor Nkx6.1 is sufficient to increase functional β-cell mass, where functional β-cell mass refers to the combination of β-cell proliferation, glucose-stimulated insulin secretion (GSIS) and β-cell survival. Here, we demonstrate that the histone deacetylase 1 (HDAC1), which is an early target of Nkx6.1, is sufficient to increase functional β-cell mass. We show that HDAC activity is necessary for Nkx6.1-mediated proliferation, and that HDAC1 is sufficient to increase β-cell proliferation in primary rat islets and the INS-1 832/13 β-cell line. The increase in HDAC1-mediated proliferation occurs while maintaining GSIS and increasing β-cell survival in response to apoptotic stimuli. We demonstrate that HDAC1 overexpression results in decreased expression of the cell cycle inhibitor Cdkn1b/p27 which is essential for inhibiting the G1 to S phase transition of the cell cycle. This corresponds with increased expression of key cell cycle activators, such as Cyclin A2, Cyclin B1 and E2F1, which are activated by activation of the Cdk4/Cdk6/Cyclin D holoenzymes due to down-regulation of Cdkn1b/p27. Finally, we demonstrate that overexpression of Cdkn1b/p27 inhibits HDAC1-mediated β-cell proliferation. Our data suggest that HDAC1 is critical for the Nkx6.1-mediated pathway that enhances functional β-cell mass.
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http://dx.doi.org/10.1042/BCJ20180465DOI Listing
December 2018

Common and Unique Neural Systems Underlying the Working Memory Maintenance of Emotional vs. Bodily Reactions to Affective Stimuli: The Moderating Role of Trait Emotional Awareness.

Front Hum Neurosci 2018 18;12:370. Epub 2018 Sep 18.

Department of Psychiatry, University of Arizona, Tucson, AZ, United States.

Many leading theories suggest that the neural processes underlying the experience of one's own emotional reactions partially overlap with those underlying bodily perception (i.e., interoception, somatosensation, and proprioception). However, the goal-directed maintenance of one's own emotions in working memory (EWM) has not yet been compared to WM maintenance of one's own bodily reactions (BWM). In this study, we contrasted WM maintenance of emotional vs. bodily reactions to affective stimuli in 26 healthy individuals while they underwent functional magnetic resonance imaging. Specifically, we examined the a priori hypothesis that individual differences in trait emotional awareness (tEA) would lead to greater differences between these two WM conditions within medial prefrontal cortex (MPFC). We observed that MPFC activation during EWM (relative to BWM) was positively associated with tEA. Whole-brain analyses otherwise suggested considerable similarity in the neural activation patterns associated with EWM and BWM. In conjunction with previous literature, our findings not only support a central role of body state representation/maintenance in EWM, but also suggest greater engagement of MPFC-mediated conceptualization processes during EWM in those with higher tEA.
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http://dx.doi.org/10.3389/fnhum.2018.00370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153922PMC
September 2018

ALS-associated genes display CNS expression in the developing zebrafish.

Gene Expr Patterns 2018 12 27;30:14-31. Epub 2018 Aug 27.

Department of Genetics, Development and Cell Biology, 2437 Pammel Drive, 2114 Molecular Biology, Iowa State University, Ames, IA, 50011, USA. Electronic address:

Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle atrophy resulting from the deterioration of motor neurons in the central nervous system (CNS). Recent genome-wide association studies have revealed several genes linked to ALS, further demonstrating the complexity of the disease. The zebrafish (Danio rerio) is an attractive model organism to study the function of the rapidly expanding number of ALS-associated genes, in part, due to the development of genome editing techniques that have facilitated specific gene targeting. Before investing in the manipulation and phenotypic examination of these genes, however, it is important to ascertain the localization of expression in this organism. We performed an expression analysis of 29 total ALS-linked genes in the developing zebrafish, specifically focusing on those genes that displayed robust and reproducible expression at multiple different timepoints. First, we classified a subset of the most robustly expressed genes into three distinct groups: head-only expression, head and weak trunk expression, and head and robust trunk expression. Then, we defined the characteristic pattern of each gene at 2, 3, and 4 days post fertilization. This analysis will facilitate improved mutant phenotype assessment in zebrafish by focusing researchers on the areas of expression.
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http://dx.doi.org/10.1016/j.gep.2018.08.003DOI Listing
December 2018

The impact of organized breast assessment on survival by stage for screened women diagnosed with invasive breast cancer.

