Publications by authors named "Joseph Hernandez"

27 Publications

  • Page 1 of 1

Development of multiple features of antigen-induced asthma pathology in a new strain of mast cell deficient BALB/c-Kit mice.

Lab Invest 2020 04 19;100(4):516-526. Epub 2019 Dec 19.

Department of Pathology and the Sean N. Parker Center for Allergy & Asthma Research, Stanford University School of Medicine, Stanford, CA, USA.

Mast cell-deficient mice are widely used to identify and quantify contributions of mast cells to diverse biological responses in vivo, including allergic inflammation. However, despite the fact that scores of genes have been identified as modifiers of allergic inflammation, most mast cell-deficient models have been available only on a single genetic background. We transferred the Kit allele onto the BALB/c background to generate BALB/c mast cell-deficient mice (BALB/c-Kit). BALB/c-Kit mice have dramatically reduced mast cell numbers (0-2% of wild type) in all tissues examined, as well as subtle hematologic differences from the corresponding wild type mice, including splenomegaly with evidence of increased splenic hematopoiesis. We examined in BALB/c-Kit mice models of allergic inflammation that are substantially diminished in C57BL/6-Kit mast cell-deficient mice. In a model of acute allergic inflammation, i.e., IgE-dependent passive cutaneous anaphylaxis, both ear swelling and leukocyte infiltration were largely or entirely absent in BALB/c-Kit mice. In contrast, in two different models of allergic airway inflammation, airway hyperresponsiveness, lung inflammation, and airway remodeling developed robustly in mast cell-deficient BALB/c-Kit mice. These results support the conclusion that the importance of mast cell contributions in various models of allergic inflammation may be at least partially determined by genetic background.
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http://dx.doi.org/10.1038/s41374-019-0354-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102933PMC
April 2020

Can catatonia be a pathological response to fear and trauma?

Ann Clin Psychiatry 2019 08;31(3):222-223

Nagy A. Youssef, MD, Department of Psychiatry and Human Behavior, Office of Academic Affairs, Medical College of Georgia, Augusta University, Augusta, GA USA. E-MAIL:

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August 2019

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):1970-1985.e4. Epub 2019 Mar 12.

Division of Pediatric Blood and Marrow Transplantation, Duke University School of Medicine, Durham, NC.

Background: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series.

Objective: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency.

Methods: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology.

Results: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients.

Conclusions: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.
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http://dx.doi.org/10.1016/j.jaip.2019.02.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612449PMC
September 2020

Influence of Future Possible Selves on Outcome Expectancies, Intended Behavior, and Academic Performance.

Psychol Rep 2019 Dec 14;122(6):2320-2330. Epub 2018 Nov 14.

Vanderbilt Brain Institute, Vanderbilt University, USA.

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http://dx.doi.org/10.1177/0033294118806483DOI Listing
December 2019

Reply.

J Allergy Clin Immunol Pract 2018 Nov - Dec;6(6):2178

Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University, School of Medicine, Stanford, Calif.

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http://dx.doi.org/10.1016/j.jaip.2018.09.001DOI Listing
October 2019

Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome.

Pediatr Allergy Immunol Pulmonol 2018 Sep 17;31(3):158-165. Epub 2018 Sep 17.

Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California.

The prevalence and impact of allergic and immune-mediated food disorders in pediatric acute-onset neuropsychiatric syndrome (PANS) are mostly unknown. We sought to explore the prevalence of atopic dermatitis (AD), asthma, allergic rhinitis (AR), IgE-mediated food allergies (FAs), and other immune-mediated food disorders requiring food avoidance in patients with PANS. In addition, to further understand the extent of food restriction in this population, we investigated the empiric use of dietary measures to improve PANS symptoms. Pediatric patients in a PANS Clinic and Research Program were given surveys regarding their caregiver burdens, allergic and food-related medical history, and whether food elimination resulted in perception of improvement of PANS symptoms. A review of health records was conducted to confirm that all responses in the survey were concordant with documentation of each patient's medical chart. Sixty-nine (ages 4-20 years) of 80 subjects who fulfilled PANS criteria completed the surveys. Thirteen (18.8%) had AD, 11 (15.9%) asthma, 33 (47.8%) AR, 11 (15.9%) FA, 1 (1.4%) eosinophilic gastrointestinal disorders, 1 (1.4%) food protein-induced enterocolitis syndrome, 3 (4.3%) milk protein-induced proctocolitis syndrome, and 3 (4.3%) celiac disease. Thirty subjects (43.5%) avoided foods due to PANS; elimination of gluten and dairy was most common and was associated with perceived improvement of PANS symptoms (by parents). This perceived improvement was not confirmed with objective data. The prevalence of allergic and immune-mediated food disorders in PANS is similar to the general population as reported in the literature, with the exception of AR that appears to be more prevalent in our PANS cohort. More research will be required to establish whether diet or allergies influence PANS symptoms.
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http://dx.doi.org/10.1089/ped.2018.0888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154445PMC
September 2018

