MHC class II protein turnover in vivo and its relevance for autoimmunity in non-obese diabetic mice

Major histocompatibility complex class II (MHCII) proteins are loaded with endosomal peptides and reside at the surface of antigen-presenting cells (APCs) for a time before being degraded. In vitro, MHCII protein levels and turnover are affected by peptide loading and by rates of ubiquitin-dependent internalization from the cell surface, which is in turn affected by APC type and activation state. Prior work suggested that fast turnover of disease-associated MHCII alleles may contribute to autoimmunity. We recently developed novel stable isotope tracer techniques to test this hypothesis in vivo. In non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D), MHCII turnover was affected by APC type, but unaffected by disease-associated structural polymorphism. Differences in MHCII turnover were observed between NOD colonies with high and low T1D incidence, but fast turnover was dispensable for autoimmunity. Moreover, NOD mice with gene knockouts of peptide loading cofactors do not develop T1D. Thus, fast turnover does not appear pathogenic, and conventional antigen presentation is critical for autoimmunity in NOD mice. However, shared environmental factors may underpin colony differences in MHCII protein turnover, immune regulation, and pathogenesis

Role of major histocompatibility complex class II molecules in the maintenance of CD4 memory T cell function

The inheritable modifications that occur during activation enable memory T cells to mount a faster and stronger immune response than naive cells upon re-encounter with the same antigen. Memory CD4 T cells do not require MHC class II contact for survival, but previous analyses from our lab have underlined important differences between CD4 T cells transferred in MHC class II competent or deficient hosts that question the complete independency of memory cells from signals derived from MHC class II contact in terms of functionality. In this study, resting memory CD4 T cells generated in MHC class II competent or deficient hosts were characterised at the molecular level by analysis of gene expression with the aim to identify potential mechanisms to explain how MHC class II molecules preserve memory CD4 T cell function. Candidate molecules highlighted by analysis of gene expression were further investigated using FACS analysis and in vitro and in vivo experiments. As the phenotypic and functional characteristics of memory CD4 T cells generated in MHC class II deficient hosts were found established already in the early stages of the memory phase, the analysis was extended to the effector phase. The results obtained indicated that CD4 T cells may not achieve an optimal differentiation into effector cells in MHC class II deficient hosts suggesting that CD4 T cells require non-cognate interactions with MHC class II molecules during activation. Therefore, a universal role of MHC contact with non-antigen presenting MHC molecules during the initial activation step may be instrumental in shaping the functional competence of memory T cells

Dust remobilization in fusion plasmas under steady state conditions

The first combined experimental and theoretical studies of dust remobilization by plasma forces are reported. The main theoretical aspects of remobilization in fusion devices under steady state conditions are analyzed. In particular, the dominant role of adhesive forces is highlighted and generic remobilization conditions - direct lift-up, sliding, rolling - are formulated. A novel experimental technique is proposed, based on controlled adhesion of dust grains on tungsten samples combined with detailed mapping of the dust deposition profile prior and post plasma exposure. Proof-of-principle experiments in the TEXTOR tokamak and the EXTRAP-T2R reversed-field pinch are presented. The versatile environment of the linear device Pilot-PSI allowed for experiments with different magnetic field topologies and varying plasma conditions that were complemented with camera observations.Comment: 16 pages, 11 figures, 3 table

Conjunctival tumors in children: histopathologic diagnosis in 165 cases

ABSTRACT Purpose: Conjunctival tissue tumors have a varied presentation, and few series studies on pediatric patients have been published. The objective of this paper is to report the histopathologic diagnoses (spanning over 1988-2013) of conjunctival tumors in children younger than 14 years. Methods: We conducted a retrospective, descriptive, and observational study by reviewing the database of all children in whom a conjunctival tumor was surgically removed at Hospital de Ojos y Oídos "Dr. Rodolfo Robles V.," Benemérito Comité Pro Ciegos y Sordos de Guatemala. The data pertaining to gender, age, and histopathologic diagnosis of all cases was collected. The same ocular pathologist made all diagnoses. Results: One hundred sixty-five cases were found, with a mean age of 7.88 years, being 91 (55.15%) male subjects. Melanocytic lesions were the most common tumors found (30.91% of cases), with only one case (0.60%) being malignant. Conclusions: Melanocytic lesions were the most common tumors found, and of all the cases, only one was malignant; this was in a patient with xeroderma pigmentosum. These findings are consistent with those reported in other studies regarding the frequencies of the histopathology of conjunctival tumors in the pediatric population

