ER stress affects processing of MHC class I-associated peptides

<p>Abstract</p> <p>Background</p> <p>Viral infection and neoplastic transformation trigger endoplasmic reticulum (ER) stress. Thus, a large proportion of the cells that must be recognized by the immune system are stressed cells. Cells respond to ER stress by launching the unfolded protein response (UPR). The UPR regulates the two key processes that control major histocompatibility complex class I (MHC I)-peptide presentation: protein synthesis and degradation. We therefore asked whether and how the UPR impinges on MHC I-peptide presentation.</p> <p>Results</p> <p>We evaluated the impact of the UPR on global MHC I expression and on presentation of the H2K^b-associated SIINFEKL peptide. EL4 cells stably transfected with vectors coding hen egg lysozyme (HEL)-SIINFEKL protein variants were stressed with palmitate or exposed to glucose deprivation. UPR decreased surface expression of MHC I but did not affect MHC I mRNA level nor the total amount of intracellular MHC I proteins. Impaired MHC I-peptide presentation was due mainly to reduced supply of peptides owing to an inhibition of overall protein synthesis. Consequently, generation of H2K^b-SIINFEKL complexes was curtailed during ER stress, illustrating how generation of MHC I peptide ligands is tightly coupled to ongoing protein synthesis. Notably, the UPR-induced decline of MHC I-peptide presentation was more severe when the protein source of peptides was localized in the cytosol than in the ER. This difference was not due to changes in the translation rates of the precursor proteins but to increased stability of the cytosolic protein during ER stress.</p> <p>Conclusion</p> <p>Our results demonstrate that ER stress impairs MHC I-peptide presentation, and that it differentially regulates expression of ER- vs. cytosol-derived peptides. Furthermore, this work illustrates how ER stress, a typical feature of infected and malignant cells, can impinge on cues for adaptive immune recognition.</p

Strategies to reduce waiting times in outpatient rehabilitation services for adults with physical disabilities : a systematic literature review

Objective: Identifying effective strategies to reduce waiting times is a crucial issue in many areas of health services. Long waiting times for rehabilitation services have been associated with numerous adverse effects in people with disabilities. The main objective of this study was to conduct a systematic literature review to assess the effectiveness of service redesign strategies to reduce waiting times in outpatient rehabilitation services for adults with physical disabilities. Methods: We conducted a systematic review, searching three databases (MEDLINE, CINAHL and EMBASE) from their inception until May 2021. We identified studies with comparative data evaluating the effect of rehabilitation services redesign strategies on reducing waiting times. The Mixed Methods Appraisal Tool was used to assess the methodological quality of the studies. A narrative synthesis was conducted. Results: Nineteen articles including various settings and populations met the selection criteria. They covered physiotherapy (n = 11), occupational therapy (n = 2), prosthetics (n = 1), exercise physiology (n = 1) and multidisciplinary (n = 4) services. The methodological quality varied (n = 10 high quality, n = 6 medium, n = 3 low); common flaws being missing information on the pre-redesign setting and characteristics of the populations. Seven articles assessed access processes or referral management strategies (e.g. self-referral), four focused on extending/modifying the roles of service providers (e.g. to triage) and eight changed the model of care delivery (e.g. mode of intervention). The different redesign strategies had positive effects on waiting times in outpatient rehabilitation services. Conclusions: This review highlights the positive effects of many service redesign strategies. These findings suggest that there are several effective strategies to choose from to reduce waiting times and help better respond to the needs of persons experiencing physical disabilities

The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection

Autoantibodies to components of apoptotic cells, such as anti-perlecan antibodies, contribute to rejection in organ transplant recipients. However, mechanisms of immunization to apoptotic components remain largely uncharacterized. We used large-scale proteomics, with validation by electron microscopy and biochemical methods, to compare the protein profiles of apoptotic bodies and apoptotic exosome-like vesicles, smaller extracellular vesicles released by endothelial cells downstream of caspase-3 activation. We identified apoptotic exosome-like vesicles as a central trigger for production of anti-perlecan antibodies and acceleration of rejection. Unlike apoptotic bodies, apoptotic exosome-like vesicles triggered the production of anti-perlecan antibodies in naïve mice and enhanced anti-perlecan antibody production and allograft inflammation in mice transplanted with an MHC (major histocompatibility complex)–incompatible aortic graft. The 20S proteasome core was active within apoptotic exosome-like vesicles and controlled their immunogenic activity. Finally, we showed that proteasome activity in circulating exosome-like vesicles increased after vascular injury in mice. These findings open new avenues for predicting and controlling maladaptive humoral responses to apoptotic cell components that enhance the risk of rejection after transplantation

Exercise therapy in Type 2 diabetes

Structured exercise is considered an important cornerstone to achieve good glycemic control and improve cardiovascular risk profile in Type 2 diabetes. Current clinical guidelines acknowledge the therapeutic strength of exercise intervention. This paper reviews the wide pathophysiological problems associated with Type 2 diabetes and discusses the benefits of exercise therapy on phenotype characteristics, glycemic control and cardiovascular risk profile in Type 2 diabetes patients. Based on the currently available literature, it is concluded that Type 2 diabetes patients should be stimulated to participate in specifically designed exercise intervention programs. More attention should be paid to cardiovascular and musculoskeletal deconditioning as well as motivational factors to improve long-term treatment adherence and clinical efficacy. More clinical research is warranted to establish the efficacy of exercise intervention in a more differentiated approach for Type 2 diabetes subpopulations within different stages of the disease and various levels of co-morbidity

Recension des facteurs associés à l’établissement de relations enfant-éducateur au service du sain développement de l’enfant

De 0 à 5 ans, l’enfant établit des liens socioaffectifs avec les adultes qui l’entourent, avec ses parents d’abord, mais également avec ses éducateurs. Puisque la qualité de ses relations influence son développement social, cognitif et comportemental ainsi que sa réussite scolaire, cette recherche documentaire tente de répertorier les facteurs associés à celle-ci. Parmi ces facteurs, on note certains attributs propres à l’enfant et à l’éducateur ainsi que des facteurs psychologiques et contextuels. Au terme de cette recension, les auteurs souhaitent que les chercheurs et les éducateurs puissent mieux cerner les facteurs susceptibles d’améliorer la qualité des relations enfant-éducateur.From 0 to 5 years old, a child establishes socio-emotional relationships with the adults around them, starting with his parents, but also with his teachers. Because the quality of these relationships influence his social, cognitive and behavioral development, and also his school success, this paper tries to identify the factors associated to it. The results of this review reveal that the main factors are child and teacher characteristics, as well as psychological and contextual factors. The authors whish this review will help researchers and educators identify more precisely the factors that could increase the quality of child-teacher relationships.De 0 a 5 años, el niño establece lazos socioafectivos con los adultos de su entorno, primero con sus padres, pero también con sus educadores. Puesto que la calidad de sus relaciones influye sobre su desarrollo social, cognitivo y comportamental así como su éxito escolar, esta investigación documental se propone catalogar los factores asociados a ésta. Dentro de estos factores se destacan algunos atributos propios del niño y del educador así como factores psicológicos y contextuales. Al término de esta revisión, los autores esperan que los investigadores y los educadores puedan delimitar mejor los factores susceptibles de mejorar la calidad de las relaciones niño-educador