Externally applied compression therapy for Fontan patients.

Transl Pediatr 2018 Jan;7(1):14-22

BioCirc Research Laboratory, School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.

Background: Limited therapeutic options are available for Fontan patients with dysfunctional or failing single ventricle physiology. This study describes the evaluation of an alternative, non-invasive, at-home therapeutic compression treatment for Fontan patients. Our hypothesis is that routinely administered, externally applied compression treatments to the lower extremities will augment systemic venous return, improve ventricular preload, and thus enhance cardiac output in Fontan patients.

Methods: To initially evaluate this hypothesis, we employed the NormaTec pneumatic compression device (PCD) in a pilot clinical study (n=2). This device is composed of inflatable trouser compartments that facilitate circumferentially and uniformly applied pressure to a patient's lower extremities. Following an initial health screening, test subjects were pre-evaluated with a modified-Bruce treadmill exercise stress test, and baseline data on cardiorespiratory health was collected. After training, test subjects conducted 6 days of external compression therapy at-home. Subjects were then re-evaluated with a final treadmill stress test and data acquisition of new cardiorespiratory parameters.

Results: Both subjects demonstrated improvement in exercise duration time, peak oxygen volume, and ventilator threshold, as compared to the baseline evaluation.

Conclusions: These findings are promising and provide the foundation for future studies that will focus on increasing study participation (sample size) to better assess the clinical benefit of compression therapy for Fontan patients.
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http://dx.doi.org/10.21037/tp.2017.08.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803019PMC
January 2018

Anaphylaxis to invasive chlorhexidine administration despite tolerance of topical chlorhexidine use.

J Allergy Clin Immunol Pract 2018 May - Jun;6(3):1067-1069.e1. Epub 2017 Dec 7.

Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University, School of Medicine, Stanford, Calif.

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http://dx.doi.org/10.1016/j.jaip.2017.11.001DOI Listing
October 2019

The pathophysiology of anaphylaxis.

J Allergy Clin Immunol 2017 Aug;140(2):335-348

Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, Calif. Electronic address:

Anaphylaxis is a severe systemic hypersensitivity reaction that is rapid in onset; characterized by life-threatening airway, breathing, and/or circulatory problems; and usually associated with skin and mucosal changes. Because it can be triggered in some persons by minute amounts of antigen (eg, certain foods or single insect stings), anaphylaxis can be considered the most aberrant example of an imbalance between the cost and benefit of an immune response. This review will describe current understanding of the immunopathogenesis and pathophysiology of anaphylaxis, focusing on the roles of IgE and IgG antibodies, immune effector cells, and mediators thought to contribute to examples of the disorder. Evidence from studies of anaphylaxis in human subjects will be discussed, as well as insights gained from analyses of animal models, including mice genetically deficient in the antibodies, antibody receptors, effector cells, or mediators implicated in anaphylaxis and mice that have been "humanized" for some of these elements. We also review possible host factors that might influence the occurrence or severity of anaphylaxis. Finally, we will speculate about anaphylaxis from an evolutionary perspective and argue that, in the context of severe envenomation by arthropods or reptiles, anaphylaxis might even provide a survival advantage.
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http://dx.doi.org/10.1016/j.jaci.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657389PMC
August 2017

Pediatric Acute-Onset Neuropsychiatric Syndrome Response to Oral Corticosteroid Bursts: An Observational Study of Patients in an Academic Community-Based PANS Clinic.

