The various forms of tooth resorption.

Tooth resorption refers to the loss of the organic and inorganic components of tooth structure by clastic cells. The complex and multifaceted nature of its aetiology, along with the several classification schemes published in the area, are likely to create confusion amongst researchers and clinicians, and may lead to compromised treatment decisions. Therefore, this paper will categorise and address tooth resorption based on aetiology in order to help clinicians diagnose and filter treatment options based on the pathophysiology of the resorption at hand.

GILT Expression in Human Melanoma Cells Enhances Generation of Antigenic Peptides for HLA Class II-Mediated Immune Recognition.

Melanoma is an aggressive skin cancer that has become increasingly prevalent in western populations. Current treatments such as surgery, chemotherapy, and high-dose radiation have had limited success, often failing to treat late stage, metastatic melanoma. Alternative strategies such as immunotherapies have been successful in treating a small percentage of patients with metastatic disease, although these treatments to date have not been proven to enhance overall survival.

Expression of gilt acts as a positive regulator of mouse hematopoietic progenitor cells.

Gamma interferon inducible lysosomal thiol reductase (GILT), is known to be involved in immunity, but its role in hematopoiesis has not been previously reported. Herein, we demonstrate using gilt knockout (-/-) mice that loss of gilt associates with decreased numbers and cycling status of femoral hematopoietic progenitor cells (CFU-GM, BFU-E, and CFU-GEMM) with more modest effects on splenic progenitor cells. Thus, GILT is associated with positive regulation of hematopoietic progenitor cells in mice, mainly in bone marrow.

Arsenolipids in Cultured Strain ML and Their Occurrence in Biota and Sediment from Mono Lake, California.

Primary production in Mono Lake, a hypersaline soda lake rich in dissolved inorganic arsenic, is dominated by strain ML. We set out to determine if this photoautotrophic picoplankter could metabolize inorganic arsenic and in doing so form unusual arsenolipids (e.g.

Convening on the influenza human viral challenge model for universal influenza vaccines, Part 2: Methodologic considerations.

In response to global interest in the development of a universal influenza vaccine, the Bill & Melinda Gates Foundation, PATH, and the Global Funders Consortium for Universal Influenza Vaccine Development convened a meeting of experts (London, UK, May 2018) to assess the role of a standardized controlled human influenza virus infection model (CHIVIM) towards the development of novel influenza vaccine candidates. This report (in two parts) summarizes those discussions and offers consensus recommendations. Part 1 covers challenge virus selection, regulatory and ethical considerations, and issues concerning standardization, access, and capacity.

Meeting report: Convening on the influenza human viral challenge model for universal influenza vaccines, Part 1: Value; challenge virus selection; regulatory, industry and ethical considerations; increasing standardization, access and capacity.

In response to global interest in the development of a universal influenza vaccine, the Bill & Melinda Gates Foundation, PATH, and the Global Funders Consortium for Universal Influenza Vaccine Development convened a meeting of experts (London, UK, May 2018) to assess the role of a standardized controlled human influenza virus infection model (CHIVIM) towards the development of novel influenza vaccine candidates. This report (in two parts) summarizes those discussions and offers consensus recommendations. This article (Part 1) covers challenge virus selection, regulatory and ethical considerations, and issues concerning standardization, access, and capacity.

Analysis of serum Hsp90 as a potential biomarker of β cell autoimmunity in type 1 diabetes.

Heat shock protein 90 (Hsp90) is a protein chaperone that is upregulated and released from pancreatic β cells under pro-inflammatory conditions. We hypothesized that serum Hsp90 may have utility as a biomarker of type 1 diabetes risk and exhibit elevations before the onset of clinically significant hyperglycemia. To this end, total levels of the alpha cytoplasmic isoform of Hsp90 were assayed in autoantibody-positive progressors to type 1 diabetes using banked serum samples from the TrialNet Pathway to Prevention Cohort that had been collected 12 months prior to diabetes onset, with comparison to age, sex, and BMI-category matched autoantibody-positive nonprogressors and healthy controls.

Melanoma LAMP-2C Modulates Tumor Growth and Autophagy.

