Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides.

Tissue-specific autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential for initiating autoimmune type 1 diabetes in non-obese diabetic mice1,2. A major set of pathogenic CD4 T cells specifically recognizes the 12-20 segment of the insulin B-chain (B:12-20), an epitope that is generated from direct presentation of insulin peptides by antigen-presenting cells3,4. These T cells do not respond to antigen-presenting cells that have taken up insulin that, after processing, leads to presentation of a different segment representing a one-residue shift, B:13-214. CD4 T cells that recognize B:12-20 escape negative selection in the thymus and cause diabetes, whereas those that recognize B:13-21 have only a minor role in autoimmunity3-5. Although presentation of B:12-20 is evident in the islets3,6, insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread7,8. Here we use live imaging to document the distribution of insulin recognition by CD4 T cells throughout various lymph nodes. Furthermore, we identify catabolized insulin peptide fragments containing defined pathogenic epitopes in β-cell granules from mice and humans. Upon glucose challenge, these fragments are released into the circulation and are recognized by CD4 T cells, leading to an activation state that results in transcriptional reprogramming and enhanced diabetogenicity. Therefore, a tissue such as pancreatic islets, by releasing catabolized products, imposes a constant threat to self-tolerance. These findings reveal a self-recognition pathway underlying a primary autoantigen and provide a foundation for assessing antigenic targets that precipitate pathogenic outcomes by systemically sensitizing lymphoid tissues

Predominant Expression of Hybrid N-Glycans Has Distinct Cellular Roles Relative to Complex and Oligomannose N-Glycans

Glycosylation modulates growth, maintenance, and stress signaling processes. Consequently, altered N-glycosylation is associated with reduced fitness and disease. Therefore, expanding our understanding of N-glycans in altering biological processes is of utmost interest. Herein, clustered regularly interspaced short palindromic repeats/caspase9 (CRISPR/Cas9) technology was employed to engineer a glycosylation mutant Chinese Hamster Ovary (CHO) cell line, K16, which expresses predominantly hybrid type N-glycans. This newly engineered cell line enabled us to compare N-glycan effects on cellular properties of hybrid type N-glycans, to the well-established Pro´5 and Lec1 cell lines, which express complex and oligomannose types of N-glycans, respectively. Lectin binding studies revealed the predominant N-glycan expressed in K16 is hybrid type. Cell dissociation and migration assays demonstrated the greatest strength of cell–cell adhesion and fastest migratory rates for oligomannose N-glycans, and these properties decreased as oligomannose type were converted to hybrid type, and further decreased upon conversion to complex type. Next, we examined the roles of three general types of N-glycans on ectopic expression of E-cadherin, a cell–cell adhesion protein. Microscopy revealed more functional E-cadherin at the cell–cell border when N-glycans were oligomannose and these levels decreased as the oligomannose N-glycans were processed to hybrid and then to complex. Thus, we provide evidence that all three general types of N-glycans impact plasma membrane architecture and cellular properti

Resident and family perceptions of the nurse practitioner role in long term care settings: a qualitative descriptive study

BACKGROUND: Research evidence supports the positive impact on resident outcomes of nurse practitioners (NPs) working in long term care (LTC) homes. There are few studies that report the perceptions of residents and family members about the role of the NP in these settings. The purpose of this study was to explore the perceptions of residents and family members regarding the role of the NP in LTC homes. METHODS: The study applied a qualitative descriptive approach. In-depth individual and focus group interviews were conducted with 35 residents and family members from four LTC settings that employed a NP. Conventional content analysis was used to identify themes and sub-themes. RESULTS: Two major themes were identified: NPs were seen as providing resident and family-centred care and as providing enhanced quality of care. NPs established caring relationships with residents and families, providing both informational and emotional support, as well as facilitating their participation in decision making. Residents and families perceived the NP as improving availability and timeliness of care and helping to prevent unnecessary hospitalization. CONCLUSIONS: The perceptions of residents and family members of the NP role in LTC are consistent with the concepts of person-centred and relationship-centred care. The relationships NPs develop with residents and families are a central means through which enhanced quality of care occurs. Given the limited use of NPs in LTC settings, there is an opportunity for health care policy and decision makers to address service inadequacies through strategic deployment of NPs in LTC settings. NPs can use their expert knowledge and skill to assist residents and families to make informed choices regarding their health care and maintain a positive care experience