J Child Adolesc Psychopharmacol 2017 Sep 17;27(7):629-639. Epub 2017 Jul 17.

1 Division of Pediatrics, Department of Allergy, Immunology, and Rheumatology, Stanford University School of Medicine , Palo Alto, California.

Background: Sudden-onset severe obsessive-compulsive symptoms and/or severely restrictive food intake with at least two coinciding, similarly debilitating neuropsychiatric symptoms define Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). When associated with Group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. Most patients have a relapsing-remitting course. Treatment outcome data for youth with PANS and PANDAS are limited.

Methods: One hundred seventy-eight consecutive patients were seen in the Stanford PANS clinic between September 1, 2012 and January 15, 2016, of whom 98 met PANS or PANDAS criteria, had a single episode of PANS or relapsing/remitting course, and collectively experienced 403 flares. Eighty-five flares were treated with 102 total courses of oral corticosteroids of either short (4-5 days) or long (5 days-8 weeks) duration. Response to treatment was assessed within 14 days of initiating a short burst of corticosteroids and at the end of a long burst based on clinician documentation and patient questionnaires. Data were analyzed by using multilevel random-effects models.

Results: Patients experienced shorter flares when treated with oral corticosteroids (6.4 ± 5.0 weeks vs. 11.4 ± 8.6 weeks) than when not treated (p < 0.001), even after controlling for presumed confounding variables, including age at flare, weeks since onset of PANS illness, sex, antibiotic treatment, prophylactic antibiotics, previous immunomodulatory treatment, maintenance anti-inflammatory therapy, psychiatric medications, and cognitive behavioral therapy (p < 0.01). When corticosteroids were given for the initial PANS episode, flares tended to be shorter (10.3 ± 5.7 weeks) than when not treated (16.5 ± 9.6 weeks) (p = 0.06). This difference was statistically significant after controlling for the relevant confounding variables listed earlier (p < 0.01). Earlier use of corticosteroids was associated with shorter flare durations (p < 0.001). Longer courses of corticosteroids were associated with a more enduring impact on the duration of neuropsychiatric symptom improvement (p = 0.014).

Conclusion: Corticosteroids may be a helpful treatment intervention in patients with new-onset and relapsing/remitting PANS and PANDAS, hastening symptom improvement or resolution. When corticosteroids are given earlier in a disease flare, symptoms improve more quickly and patients achieve clinical remission sooner. Longer courses of corticosteroids may result in more durable remissions. A double-blind placebo-controlled clinical trial of corticosteroids in PANS is warranted to formally assess treatment efficacy.
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http://dx.doi.org/10.1089/cap.2016.0139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749576PMC
September 2017

A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice.

Nat Commun 2016 12 16;7:13696. Epub 2016 Dec 16.

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.

Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support T2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology.
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http://dx.doi.org/10.1038/ncomms13696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171877PMC
December 2016

Novel tools for primary immunodeficiency diagnosis: making a case for deep profiling.

Curr Opin Allergy Clin Immunol 2016 12;16(6):549-556

aDepartment of Immunology and Microbiology, University of Colorado Denver, School of Medicine bDepartment of Pediatrics, Division of Allergy and Immunology, University of Colorado Denver, School of Medicine and Children's Hospital Colorado, Aurora, Colorado cDepartment of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, School of Medicine, Stanford, California, USA.

Purpose Of Review: This review gives an overview of the systems-immunology single-cell proteomic and transcriptomic approaches that can be applied to study primary immunodeficiency. It also introduces recent advances in multiparameter tissue imaging, which allows extensive immune phenotyping in disease-affected tissue.

Recent Findings: Mass cytometry is a variation of flow cytometry that uses rare earth metal isotopes instead of fluorophores as tags bound to antibodies, allowing simultaneous measurement of over 40 parameters per single-cell. Mass cytomety enables comprehensive single-cell immunophenotyping and functional assessments, capturing the complexity of the immune system, and the molecularly heterogeneous consequences of primary immunodeficiency defects. Protein epitopes and transcripts can be simultaneously detected allowing immunophenotype and gene expression evaluation in mixed cell populations. Multiplexed epitope imaging has the potential to provide extensive phenotypic characterization at the subcellular level, in the context of 3D tissue microenvironment.

