Normalization of Cystic Fibrosis Immune System Reverses Intestinal Neutrophilic Inflammation and Significantly Improves the Survival of Cystic Fibrosis Mice.

Background & Aims: Cystic fibrosis (CF) is an autosomal recessive genetic disorder, affecting multiple organ systems. CF intestinal disease develops early, manifesting as intestinal bacterial overgrowth/dysbiosis, neutrophilic inflammation, and obstruction. As unresolvable infection and inflammation reflect host immune deficiency, we sought to determine if the CF-affected immune system plays any significant role in CF intestinal disease pathogenesis.

Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation.

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) gene. The most severe pathologies of CF occur in the lung, manifesting as chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite increasing knowledge of the CF primary defect and the resulting clinical sequelae, the relationship between the CFTR loss of function and the neutrophilic inflammation remains incompletely understood.

Aberrant immune programming in neutrophils in cystic fibrosis.

Cystic fibrosis is a life-shortening genetic disorder, caused by mutations in the gene that encodes cystic fibrosis transmembrane-conductance regulator, a cAMP-activated chloride and bicarbonate channel. Persistent neutrophilic inflammation is a major contributor to cystic fibrosis lung disease. However, how cystic fibrosis transmembrane-conductance regulator loss of function leads to excessive inflammation and its clinical sequela remains incompletely understood.

Genome Editing for Cystic Fibrosis.

Cystic fibrosis (CF) is a monogenic recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator gene (). Remarkable progress in basic research has led to the discovery of highly effective CFTR modulators. Now ~90% of CF patients are treatable.

Neutrophil defect and lung pathogen selection in cystic fibrosis.

Cystic fibrosis is a life-threatening genetic disorder caused by mutations in the CFTR chloride channel. Clinically, over 90% of patients with cystic fibrosis succumb to pulmonary complications precipitated by chronic bacterial infections, predominantly by Pseudomonas aeruginosa and Staphylococcus aureus. Despite the well-characterized gene defect and clearly defined clinical sequelae of cystic fibrosis, the critical link between the chloride channel defect and the host defense failure against these specific pathogens has not been established.

ABERRANT IMMUNE PROGRAMMING IN NEUTROPHILS IN CYSTIC FIBROSIS.

Cystic fibrosis (CF) is a life-shortening genetic disorder, caused by mutations in the gene that encodes Cystic Fibrosis Transmembrane-conductance Regulator (CFTR), a cAMP-activated chloride and bicarbonate channel. Although multiple organ systems can be affected, CF lung disease claims the most morbidity and mortality due to chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite the clear predominance of neutrophils in these pathologies, how CFTR loss-of-function affects these cells remains incompletely understood.

Dysregulation of tryptophan metabolism and distortion of cell signaling after oral exposure to ethanol and Kynurenic acid.

Kynurenic acid (KYNA), an unavoidable tryptophan metabolite during fermentation is naturally blended with alcohol in all alcoholic beverages. Thus, alcohol drinking inevitably results in co-intake of KYNA. Effects of alcohol or KYNA on human health have been widely studied.

Cftr deletion in mouse epithelial and immune cells differentially influence the intestinal microbiota.

Cystic fibrosis (CF) is a life-threatening genetic disorder, caused by mutations in the CF transmembrane-conductance regulator gene (cftr) that encodes CFTR, a cAMP-activated chloride and bicarbonate channel. Clinically, CF lung disease dominates the adult patient population. However, its gastrointestinal illness claims the early morbidity and mortality, manifesting as intestinal dysbiosis, inflammation and obstruction.

Neural network interpolation operators optimized by Lagrange polynomial.

In this paper, we introduce a new type of interpolation operators by using Lagrange polynomials of degree r, which can be regarded as feedforward neural networks with four layers. The approximation rate of the new operators can be estimated by the (r+1)-th modulus of smoothness of the objective functions. By adding some smooth assumptions on the activation function, we establish two important inequalities of the derivatives of the operators.