Autophagy plays critical but diverse roles in cellular quality control and homeostasis potentially checking tumor development by removing mutated or damaged macromolecules, while conversely fostering tumor survival by supplying essential nutrients during cancer progression. This report documents a novel inhibitory role for a lysosome-associated membrane protein, LAMP-2C in modulating autophagy and melanoma cell growth and . Solid tumors such as melanomas encounter a variety of stresses including inflammatory cytokines produced by infiltrating lymphocytes directed at limiting tumor growth and spread.

Arsenate-dependent growth is independent of an ArrA mechanism of arsenate respiration in the termite hindgut isolate Citrobacter sp. strain TSA-1.

Citrobacter sp. strain TSA-1 is an enteric bacterium isolated from the hindgut of the termite. Strain TSA-1 displays anaerobic growth with selenite, fumarate, tetrathionate, nitrate, or arsenate serving as electron acceptors, and it also grows aerobically.

Early activation of peripheral monocytes with hallmarks of M1 and M2 monocytic cells in excessive alcohol drinkers: a pilot study.

Excessive drinking can lead to the development of immune dysfunction. Our aim is to investigate the effect of alcohol on immune activation from circulating peripheral blood monocytes in excessive drinkers (EDs). Twenty-two EDs and healthy controls were enrolled.

Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy.

Activation of the lysosomal ceramide-producing enzyme, acid sphingomyelinase (ASM), by various stresses is centrally involved in cell death and has been implicated in autophagy. We set out to investigate the role of the baseline ASM activity in maintaining physiological functions of lysosomes, focusing on the lysosomal nutrient-sensing complex (LYNUS), a lysosomal membrane-anchored multiprotein complex that includes mammalian target of rapamycin (mTOR) and transcription factor EB (TFEB). ASM inhibition with imipramine or sphingomyelin phosphodiesterase 1 () siRNA in human lung cells, or by transgenic haploinsufficiency of mouse lungs, markedly reduced mTOR- and P70-S6 kinase (Thr 389)-phosphorylation and modified TFEB in a pattern consistent with its activation.

Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90α.

A major obstacle in predicting and preventing the development of autoimmune type 1 diabetes (T1D) in at-risk individuals is the lack of well-established early biomarkers indicative of ongoing beta cell stress during the pre-clinical phase of disease. Recently, serum levels of the α cytoplasmic isoform of heat-shock protein 90 (hsp90) were shown to be elevated in individuals with new-onset T1D. We therefore hypothesized that hsp90α could be released from beta cells in response to cellular stress and inflammation associated with the earliest stages of T1D.

Hypoxia-Inducible Factor-1α Regulates CD55 in Airway Epithelium.

Airway epithelial CD55 down-regulation occurs in several hypoxia-associated pulmonary diseases, but the mechanism is unknown. Using in vivo and in vitro assays of pharmacologic inhibition and gene silencing, the current study investigated the role of hypoxia-inducible factor (HIF)-1α in regulating airway epithelial CD55 expression. Hypoxia down-regulated CD55 expression on small-airway epithelial cells in vitro, and in murine lungs in vivo; the latter was associated with local complement activation.

Physical Characterization and Innate Immunogenicity of Aggregated Intravenous Immunoglobulin (IGIV) in an In Vitro Cell-Based Model.

Purpose: To investigate in vitro the innate immune response to accelerated stress-induced aggregates of intravenous immunoglobulin (IGIV) using a well-defined human cell-line model, and to correlate the innate response to physical properties of the aggregates.

Methods: IGIV aggregates were prepared by applying various accelerated stress methods, and particle size, count and structure were characterized. Immune cell activation as tracked by inflammatory cytokines released in response to aggregates was evaluated in vitro using peripheral blood mononuclear cells (PBMC), primary monocytes and immortalized human monocyte-like cell lines.

The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants.

Aims/hypothesis: The incidence of type 1 diabetes is increasing at a rate of 3-5% per year. Genetics cannot fully account for this trend, suggesting an influence of environmental factors. The accelerator hypothesis proposes an effect of metabolic factors on type 1 diabetes risk.

Immunogenicity of Therapeutic Protein Aggregates.