Summary: Mass cytometry and multiplexed epitope imaging can complement genetic methods in diagnosis and study of the pathogenesis of primary immunodeficiencies. The ability to understand the effect of a specific defect across multiple immune cell types and pathways, and in affected tissues, may provide new insight into tissue-specific disease pathogenesis and evaluate effects of therapeutic interventions.
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http://dx.doi.org/10.1097/ACI.0000000000000319DOI Listing
December 2016

Different activation signals induce distinct mast cell degranulation strategies.

J Clin Invest 2016 10 19;126(10):3981-3998. Epub 2016 Sep 19.

Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.
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http://dx.doi.org/10.1172/JCI85538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096814PMC
October 2016

Molecular and cellular mechanisms of food allergy and food tolerance.

J Allergy Clin Immunol 2016 Apr;137(4):984-997

Department of Medicine, Stanford University School of Medicine, Stanford, Calif; Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif; Sean N. Parker Center for Allergy & Asthma Research, Stanford University School of Medicine, Stanford, Calif. Electronic address:

Ingestion of innocuous antigens, including food proteins, normally results in local and systemic immune nonresponsiveness in a process termed oral tolerance. Oral tolerance to food proteins is likely to be intimately linked to mechanisms that are responsible for gastrointestinal tolerance to large numbers of commensal microbes. Here we review our current understanding of the immune mechanisms responsible for oral tolerance and how perturbations in these mechanisms might promote the loss of oral tolerance and development of food allergies. Roles for the commensal microbiome in promoting oral tolerance and the association of intestinal dysbiosis with food allergy are discussed. Growing evidence supports cutaneous sensitization to food antigens as one possible mechanism leading to the failure to develop or loss of oral tolerance. A goal of immunotherapy for food allergies is to induce sustained desensitization or even true long-term oral tolerance to food allergens through mechanisms that might in part overlap with those associated with the development of natural oral tolerance.
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http://dx.doi.org/10.1016/j.jaci.2016.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030841PMC
April 2016

Single-cell systems-level analysis of human Toll-like receptor activation defines a chemokine signature in patients with systemic lupus erythematosus.

J Allergy Clin Immunol 2015 Nov 30;136(5):1326-36. Epub 2015 May 30.

Department of Microbiology and Immunology, Stanford University, Stanford, Calif; Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, Calif; Howard Hughes Medical Institute, Stanford University, Stanford, Calif. Electronic address:

Background: Activation of Toll-like receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in patients with systemic lupus erythematosus (SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has not been described.

Objective: We sought to characterize TLR activation across multiple immune cell subsets and subjects, with the goal of establishing a reference framework against which to compare pathologic processes.

Methods: Peripheral whole-blood samples were stimulated with TLR ligands and analyzed by means of mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied 17 healthy volunteer donors and 8 patients with newly diagnosed and untreated SLE.

Results: Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of natural killer cells and T cells selectively induced nuclear factor κ light chain enhancer of activated B cells in response to TLR2 ligands. CD14(hi) monocytes exhibited the most polyfunctional cytokine expression patterns, with more than 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared among a group of healthy donors, with minimal intraindividual and interindividual variability. Furthermore, autoimmune disease altered baseline cytokine production; newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity.

Conclusion: Mass cytometry defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in patients with inflammatory diseases, such as SLE.
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http://dx.doi.org/10.1016/j.jaci.2015.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640970PMC
November 2015

From genes to milk: genomic organization and epigenetic regulation of the mammary transcriptome.

PLoS One 2013 26;8(9):e75030. Epub 2013 Sep 26.

Genome Center, University of California Davis, Davis, California, United States of America.