Supraspliceosomes at defined functional states portray the pre-assembled nature of the pre-mRNA processing machine in the cell nucleus

When isolated from mammalian cell nuclei, all nuclear pre-mRNAs are packaged in multi-subunit large ribonucleoprotein complexes—supraspliceosomes—composed of four native spliceosomes interconnected by the pre-mRNA. Supraspliceosomes contain all five spliceosomal U snRNPs, together with other splicing factors, and are functional in splicing. Supraspliceosomes studied thus far represent the steady-state population of nuclear pre-mRNAs that were isolated at different stages of the splicing reaction. To analyze specific splicing complexes, here, we affinity purified Pseudomonas aeruginosa phage 7 (PP7)-tagged splicing complexes assembled in vivo on Adenovirus Major Late (AdML) transcripts at specific functional stages, and characterized them using molecular techniques including mass spectrometry. First, we show that these affinity purified splicing complexes assembled on PP7-tagged AdML mRNA or on PP7-tagged AdML pre-mRNA are assembled in supraspliceosomes. Second, similar to the general population of supraspliceosomes, these defined supraspliceosomes populations are assembled with all five U snRNPs at all splicing stages. This study shows that dynamic changes in base-pairing interactions of U snRNA:U snRNA and U snRNA:pre-mRNA that occur in vivo during the splicing reaction do not require changes in U snRNP composition of the supraspliceosome. Furthermore, there is no need to reassemble a native spliceosome for the splicing of each intron, and rearrangements of the interactions will suffice

Understanding the relevance of in-mouth food processing. A review of in vitro techniques

[EN] Oral processing of food is the first step in the eating process. Although the food undergoes a number of changes during mastication that influence the subsequent steps, this stage has very often been neglected in studies of digestion, bioavailability, flavor release, satiety potential, glycemic index determination, etc. The present review draws on different sources such as nutrition, medicine, phoniatry and dentistry to explain some in vitro oral processing methods and techniques that could be transferred to food technology studies to mimic in vivo comminution, insalivation, and bolus formation, describing, as a necessary reference, the respective in vivo physiological processes they attempt to imitate. Developing a deeper understanding of all the aspects of in-mouth process will help food technologists to give this crucial step the necessary attention its due importance and to consider better ways to incorporate it into their studies.The authors wish to acknowledge the financial support of the Spanish Government (project AGL2012-36753-C02) and gratefully acknowledge the financial support of EU FEDER funds. Mary Georgina Hardinge assisted with the translation and corrected the English text.Morell Esteve, P.; Hernando Hernando, MI.; Fiszman, SM. (2014). Understanding the relevance of in-mouth food processing. A review of in vitro techniques. Trends in Food Science and Technology. 35(1):18-31. https://doi.org/10.1016/j.tifs.2013.10.005S183135

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Resident and family perceptions of the nurse practitioner role in long term care settings: a qualitative descriptive study

BackgroundResearch evidence supports the positive impact on resident outcomes of nurse practitioners (NPs) working in long term care (LTC) homes. There are few studies that report the perceptions of residents and family members about the role of the NP in these settings. The purpose of this study was to explore the perceptions of residents and family members regarding the role of the NP in LTC homes.MethodsThe study applied a qualitative descriptive approach. In-depth individual and focus group interviews were conducted with 35 residents and family members from four LTC settings that employed a NP. Conventional content analysis was used to identify themes and sub-themes.ResultsTwo major themes were identified: NPs were seen as providing resident and family-centred care and as providing enhanced quality of care. NPs established caring relationships with residents and families, providing both informational and emotional support, as well as facilitating their participation in decision making. Residents and families perceived the NP as improving availability and timeliness of care and helping to prevent unnecessary hospitalization.ConclusionsThe perceptions of residents and family members of the NP role in LTC are consistent with the concepts of person-centred and relationship-centred care. The relationships NPs develop with residents and families are a central means through which enhanced quality of care occurs. Given the limited use of NPs in LTC settings, there is an opportunity for health care policy and decision makers to address service inadequacies through strategic deployment of NPs in LTC settings. NPs can use their expert knowledge and skill to assist residents and families to make informed choices regarding their health care and maintain a positive care experience

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men