Excitons and charged excitons in semiconductor quantum wells

A variational calculation of the ground-state energy of neutral excitons and of positively and negatively charged excitons (trions) confined in a single-quantum well is presented. We study the dependence of the correlation energy and of the binding energy on the well width and on the hole mass. The conditional probability distribution for positively and negatively charged excitons is obtained, providing information on the correlation and the charge distribution in the system. A comparison is made with available experimental data on trion binding energies in GaAs-, ZnSe-, and CdTe-based quantum well structures, which indicates that trions become localized with decreasing quantum well width.Comment: 9 pages, 11 figure

Celecoxib inhibits proliferation and survival of chronic myelogeous leukemia (CML) cells via AMPK-dependent regulation of β-catenin and mTORC1/2.

CML is effectively treated with tyrosine kinase inhibitors (TKIs). However, the efficacy of these drugs is confined to the chronic phase of the disease and development of resistance to TKIs remains a pressing issue. The anti-inflammatory COX2 inhibitor celecoxib has been utilized as anti-tumour drug due to its anti-proliferative activity. However, its effects in hematological malignancies, in particular CML, have not been investigated yet. Thus, we tested biological effects and mechanisms of action of celecoxib in Philadelphia-positive (Ph+) CML and ALL cells.We show here that celecoxib suppresses the growth of Ph+ cell lines by increasing G1-phase and apoptotic cells and reducing S- and G2-phase cells. These effects were independent of COX2 inhibition but required the rapid activation of AMP-activated protein kinase (AMPK) and the consequent inhibition mTORC1 and 2. Treatment with celecoxib also restored GSK3β function and led to down-regulation of β-catenin activity through transcriptional and post-translational mechanisms, two effects likely to contribute to Ph+ cell growth suppression by celecoxib.Celecoxib inhibited colony formation of TKI-resistant Ph+ cell lines including those with the T315I BCR-ABL mutation and acted synergistically with imatinib in suppressing colony formation of TKI-sensitive Ph+ cell lines. Finally, it suppressed colony formation of CD34+ cells from CML patients, while sparing most CD34+ progenitors from healthy donors, and induced apoptosis of primary Ph+ ALL cells.Together, these findings indicate that celecoxib may serve as a COX2-independent lead compound to simultaneously target the mTOR and β-catenin pathways, key players in the resistance of CML stem cells to TKIs

Long-term Occupancy (1900–2015) of an Egyptian Vulture Nest

Peer reviewe

Occupational risks in midwifery. From Bernardino Ramazzini to modern times

Occupational risks are often underestimated in midwifery. It is not commonly known that they were originally described by the Italian physician Bernardino Ramazzini (1633-1714) at the beginning of the eighteenth century. Our aim was to describe occupational risks in midwifery from Ramazzini to modern times. The original text by Bernardino Ramazzini was analyzed. A review of modern scientific papers on occupational risks in midwifery was conducted. Ramazzini identified two major occupational risks in midwifery: infections and awkward postures. Modern literature seems to agree with his considerations, focusing on infection, use of universal protection and personal protective equipment, and musculoskeletal problems. Modern studies also evidenced Post-Traumatic Stress Disorder that was probably postulated by Ramazzini himself. The poor number of papers in literature on midwives’ occupational risks evidences a lack of interest towards this issue. Prevention should therefore be emphasized in this field, so high-quality studies on occupational risks in midwifery are neede