Even in genomes lacking operons, a gene's position in the genome influences its potential for expression. The mechanisms by which adjacent genes are co-expressed are still not completely understood. Using lactation and the mammary gland as a model system, we explore the hypothesis that chromatin state contributes to the co-regulation of gene neighborhoods. The mammary gland represents a unique evolutionary model, due to its recent appearance, in the context of vertebrate genomes. An understanding of how the mammary gland is regulated to produce milk is also of biomedical and agricultural importance for human lactation and dairying. Here, we integrate epigenomic and transcriptomic data to develop a comprehensive regulatory model. Neighborhoods of mammary-expressed genes were determined using expression data derived from pregnant and lactating mice and a neighborhood scoring tool, G-NEST. Regions of open and closed chromatin were identified by ChIP-Seq of histone modifications H3K36me3, H3K4me2, and H3K27me3 in the mouse mammary gland and liver tissue during lactation. We found that neighborhoods of genes in regions of uniquely active chromatin in the lactating mammary gland, compared with liver tissue, were extremely rare. Rather, genes in most neighborhoods were suppressed during lactation as reflected in their expression levels and their location in regions of silenced chromatin. Chromatin silencing was largely shared between the liver and mammary gland during lactation, and what distinguished the mammary gland was mainly a small tissue-specific repertoire of isolated, expressed genes. These findings suggest that an advantage of the neighborhood organization is in the collective repression of groups of genes via a shared mechanism of chromatin repression. Genes essential to the mammary gland's uniqueness are isolated from neighbors, and likely have less tolerance for variation in expression, properties they share with genes responsible for an organism's survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075030PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784412PMC
August 2014

Epigenetic modifications unlock the milk protein gene loci during mouse mammary gland development and differentiation.

PLoS One 2013 2;8(1):e53270. Epub 2013 Jan 2.

United States Department of Agriculture/Agriculture Research Service Children's Nutrition Research Center, Department of Pediatrics-Nutrition, Baylor College of Medicine, Houston, Texas, United States of America.

Background: Unlike other tissues, development and differentiation of the mammary gland occur mostly after birth. The roles of systemic hormones and local growth factors important for this development and functional differentiation are well-studied. In other tissues, it has been shown that chromatin organization plays a key role in transcriptional regulation and underlies epigenetic regulation during development and differentiation. However, the role of chromatin organization in mammary gland development and differentiation is less well-defined. Here, we have studied the changes in chromatin organization at the milk protein gene loci (casein, whey acidic protein, and others) in the mouse mammary gland before and after functional differentiation.

Methodology/principal Findings: Distal regulatory elements within the casein gene cluster and whey acidic protein gene region have an open chromatin organization after pubertal development, while proximal promoters only gain open-chromatin marks during pregnancy in conjunction with the major induction of their expression. In contrast, other milk protein genes, such as alpha-lactalbumin, already have an open chromatin organization in the mature virgin gland. Changes in chromatin organization in the casein gene cluster region that are present after puberty persisted after lactation has ceased, while the changes which occurred during pregnancy at the gene promoters were not maintained. In general, mammary gland expressed genes and their regulatory elements exhibit developmental stage- and tissue-specific chromatin organization.

Conclusions/significance: A progressive gain of epigenetic marks indicative of open/active chromatin on genes marking functional differentiation accompanies the development of the mammary gland. These results support a model in which a chromatin organization is established during pubertal development that is then poised to respond to the systemic hormonal signals of pregnancy and lactation to achieve the full functional capacity of the mammary gland.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053270PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534698PMC
August 2013

High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation.

BMC Genomics 2010 Jan 12;11:25. Epub 2010 Jan 12.

Pharmaceutical Genomics Division, Translational Genomics Research Institute, Scottsdale, Arizona 85251, USA.

Background: Neurofibrillary tangles (NFT), a cardinal neuropathological feature of Alzheimer's disease (AD) that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments.

Results: We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2), the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and the A-kinase anchor protein 13 (AKAP13) on tau phosphorylation at the 12E8 epitope (serine 262/serine 356). We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways.

Conclusions: These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.
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http://dx.doi.org/10.1186/1471-2164-11-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820455PMC
January 2010

Multivalent interactions between lectins and supramolecular complexes: Galectin-1 and self-assembled pseudopolyrotaxanes.