Breast 2018 Oct 18;41:25-33. Epub 2018 Jun 18.

Prevention and Cancer Control, Cancer Care Ontario, 620 University Avenue Toronto, Ontario M5G 2L7, Canada; St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; Department of Medical Imaging, University of Toronto, 263 McCaul Street, 4th Floor Toronto, Ontario M5T 1W7, Canada.

Purpose: Since 1998, the Ontario Breast Screening Program (OBSP) has offered organized assessment through Breast Assessment Centres (BAC). This study compares survival between screened women diagnosed with breast cancer who have undergone assessment through a BAC and usual care (UC).

Methods: A retrospective design identified two concurrent cohorts of women aged 50 to 69 within the OBSP diagnosed with screen-detected invasive breast cancer at a BAC (n = 2010) and UC (n = 1844) between 2002 and 2010 and followed until 2016. Demographic and assessment characteristics were obtained from the OBSP. Abstraction of medical charts provided prognostic and treatment data. Death data were assessed from the Registered Person's Database and the Ontario Registrar General All-Cause Mortality File. Multivariable Cox proportional hazards models compared overall survival by assessment type (BAC/UC), stratified by stage.

Results: There were 505 deaths during the study (BAC = 239; UC = 266). Among women with stage I screen-detected breast cancer, those diagnosed through a BAC had 31% reduced risk of all-cause mortality (HR = 0.69, 95% CI = 0.53-0.90) compared to UC. Diagnosis within 7 weeks of an abnormal mammogram reduced the hazard of death from all causes by 34% among all women with stage I breast cancers (HR = 0.66, 95% CI = 0.47-0.91), and was more likely in BAC (79.7%) than UC (66.9%).

Conclusion: The significant improvement in overall survival for women with stage I screen-detected invasive breast cancer assessed through BACs further supports the recommendation that women with abnormal mammograms should be managed through organized assessment.
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http://dx.doi.org/10.1016/j.breast.2018.06.007DOI Listing
October 2018

Validity of Administrative Databases in Comparison to Medical Charts for Breast Cancer Treatment Data.

J Cancer Epidemiol 2018 14;2018:9218595. Epub 2018 May 14.

Prevention and Cancer Control, Cancer Care Ontario, 620 University Avenue, Toronto, ON, Canada M5G 2L7.

Objective: Medical chart abstraction is the gold standard for collecting breast cancer treatment data for monitoring and research. A less costly alternative is the use of administrative databases. This study will evaluate administrative data in comparison to medical charts for breast cancer treatment information.

Study Design And Setting: A retrospective cohort design identified 2,401 women in the Ontario Breast Screening Program diagnosed with invasive breast cancer from 2006 to 2009. Treatment data were obtained from the Activity Level Reporting and Canadian Institute of Health Information databases. Medical charts were abstracted at cancer centres. Sensitivity, specificity, positive and negative predictive value, and kappa were calculated for receipt and type of treatment, and agreement was assessed for dates. Logistic regression evaluated factors influencing agreement.

Results: Sensitivity and specificity for receipt of radiotherapy (92.0%, 99.3%), chemotherapy (77.7%, 99.2%), and surgery (95.8%, 100%) were high but decreased slightly for specific radiotherapy anatomic locations, chemotherapy protocols, and surgeries. Agreement increased by radiotherapy year (trend test, < 0.0001). Stage II/III compared to stage I cancer decreased odds of agreement for chemotherapy (OR = 0.66, 95% CI: 0.48-0.91) and increased agreement for partial mastectomy (OR = 3.36, 95% CI: 2.27-4.99). Exact agreement in treatment dates varied from 83.0% to 96.5%.