Therapeutic proteins have a propensity for aggregation during manufacturing, shipping, and storage. The presence of aggregates in protein drug products can induce adverse immune responses in patients that may affect safety and efficacy, and so it is of concern to both manufacturers and regulatory agencies. In this vein, there is a lack of understanding of the physicochemical determinants of immunological responses and a lack of standardized analytical methods to survey the molecular properties of aggregates associated with immune activation.

LAMP-2C Inhibits MHC Class II Presentation of Cytoplasmic Antigens by Disrupting Chaperone-Mediated Autophagy.

Cells use multiple autophagy pathways to sequester macromolecules, senescent organelles, and pathogens. Several conserved isoforms of the lysosome-associated membrane protein-2 (LAMP-2) regulate these pathways influencing immune recognition and responses. LAMP-2A is required for chaperone-mediated autophagy (CMA), which promotes Ag capture and MHC class II (MHCII) presentation in B cells and signaling in T cells.

Critical role of PPARγ in myeloid-derived suppressor cell-stimulated cancer cell proliferation and metastasis.

Lysosomal acid lipase (LAL) is a key enzyme controlling neutral lipid metabolic signaling in myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient (lal-/-) mice directly stimulate cancer cell proliferation. PPARγ ligand treatment inhibited lal-/- MDSCs stimulation of tumor cell growth and metastasis in vivo, and tumor cell proliferation and migration in vitro.

Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes.

Rapid evaluation of therapies designed to preserve β cells in persons with type 1 diabetes (T1D) is hampered by limited availability of sensitive β-cell health biomarkers. In particular, biomarkers elucidating the presence and degree of β-cell stress are needed. We characterized β-cell secretory activity and stress in 29 new-onset T1D subjects (10.

Hyper-responsive Toll-like receptor 7 and 9 activation in NADPH oxidase-deficient B lymphoblasts.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency linked with mutations in the multi-subunit leucocyte NADPH oxidase. Myeloid-derived phagocytic cells deficient in NADPH oxidase fail to produce sufficient levels of reactive oxygen species to clear engulfed pathogens. In this study we show that oxidase also influences B-cell functions, including responses to single-stranded RNA or unmethylated DNA by endosomal Toll-like receptors (TLRs) 7 and 9.

A central role for HSC70 in regulating antigen trafficking and MHC class II presentation.

Cells rely on multiple intracellular trafficking pathways to capture antigens for proteolysis. The resulting peptides bind to MHC class II molecules to promote CD4(+) T cell recognition. Endocytosis enhances the capture of extracellular and cell surface bound antigens for processing and presentation, while autophagy pathways shunt cytoplasmic and nuclear antigens for presentation in the context of MHC class II molecules.

Elevation of c-MYC disrupts HLA class II-mediated immune recognition of human B cell tumors.

Elevated levels of the transcription factor c-myc are strongly associated with various cancers, and in particular B cell lymphomas. Although many of c-MYC's functions have been elucidated, its effect on the presentation of Ag through the HLA class II pathway has not been reported previously. This is an issue of considerable importance, given the low immunogenicity of many c-MYC-positive tumors.

Macronutrient deprivation modulates antigen trafficking and immune recognition through HSC70 accessibility.

B lymphocytes exploit macroautophagy to capture cytoplasmic and nuclear proteins within autophagosomes. Fusion of autophagosomes with lysosomes and endosomes facilitates content proteolysis, with the resulting peptides selectively binding MHC class II (MHC II) molecules, which are displayed for recognition by T lymphocytes. Nutrient deprivation or stress amplified this pathway, favoring increased MHC II presentation of cytoplasmic Ags targeted to autophagosomes.

Serum and mucosal antibody responses to inactivated polio vaccine after sublingual immunization using a thermoresponsive gel delivery system.

Administering vaccines directly to mucosal surfaces can induce both serum and mucosal immune responses. Mucosal responses may prevent establishment of initial infection at the port of entry and subsequent dissemination to other sites. The sublingual route is attractive for mucosal vaccination, but both a safe, potent adjuvant and a novel formulation are needed to achieve an adequate immune response.