Chem Biol 2007 Oct;14(10):1140-51

California NanoSystems Institute, Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Supramolecular chemistry has been employed to develop flexible and adaptable multivalent neoglycoconjugates for binding galectin-1 (Gal-1). Gal-1, a dimeric lectin with two galactoside-binding sites, regulates cancer progression and immune responses. Self-assembled pseudopolyrotaxanes consisting of lactoside-displaying cyclodextrin (LCD) "beads" threaded onto polyviologen "strings" display mobile ligands as a result of cyclodextrin rotation about, and limited translation along, the polymer chain. The pseudopolyrotaxanes rapidly and efficiently precipitate Gal-1 and provide valency-corrected enhancements of up to 30-fold compared to native lactose and 20-fold over free LCD in a T-cell agglutination assay. A supramolecular statistical effect was observed, wherein the efficacy of Gal-1 inhibition correlates with the number of ligands connected to each other solely through mechanical and noncovalent interactions. Such flexible and adaptable self-assembled pseudopolyrotaxanes show promise for the study of multivalent interactions and targeting of therapeutically relevant lectins.
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http://dx.doi.org/10.1016/j.chembiol.2007.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2072908PMC
October 2007

T-cell activation results in microheterogeneous changes in glycosylation of CD45.

Int Immunol 2007 Jul 2;19(7):847-56. Epub 2007 Jul 2.

Department of Pathology and Laboratory Medicine, UCLA School of Medicine, 10833 LeConte Avenue, Los Angeles, CA 90095, USA..

During T-cell development and activation, dramatic changes occur in glycan structures that decorate cell-surface glycoproteins. These changes have been considered to be general cellular events that affect many glycans on many glycoproteins. For example, loss of sialic acid from core 1 O-glycans on T-cell surface glycoproteins CD45, CD43 and CD8, detected with peanut agglutinin (PNA), is a hallmark of immature thymocytes and activated peripheral T cells. Loss of cell-surface sialic acid during T-cell activation has been proposed to enhance TCR reactivity with antigen. However, CD4 T-cell activation also results in increased binding of the CZ-1 antibody that recognizes a sialic acid-containing epitope on CD45RB. This indicates that increased sialylation of the CZ-1 epitope occurs during CD4 T cell activation, and that loss of cell surface sialic acid during T-cell activation is a selective event rather than affecting all cell surface glycans. As specific glycans on specific glycoprotein backbones control critical events in T-cell maturation and survival, understanding mechanisms of selective glycoprotein glycosylation is important for regulating T-cell development and function. We define the sialylated O-glycan epitope recognized by CZ-1, and find that, paradoxically, CZ-1 and PNA binding are simultaneously increased on activated CD4(+) T cells, demonstrating site-specific changes in CD45 sialylation. Moreover, we identify ST3Gal I as the sialyltransferase responsible for creating the CZ-1 epitope. Thus, changes in glycan structure during T-cell activation are microheterogeneous and unique to individual glycans on specific glycoproteins, implying that these glycans have precise functions in T-cell biology.
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http://dx.doi.org/10.1093/intimm/dxm053DOI Listing
July 2007

Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death.

Nat Immunol 2007 Aug 24;8(8):825-34. Epub 2007 Jun 24.

División de Immunogenética. Hospital de Clínicas José de San Martín, Facultad de Medicina, Universidad de Buenos Aires, C1120AAF Buenos Aires, Argentina.

Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper type 1 (TH1), TH2 or interleukin 17-producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17-differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1-induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1-deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response.
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http://dx.doi.org/10.1038/ni1482DOI Listing
August 2007

Galectin-1 binds different CD43 glycoforms to cluster CD43 and regulate T cell death.

J Immunol 2006 Oct;177(8):5328-36

Department of Pathology and Laboratory Medicine, University of California Los Angeles School of Medicine, Los Angeles, CA 90095, USA.