Corrigendum: Short-Chain Alcohols Upregulate GILZ Gene Expression and Attenuate LPS-Induced Septic Immune Response.

[This corrects the article DOI: 10.3389/fimmu.2020.

Neutrophil dysfunction in the pathogenesis of cystic fibrosis.

Polymorphonuclear neutrophils (PMNs) figure prominently in host defense against infection and in noninfectious inflammation. Mobilized early in an inflammatory response, PMNs mediate immediate cellular defense against microbes and orchestrate events that culminate in cessation of inflammation and restoration of homeostasis. Failure to terminate the inflammatory response and its causes can fuel exuberant inflammation characteristic of many human diseases, including cystic fibrosis (CF), an autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator.

Myeloid CFTR loss-of-function causes persistent neutrophilic inflammation in cystic fibrosis.

Persistent neutrophilic inflammation is a hallmark of cystic fibrosis (CF). However, the mechanisms underlying this outstanding pathology remain incompletely understood. Here, we report that CFTR in myeloid immune cells plays a pivotal role in control of neutrophilic inflammation.

Short-Chain Alcohols Upregulate GILZ Gene Expression and Attenuate LPS-Induced Septic Immune Response.

Alcohol differentially affects human health, depending on the pattern of exposure. Moderate intake provides beneficial mood modulation and an anti-inflammatory effect, while excessive consumption leads to immunosuppression and various alcohol use disorders. The mechanism underlying this bi-phasic action mode of alcohol has not been clearly defined.

Organ-differential responses to ethanol and kynurenic acid, a component of alcoholic beverages in gene transcription.

Excessive alcohol (ethanol) use has long been known to affect human health negatively. However, the underlying molecular basis is incompletely understood. Moreover, consumption of alcohol is often mixed with kynurenic acid (KYNA), an abundant tryptophan metabolite produced during fermentation.

Efficient Gene Editing at Major CFTR Mutation Loci.

Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Nuclease-mediated precise gene editing (PGE) represents a promising therapy for CF, for which an efficient strategy that is free of viral vector, drug selection, and reporter enrichment (VDR free) is desirable. Here we compared different transfection methods (lipofectamine versus electroporation) and formats (plasmid DNA versus ribonucleoprotein) in delivering the CRISPR/Cas9 elements along with single-stranded oligodeoxynucleotides (ssODNs) to clinically relevant cells targeting major CFTR mutation loci.

Establishment of a ΔF508-CF promyelocytic cell line for cystic fibrosis research and drug screening.

Cystic fibrosis (CF), one of the most common genetic disorders, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In spite of significant improvement in patient life expectancy, the disease remains lethal and incurable. Clinically, CF lung disease claims the most morbidity and mortality, characterized by chronic bacterial infection, persistent neutrophilic inflammation, and purulent small airway obstruction.

Bacterial and Infections in the Lungs of Gene-Knockout Rabbits with Severe Combined Immunodeficiency.

Using the CRISPR/Cas9 gene-editing technology, we recently produced a number of rabbits with mutations in immune function genes, including FOXN1, PRKDC, RAG1, RAG2, and IL2RG. Seven founder knockout rabbits (F0) and three male IL2RG null (-/y) F1 animals demonstrated severe combined immunodeficiency (SCID), characterized by absence or pronounced hypoplasia of the thymus and splenic white pulp, and absence of immature and mature T and B-lymphocytes in peripheral blood. Complete blood count analysis showed severe leukopenia and lymphocytopenia accompanied by severe neutrophilia.

Non-canonical Glucocorticoid Receptor Transactivation of by Alcohol Suppresses Cell Inflammatory Response.

Acute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR) signaling in the absence of glucocorticoids (GCs) and upregulated glucocorticoid-induced leucine zipper (), a prominent GC-responsive gene.

Metabolism of selective 20-epi-vitamin D analogs in rat osteosarcoma UMR-106 cells: Isolation and identification of four novel C-1 fatty acid esters of 1α,25-dihydroxy-16-ene-20-epi-vitamin D.