Conclusion: Administrative data can be accurately utilized for future breast cancer treatment studies.
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http://dx.doi.org/10.1155/2018/9218595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976924PMC
May 2018

Positive Value of a Women's Junior Faculty Mentoring Program: A Mentor-Mentee Analysis.

J Womens Health (Larchmt) 2018 08 29;27(8):1045-1053. Epub 2018 May 29.

2 Office of Women in Medicine and Science , Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background: Recently appointed women faculty in academic medicine face many challenges during their careers and can become overwhelmed managing their multiple faculty roles as teacher, scholar, and clinician, in addition to their roles in personal life. Although a mentor can be invaluable in assisting a woman junior faculty member to adjust to faculty life and providing critical career guidance, not all medical institutions have faculty mentoring programs. We created a mentoring program specifically for our women junior faculty to address this issue at our own institution.

Materials And Methods: To assess the value of this program, we conducted a novel mentor-mentee paired-data analysis of annual surveys collected from 2010 to 2015. Of the 470 responses received, 83 were from unique mentees and 61 from unique mentors.

Results: Career development, research, and promotion were the top topics discussed among the mentoring pairs, followed by discussions of institutional resources and administration/service. There was high congruency among the mentoring pairs that they thought these discussions, as well as other conversations about mentee professional development and well-being, had been helpful. However in some instances, mentors felt they had not been helpful to their mentee, whereas their mentees felt otherwise; this finding speaks to the value and importance of mentees providing positive feedback to their mentors. Overall, both mentees and mentors thought that the mentees had significantly benefited from the mentorship. Unexpected outcomes of these relationships included promotion, grant applications/awards, articles, presentations, and professional memberships. The use of a Mentee Needs Assessment Form to individualize the mentoring relationship for each mentee may explain the high overall satisfaction and participant recommendations of the program.

Conclusions: Our findings demonstrate the value in establishing mentoring programs specifically for women faculty, especially in environments in which other mentoring opportunities do not exist.
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http://dx.doi.org/10.1089/jwh.2017.6661DOI Listing
August 2018

SpTransformer proteins from the purple sea urchin opsonize bacteria, augment phagocytosis, and retard bacterial growth.

PLoS One 2018 8;13(5):e0196890. Epub 2018 May 8.

Department of Biological Sciences, George Washington University, Washington, DC, United States of America.

The purple sea urchin, Strongylocentrotus purpuratus, has a complex and robust immune system that is mediated by a number of multi-gene families including the SpTransformer (SpTrf) gene family (formerly Sp185/333). In response to immune challenge from bacteria and various pathogen-associated molecular patterns, the SpTrf genes are up-regulated in sea urchin phagocytes and express a diverse array of SpTrf proteins. We show here that SpTrf proteins from coelomocytes and isolated by nickel affinity (cNi-SpTrf) bind to Gram-positive and Gram-negative bacteria and to Baker's yeast, Saccharomyces cerevisiae, with saturable kinetics and specificity. cNi-SpTrf opsonization of the marine bacteria, Vibrio diazotrophicus, augments phagocytosis, however, opsonization by the recombinant protein, rSpTrf-E1, does not. Binding by cNi-SpTrf proteins retards growth rates significantly for several species of bacteria. SpTrf proteins, previously thought to be strictly membrane-associated, are secreted from phagocytes in short term cultures and bind V. diazotrophicus that are located both outside of and within phagocytes. Our results demonstrate anti-microbial activities of native SpTrf proteins and suggest variable functions among different SpTrf isoforms. Multiple isoforms may act synergistically to detect a wide array of pathogens and provide flexible and efficient host immunity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196890PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940198PMC
August 2018

From Consternation to Revelation: Discovery of a Role for IGSF1 in Pituitary Control of Thyroid Function.

J Endocr Soc 2018 Mar 6;2(3):220-231. Epub 2018 Feb 6.

Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

Immunoglobulin superfamily, member 1 (IGSF1) is a transmembrane glycoprotein highly expressed in the mammalian pituitary gland. Shortly after its discovery in 1998, the protein was proposed to function as a coreceptor for inhibins (and was even temporarily renamed inhibin binding protein). However, subsequent investigations, both and , failed to support a role for IGSF1 in inhibin action. Research on IGSF1 nearly ground to a halt until 2011, when next-generation sequencing identified mutations in the X-linked gene in boys and men with congenital central hypothyroidism. IGSF1 was localized to thyrotrope cells, implicating the protein in pituitary control of the thyroid. Investigations in two knockout mouse models converged to show that IGSF1 deficiency leads to reduced expression of the receptor for thyrotropin-releasing hormone (TRH) and impaired TRH stimulation of thyrotropin secretion, providing a candidate mechanism for the central hypothyroidism observed in patients. Nevertheless, the normal functions of IGSF1 in thyrotropes and other cells remain unresolved. Moreover, mutations are also commonly associated with other clinical phenotypes, including prolactin and growth hormone dysregulation, and macroorchidism. How the loss of IGSF1 produces these characteristics is unknown. Although early studies of IGSF1 ran into roadblocks and blind alleys, armed with the results of detailed clinical investigations, powerful mouse models, and new reagents, the field is now poised to discover IGSF1's function in endocrine tissues, including the pituitary and testes.
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http://dx.doi.org/10.1210/js.2017-00478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841168PMC
March 2018

The role of medial prefrontal cortex in the working memory maintenance of one's own emotional responses.

Sci Rep 2018 02 22;8(1):3460. Epub 2018 Feb 22.

Department of Psychiatry, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ, 85724-5002, United States.

The role of medial prefrontal cortex (MPFC) in maintaining emotional information within working memory (WM) remains insufficiently investigated - with some studies suggesting this process activates MPFC and others suggesting its activity is suppressed. To reconcile these different results, we asked 26 healthy participants to complete a WM task involving the maintenance of emotional content (EWM), visual content (VWM), or no content ("rest") after exposure to emotion-provoking images. We also assessed individual differences in emotional awareness (EA). We observed that dorsal MPFC was more active during EWM than VWM; further, relative to the rest condition, both of these WM conditions involved suppression of ventral MPFC. We also observed that the dorsal anterior cingulate subregion of dorsal MPFC was positively associated with EA. We discuss how these results may be able to reconcile the findings of previous EWM studies, and extend understanding of the relationship between MPFC, EA, and WM.
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http://dx.doi.org/10.1038/s41598-018-21896-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823866PMC
February 2018

Canadian physicians' knowledge and counseling practices related to antibiotic use and antimicrobial resistance: Two-cycle national survey.

Can Fam Physician 2017 Dec;63(12):e526-e535

Senior Epidemiologist at the Centre for Chronic Disease Prevention at the Public Health Agency of Canada in Ottawa.

Objective: To establish a baseline for physicians' knowledge of and counseling practices on the use of antibiotics and antimicrobial resistance (AMR), and to determine potential changes in these measures after the implementation of a national AMR awareness campaign.

Design: Cross-sectional design.

Setting: Canada.

Participants: A total of 1600 physicians.

Main Outcome Measures: Physicians' knowledge of and counseling practices on antibiotic use and AMR at baseline and after implementation of the AMR awareness campaign.

Results: A total of 336 physicians responded to the first-cycle survey (before the campaign), and 351 physicians responded to the second-cycle survey (after the campaign). Overall, physicians' knowledge of appropriate antibiotic use and AMR was high and their counseling practices in relation to antibiotics were appropriate in both surveys. Counseling levels about topics related to infection prevention and control (eg, food handling, household hygiene) were slightly lower. Counseling levels were also lower for certain antibiotic-use practices (eg, proper disposal of antibiotics). In addition, physicians with less than 10 years of practice experience had significantly lower odds of counseling their patients on topics related to preventing antibiotic resistance and infection prevention than those with 15 or more years of practice experience (adjusted odds ratio = 0.27, 95% CI 0.10 to 0.74). Significantly more physicians from the second-cycle survey counseled patients on the appropriate disposal of antibiotics ( = .03), as well as on some of the infection prevention topics (eg, using antibacterial hand soap [ = .02] and cleaning supplies [ = .01]). Most respondents in both surveys reported feeling confident with respect to counseling their patients on the appropriate use of antibiotics and AMR.