Galectin-1 kills immature thymocytes and activated peripheral T cells by binding to glycans on T cell glycoproteins including CD7, CD45, and CD43. Although roles for CD7 and CD45 in regulating galectin-1-induced death have been described, the requirement for CD43 remains unknown. We describe a novel role for CD43 in galectin-1-induced death, and the effects of O-glycan modification on galectin-1 binding to CD43. Loss of CD43 expression reduced galectin-1 death of murine thymocytes and human T lymphoblastoid cells, indicating that CD43 is required for maximal T cell susceptibility to galectin-1. CD43, which is heavily O-glycosylated, contributes a significant fraction of galectin-1 binding sites on T cells, as T cells lacking CD43 bound approximately 50% less galectin-1 than T cells expressing CD43. Although core 2 modification of O-glycans on other glycoprotein receptors is critical for galectin-1-induced cross-linking and T cell death, galectin-1 bound to CD43 fusion proteins modified with either unbranched core 1 or branched core 2 O-glycans and expression of core 2 O-glycans did not enhance galectin-1 binding to CD43 on T cells. Moreover, galectin-1 binding clustered CD43 modified with either core 1 or core 2 O-glycans on the T cell surface. Thus, CD43 bearing either core 1 or core 2 O-glycans can positively regulate T cell susceptibility to galectin-1, identifying a novel function for CD43 in controlling cell death. In addition, these studies demonstrate that different T cell glycoproteins on the same cell have distinct requirements for glycan modifications that allow recognition and cross-linking by galectin-1.
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http://dx.doi.org/10.4049/jimmunol.177.8.5328DOI Listing
October 2006

Percutaneous coronary intervention of or through saphenous vein grafts or internal mammary arteries: the impact of stents, adjunctive pharmacology, and multicomponent distal protection.

Catheter Cardiovasc Interv 2006 Apr;67(4):571-9

Section of Cardiology, Department of Internal Medicine, SAVAHCS, and the University of Arizona, Sarver Heart Center, Tucson, 85723, USA.

We hypothesized that the use of stents and aggressive adjunctive pharmacotherapies has been associated with lower rates of complicating myocardial infarction (MI) and improved long-term outcomes compared to either previous balloon-only percutaneous coronary intervention (PCI) or atheroablative intervention for lesions of or through saphenous vein grafts (SVGs) and/or internal mammary arteries (IMAs). PCI of SVG has been complicated by relatively high rates of procedural MI and less favorable long-term outcomes than native vessel PCI, stimulating the development and application of an array of technologies. This study was based on retrospective review of stent-era (1999-2004) 5-year experience of a single center with 95 SVG procedures in 85 patients and 20 IMA procedures in 20 patients. These cases were compared with the previously published experience of one of the operators during the balloon-only period and literature review of the application of multiple technologies to SVG intervention, as well as consideration of the reoperation alternative. There was one in-hospital death each in the SVG cohort (1%) and in the IMA cohort (5%). There were SIX procedural MIs (6%), defined by total CK > normal, and 19 procedural MIs (20%) based on troponin-I > 1.0. Follow-up has been from 4 months to 5 years (average, 2.5 years), with 91% survival and one late CABG in the IMA group. SVG PCI with stents and adjunctive pharmacotherapies is associated with relatively low rates of procedural MI and favorable long-term outcomes.
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http://dx.doi.org/10.1002/ccd.20641DOI Listing
April 2006

Transient carbon monoxide inhibits the ventilatory responses to hypoxia through peripheral mechanisms in the rat.

Life Sci 2006 Apr 28;78(22):2654-61. Epub 2005 Nov 28.

Department of Pathophysiology, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.

Hypoxia inhibits K+ channels of chemoreceptors of the carotid body (CB), which is reversed by transient carbon monoxide (CO), suggesting an inhibitory effect of CO on hypoxic stimulation of carotid chemoreceptors. Therefore, we hypothesized that the ventilatory responses to hypoxic stimulation of the CB might be depressed in intact rats by transient inhalation of CO. Anesthetized, spontaneously breathing rats were exposed to room air, and 1 min of 11% O2 (HYP) and CO (0.25-2%) alone and in combination (HYP+CO). We found that transient CO did not affect baseline cardiorespiratory variables, but significantly attenuated hypoxic ventilatory augmentation, predominantly via reduction of tidal volume. To distinguish whether this CO modulation occurs at the CB or within the central nervous system, the cardiorespiratory responses to electrical stimulation of the fastigial nucleus (FN), a cerebellar nucleus known excitatory to respiration, were compared before and during transient CO. Our results showed that the FN-mediated cardiorespiratory responses were not significantly changed by transient CO exposure. To evaluate the effect of CO accumulation, we also compared baseline cardiorespiratory responses to 5 min of 1% and 2% CO, respectively. Interestingly, only the latter produced a biphasic ventilatory response (initial increase followed by decrease) associated with hypotension. We conclude that eupneic breathing in anesthetized rat was not affected by transient CO, but was altered by prolonged exposure to higher levels of CO. Moreover, transient CO depresses hypoxic ventilatory responses mainly through peripherally inhibiting hypoxic stimulation of carotid chemoreceptors.
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http://dx.doi.org/10.1016/j.lfs.2005.10.037DOI Listing
April 2006

CD45 signals outside of lipid rafts to promote ERK activation, synaptic raft clustering, and IL-2 production.