Analogs of 1α,25-dihydroxyvitamin D (S1) with 20-epi modification (20-epi analogs) possess unique biological properties. We previously reported that 1α,25-dihydroxy-20-epi-vitamin D (S2), the basic 20-epi analog is metabolized into less polar metabolites (LPMs) in rat osteosarcoma cells (UMR-106) but not in a perfused rat kidney. Furthermore, we also noted that only selective 20-epi analogs are metabolized into LPMs.

Chloride flux in phagocytes.

Phagocytes, such as neutrophils and macrophages, engulf microbes into phagosomes and launch chemical attacks to kill and degrade them. Such a critical innate immune function necessitates ion participation. Chloride, the most abundant anion in the human body, is an indispensable constituent of the myeloperoxidase (MPO)-H2 O2 -halide system that produces the potent microbicide hypochlorous acid (HOCl).

Alcohol and inflammatory responses: Highlights of the 2015 Alcohol and Immunology Research Interest Group (AIRIG) meeting.

On September 27, 2015 the 20th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite symposium at the annual meeting of the Society for Leukocyte Biology in Raleigh, NC. The 2015 meeting focused broadly on adverse effects of alcohol and alcohol-use disorders in multiple organ systems. Divided into two plenary sessions, AIRIG opened with the topic of pulmonary inflammation as a result of alcohol consumption, which was followed by alcohol's effect on multiple organs, including the brain and liver.

CFTR targeting during activation of human neutrophils.

Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, plays critical roles in phagocytic host defense. However, how activated neutrophils regulate CFTR channel distribution subcellularly is not well defined. To investigate, we tested multiple Abs against different CFTR domains, to examine CFTR expression in human peripheral blood neutrophils by flow cytometry.

Phenotypic and Molecular Characterization of Domestic Cat (Felis catus) Spermatogonial Stem Cells.

In many mammalian species, surface markers have been used to obtain enriched populations of spermatogonial stem cells (SSCs) for assisted reproduction and other applications; however, little is known about the expression patterns of feline SSCs. In this study, we assessed expression of the SSC surface markers commonly used in other species, KIT, ITGA6, CD9, GFRalpha1, ADGRA3, and THY1, in addition to the less frequently used pluripotent markers TRA-1-60, TRA-1-81, SSEA-1, and SSEA-4 in SSCs of both prepubertal and adult domestic cats (Felis catus). To further characterize cat SSCs, we sorted cells using SSC-specific markers and evaluated the expression of the pluripotent transcription factors NANOG, POU5F1, and SOX2 and the proto-oncogene MYC within these populations.

Characterization and Multilineage Differentiation of Domestic and Black-Footed Cat Mesenchymal Stromal/Stem Cells from Abdominal and Subcutaneous Adipose Tissue.

Transplantation of mesenchymal stem cells (MSCs) isolated from bone marrow or adipose tissue is emerging as a promising tool for cell replacement therapy and regenerative medicine in domestic and endangered animal species. Defining the differentiation capability of adipose-derived mesenchymal stromal/stem cells (AMSCs) collected from different depot sites of adipose tissue will be essential for developing strategies for cell replacement therapy. In the present study, we compared the biological characteristics of domestic cat AMSCs isolated from visceral fat of the abdominal cavity (AB) with AMSCs from subcutaneous (SQ) tissue, and the functional capability of domestic and black-footed cat (Felis nigripes) AMSCs to differentiate into other cell types.

Salt, chloride, bleach, and innate host defense.

Salt provides 2 life-essential elements: sodium and chlorine. Chloride, the ionic form of chlorine, derived exclusively from dietary absorption and constituting the most abundant anion in the human body, plays critical roles in many vital physiologic functions, from fluid retention and secretion to osmotic maintenance and pH balance. However, an often overlooked role of chloride is its function in innate host defense against infection.