Conclusion: Physicians' knowledge of and levels of counseling on the use of antibiotics and AMR were high and fairly stable in both survey results. This shows that Canadian physicians are demonstrating behaviour patterns of AMR stewardship. Existing gaps in counseling practices might be a result of physicians believing that pharmacists or nurses are addressing these issues with patients. Future national surveys conducted among pharmacists and nurses would contribute to the evidence base for AMR stewardship activities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729157PMC
December 2017

Greater cortical thickness within the limbic visceromotor network predicts higher levels of trait emotional awareness.

Conscious Cogn 2018 01 21;57:54-61. Epub 2017 Nov 21.

Department of Psychiatry, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724-5002, United States.

Previous studies of trait emotional awareness (EA) have not yet examined whether differences in cortical structure might account for differences in EA. Based on previous research on the relationship between EA and both emotion conceptualization and visceromotor control processes, we tested two hypotheses in a sample of 26 healthy participants: that higher EA would be predicted by greater cortical thickness within (1) regions of the default mode network (DMN; linked with conceptualization processes), and/or (2) regions of the limbic network (linked with affect generation and visceromotor control processes). A non-significant correlation was found between EA and cortical thickness in the DMN. In contrast, a significant positive correlation was observed between EA and cortical thickness within the limbic network. These findings suggest that the structural integrity of cortical regions involved in the generation of affective bodily reactions may play a more important role in explaining differences in EA than previously thought.
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http://dx.doi.org/10.1016/j.concog.2017.11.004DOI Listing
January 2018

Multidisciplinary clinic for functional movement disorders (FMD): 1-year experience from a single centre.

J Neurol Neurosurg Psychiatry 2018 09 15;89(9):1011-1012. Epub 2017 Nov 15.

Department of Neurology, University of Louisville, Louisville, Kentucky, USA.

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http://dx.doi.org/10.1136/jnnp-2017-316523DOI Listing
September 2018

Breast screening for survivors of breast cancer: A systematic review.

Prev Med 2017 Oct 29;103:70-75. Epub 2017 Jul 29.

Prevention and Cancer Control, Cancer Care Ontario, 620 University Avenue, Toronto, Ontario M5G 2L7, Canada; Dalla Lana School of Public Health, University of Toronto, 155 College Street, 6th floor, Toronto, Ontario M5T 3M7, Canada.

There is a large and growing population of women who have a personal history of breast cancer (PHBC). This systematic review was undertaken to explore the outcomes of surveillance mammography in breast cancer survivors, and to examine the evidence for screening these women within an organized population-based screening program. We searched Cochrane Central Register of Controlled Trials (CENTRAL Issue 6, 2015), OVID MEDLINE and EMBASE (January 2012 to June 22, 2015) for English-language studies of surveillance of the target population. A study author extracted study outcomes, which were audited by a research assistant. One systematic review and 5 primary studies were included. These showed that surveillance mammography may reduce breast cancer-specific mortality through early/asymptomatic detection (Hazard Ratio for those without compared to with symptoms:HR: 0.64, 95% CI 0.55 - 0.74). Three studies showed that semi-annual mammography is likely not of greater benefit than annual mammography. No evidence was found to suggest that surveillance mammography for women with a PHBC should not be conducted within an organized screening program. The small evidence-base had a high level of heterogeneity in populations, interventions and outcomes. Based on this review, organized screening programs should reassess their guidelines on surveillance mammography and consider including women with a PHBC.
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http://dx.doi.org/10.1016/j.ypmed.2017.07.026DOI Listing
October 2017

Resting state functional connectivity correlates of emotional awareness.

Neuroimage 2017 10 20;159:99-106. Epub 2017 Jul 20.