J Immunol 2005 Feb;174(3):1479-90

Department of Microbiology, University of California School of Medicine, Los Angeles, CA 90095, USA.

CD45 is dynamically repositioned within lipid rafts and the immune synapse during T cell activation, although the molecular consequences of CD45 repositioning remain unclear. In this study we examine the role of CD45 membrane compartmentalization in regulating murine T cell activation. We find that raft-localized CD45 antagonizes IL-2 production by opposing processive TCR signals, whereas raft-excluded CD45 promotes ERK-dependent polarized synaptic lipid raft clustering and IL-2 production. We propose that these dual CD45 activities ensure that only robust TCR signals proceed, whereas signals meeting threshold requirements are potentiated. Our findings highlight membrane compartmentalization as a key regulator of CD45 function and elucidate a novel signal transduction pathway by which raft-excluded CD45 positively regulates T cell activation.
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http://dx.doi.org/10.4049/jimmunol.174.3.1479DOI Listing
February 2005

Medial vestibular nucleus mediates the cardiorespiratory responses to fastigial nuclear activation and hypercapnia.

J Appl Physiol (1985) 2004 Sep;97(3):835-42

Pathophysiology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.

Electrical stimulation of the cerebellar fastigial nucleus (FN) evokes hyperventilation and hypertension responses that are similar to those induced by stimulation of the medial region of the vestibular nucleus (VNM). Because there are mutual projections between these two nuclei morphologically, we hypothesized that the FN-mediated cardiorespiratory responses were related to the integrity of the VNM. Experiments were conducted on 21 anesthetized, tracheotomized, and spontaneously breathing rats. Electrical stimulation (approximately 10 s) of the FN was used to evoke cardiorespiratory responses, and the same stimulus was repeated 30-45 min after bilateral lesions of the VNM by local microinjection of ibotenic acid (100 mM, 100 nl). We found that FN stimulation-induced hyperventilation and hypertension were attenuated significantly by the lesions. The role of the VNM in the ventilatory responses to chemical challenges was subsequently defined. The animals were exposed to hypercapnia (10% CO2) and hypoxia (10% O2) for 1-2 min randomly before and after VNM lesions. The results showed that VNM lesions significantly attenuated the cardiorespiratory responses to hypercapnia but not to hypoxia, with little effect on baseline respiratory variables. These findings suggest that the VNM is required for full expression of the cardiorespiratory responses to electrical stimulation of the FN as well as to hypercapnia. However, neurons within the VNM do not appear to be critical for maintaining eupneic breathing and the cardiorespiratory responses to hypoxia.
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http://dx.doi.org/10.1152/japplphysiol.00134.2004DOI Listing
September 2004

Ah, sweet mystery of death! Galectins and control of cell fate.

Glycobiology 2002 Oct;12(10):127R-36R

Department of Pathology and Laboratory Medicine, Johnson Comprehensive Cancer Center, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.

Control of cell death is critical in eukaryotic development, immune system homeostasis, and control of tumorigenesis. The galectin family of lectins is implicated in all of these processes. Other families of molecules function as death receptors or death effectors, but galectins are uniquely capable of acting both extracellularly and intracellularly to control cell death. Extracellularly, galectins cross-link glycan ligands to transduce signals that lead directly to death or that influence other signals regulating cell fate. Intracellular expression of galectins can modulate other signals controlling cell viability. Individual galectins can act on multiple cell types, and multiple galectins can act on the same cell. Understanding how galectins regulate cell viability and function will broaden our knowledge of the roles of galectins in basic biological processes and facilitate development of therapeutic applications for galectins in autoimmunity, transplant-related disease, and cancer.
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http://dx.doi.org/10.1093/glycob/cwf081DOI Listing
October 2002