Department of Psychiatry, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ, 85724-5002, United States.

Multiple neuroimaging studies have now linked emotional awareness (EA), as measured by the Levels of Emotional Awareness Scale (LEAS), with activation in regions of neural networks associated with both conceptualization (i.e., default mode network [DMN] regions) and interoception (i.e., salience network [SN] regions) - consistent with the definition of EA as one's ability to appropriately recognize, conceptualize, and articulate the emotions of self and other in fine-grained, differentiated ways. However, no study has yet tested the hypothesis that greater LEAS scores are associated with greater resting state functional connectivity (FC) within these networks. Twenty-six adults (13 female) underwent resting state functional magnetic resonance imaging, and also completed the LEAS. Using pre-defined functional ROIs from the DMN and SN, we observed that LEAS scores were significantly positively correlated with FC between several regions of both of these networks, even when controlling for differences in general intelligence (IQ). These results suggest that higher EA may be associated with more efficient information exchange between brain regions involved in both interoception- and conceptualization-based processing, which could plausibly contribute to more differentiated bodily feelings and more fine-grained conceptualization of those feelings.
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http://dx.doi.org/10.1016/j.neuroimage.2017.07.044DOI Listing
October 2017

The Gene Family (Formerly ) in the Purple Sea Urchin and the Functional Diversity of the Anti-Pathogen rSpTransformer-E1 Protein.

Front Immunol 2017 30;8:725. Epub 2017 Jun 30.

Department of Biological Sciences, George Washington University, Washington, DC, United States.

The complex innate immune system of sea urchins is underpinned by several multigene families including the family (; formerly ) with estimates of ~50 members, although the family size is likely variable among individuals of . The genes are small with similar structure, are tightly clustered, and have several types of repeats in the second of two exons and that surround each gene. The density of repeats suggests that the genes are positioned within regions of genomic instability, which may be required to drive sequence diversification. The second exon encodes the mature protein and is composed of blocks of sequence called elements that are present in mosaics of defined element patterns and are the major source of sequence diversity. The genes respond swiftly to immune challenge, but only a single gene is expressed per phagocyte. Many of the mRNAs appear to be edited and encode proteins with altered and/or missense sequence that are often truncated, of which some may be functional. The standard SpTrf protein structure is an N-terminal glycine-rich region, a central RGD motif, a histidine-rich region, and a C-terminal region. Function is predicted from a recombinant protein, rSpTransformer-E1 (rSpTrf-E1), which binds to and , but not to , and binds tightly to lipopolysaccharide, β-1,3-glucan, and flagellin, but not to peptidoglycan. rSpTrf-E1 is intrinsically disordered but transforms to α helical structure in the presence of binding targets including lipopolysaccharide, which may underpin the characteristics of binding to multiple targets. SpTrf proteins associate with coelomocyte membranes, and rSpTrf-E1 binds specifically to phosphatidic acid (PA). When rSpTrf-E1 is bound to PA in liposome membranes, it induces morphological changes in liposomes that correlate with PA clustering and leakage of luminal contents, and it extracts or removes PA from the bilayer. The multitasking activities of rSpTrf-E1 infer multiple and perhaps overlapping activities for the hundreds of native SpTrf proteins that are produced by individual sea urchins. This likely generates a flexible and highly protective immune system for the sea urchin in its marine habitat that it shares with broad arrays of microbes that may be pathogens and opportunists.
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http://dx.doi.org/10.3389/fimmu.2017.00725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491942PMC
June 2017

Dramatic elevation in urinary amino terminal titin fragment excretion quantified by immunoassay in Duchenne muscular dystrophy patients and in dystrophin deficient rodents.

Neuromuscul Disord 2017 Jul 12;27(7):635-645. Epub 2017 May 12.

Genetically Defined Diseases, Bristol-Myers Squibb, Wallingford, CT, USA.

Enzyme-linked and electrochemiluminescence immunoassays were developed for quantification of amino (N-) terminal fragments of the skeletal muscle protein titin (N-ter titin) and qualified for use in detection of urinary N-ter titin excretion. Urine from normal subjects contained a small but measurable level of N-ter titin (1.0 ± 0.4 ng/ml). A 365-fold increase (365.4 ± 65.0, P = 0.0001) in urinary N-ter titin excretion was seen in Duchene muscular dystrophy (DMD) patients. Urinary N-ter titin was also evaluated in dystrophin deficient rodent models. Mdx mice exhibited low urinary N-ter titin levels at 2 weeks of age followed by a robust and sustained elevation starting at 3 weeks of age, coincident with the development of systemic skeletal muscle damage in this model; fold elevation could not be determined because urinary N-ter titin was not detected in age-matched wild type mice. Levels of serum creatine kinase and serum skeletal muscle troponin I (TnI) were also low at 2 weeks, elevated at later time points and were significantly correlated with urinary N-ter titin excretion in mdx mice. Corticosteroid treatment of mdx mice resulted in improved exercise performance and lowering of both urinary N-ter titin and serum skeletal muscle TnI concentrations. Low urinary N-ter titin levels were detected in wild type rats (3.0 ± 0.6 ng/ml), while Dmd rats exhibited a 556-fold increase (1652.5 ± 405.7 ng/ml, P = 0.002) (both at 5 months of age). These results suggest that urinary N-ter titin is present at low basal concentrations in normal urine and increases dramatically coincident with muscle damage produced by dystrophin deficiency. Urinary N-ter titin has potential as a facile, non-invasive and translational biomarker for DMD.
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http://dx.doi.org/10.1016/j.nmd.2017.05.009DOI Listing
July 2017

The Recombinant Sea Urchin Immune Effector Protein, rSpTransformer-E1, Binds to Phosphatidic Acid and Deforms Membranes.

Front Immunol 2017 12;8:481. Epub 2017 May 12.

Department of Biological Sciences, George Washington University, Science and Engineering Hall, Washington, DC, USA.

The purple sea urchin, , possesses a sophisticated innate immune system that functions without adaptive capabilities and responds to pathogens effectively by expressing the highly diverse gene family (formerly the gene family). The swift gene expression response and the sequence diversity of cDNAs suggest that the encoded proteins have immune functions. Individual sea urchins can express up to 260 distinct SpTransformer proteins, and their diversity suggests that different versions may have different functions. Although the deduced proteins are diverse, they share an overall structure of a hydrophobic leader, a glycine-rich N-terminal region, a histidine-rich region, and a C-terminal region. Circular dichroism analysis of a recombinant SpTransformer protein, rSpTransformer-E1 (rSpTrf-E1) demonstrates that it is intrinsically disordered and transforms to α helical in the presence of buffer additives and binding targets. Although native SpTrf proteins are associated with the membranes of perinuclear vesicles in the phagocyte class of coelomocytes and are present on the surface of small phagocytes, they have no predicted transmembrane region or conserved site for glycophosphatidylinositol linkage. To determine whether native SpTrf proteins associate with phagocyte membranes through interactions with lipids, when rSpTrf-E1 is incubated with lipid-embedded nylon strips, it binds to phosphatidic acid (PA) through both the glycine-rich region and the histidine-rich region. Synthetic liposomes composed of PA and phosphatidylcholine show binding between rSpTrf-E1 and PA by fluorescence resonance energy transfer, which is associated with leakage of luminal contents suggesting changes in lipid organization and perhaps liposome lysis. Interactions with liposomes also change membrane curvature leading to liposome budding, fusion, and invagination, which is associated with PA clustering induced by rSpTrf-E1 binding. Longer incubations result in the extraction of PA from the liposomes, which form disorganized clusters. CD shows that when rSpTrf-E1 binds to PA, it changes its secondary structure from disordered to α helical. These results provide evidence for how SpTransformer proteins may associate with molecules that have exposed phosphates including PA on cell membranes and how the characteristic of protein multimerization may drive changes in the organization of membrane lipids.
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http://dx.doi.org/10.3389/fimmu.2017.00481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427130PMC
May 2017