Lyn, lupus, and (B) lymphocytes, a lesson on the critical balance of kinase signaling in immunity

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by increased sensitivity to self-antigens, auto-antibody production, and systemic inflammation. B cells have been implicated in disease progression and as such represent an attractive therapeutic target. Lyn is a Src family tyrosine kinase that plays a major role in regulating signaling pathways within B cells as well as other hematopoietic cells. Its role in initiating negative signaling cascades is especially critical as exemplified by Lyn-/- mice developing an SLE-like disease with plasma cell hyperplasia, underscoring the importance of tightly regulating signaling within B cells. This review highlights recent advances in our understanding of the function of the Src family tyrosine kinase Lyn in B lymphocytes and its contribution to positive and negative signaling pathways that are dysregulated in autoimmunity

LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins

Maintenance of mitochondrial protein homeostasis is critical for proper cellular function. Under normal conditions resident molecular chaperones and proteases maintain protein homeostasis within the organelle. Under conditions of stress however, misfolded proteins accumulate leading to the activation of the mitochondrial unfolded protein response (UPRmt). While molecular chaperone assisted refolding of proteins in mammalian mitochondria has been well documented, the contribution of AAA+ proteases to the maintenance of protein homeostasis in this organelle remains unclear. To address this gap in knowledge we examined the contribution of human mitochondrial matrix proteases, LONM and CLPXP, to the turnover of OTC-Delta, a folding incompetent mutant of ornithine transcarbamylase, known to activate UPRmt. Contrary to a model whereby CLPXP is believed to degrade misfolded proteins, we found that LONM, and not CLPXP is responsible for the turnover of OTC-Delta in human mitochondria. To analyse the conformational state of proteins that are recognised by LONM, we examined the turnover of unfolded and aggregated forms of malate dehydrogenase (MDH) and OTC. This analysis revealed that LONM specifically recognises and degrades unfolded, but not aggregated proteins. Since LONM is not upregulated by UPRmt, this pathway may preferentially act to promote chaperone mediated refolding of proteins

Perrault syndrome type 3 caused by diverse molecular defects in CLPP

Abstract The maintenance of mitochondrial protein homeostasis (proteostasis) is crucial for correct cellular function. Recently, several mutations in the mitochondrial protease CLPP have been identified in patients with Perrault syndrome 3 (PRLTS3). These mutations can be arranged into two groups, those that cluster near the docking site (hydrophobic pocket, Hp) for the cognate unfoldase CLPX (i.e. T145P and C147S) and those that are adjacent to the active site of the peptidase (i.e. Y229D). Here we report the biochemical consequence of mutations in both regions. The Y229D mutant not only inhibited CLPP-peptidase activity, but unexpectedly also prevented CLPX-docking, thereby blocking the turnover of both peptide and protein substrates. In contrast, Hp mutations cause a range of biochemical defects in CLPP, from no observable change to CLPP activity for the C147S mutant, to dramatic disruption of most activities for the “gain-of-function” mutant T145P - including loss of oligomeric assembly and enhanced peptidase activity

Lyn, Lupus, and (B) Lymphocytes, a Lesson on the Critical Balance of Kinase Signaling in Immunity

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by increased sensitivity to self-antigens, auto-antibody production, and systemic inflammation. B cells have been implicated in disease progression and as such represent an attractive therapeutic target. Lyn is a Src family tyrosine kinase that plays a major role in regulating signaling pathways within B cells as well as other hematopoietic cells. Its role in initiating negative signaling cascades is especially critical as exemplified by Lyn−/− mice developing an SLE-like disease with plasma cell hyperplasia, underscoring the importance of tightly regulating signaling within B cells. This review highlights recent advances in our understanding of the function of the Src family tyrosine kinase Lyn in B lymphocytes and its contribution to positive and negative signaling pathways that are dysregulated in autoimmunity

Social Prescribing Outcomes for Trials (SPOT): Protocol for a modified Delphi study on core outcomes.

PurposeThis is a study protocol to co-create with knowledge users a core outcome set focused on middle-aged and older adults (40 years+) for use in social prescribing research.MethodsWe will follow the Core Outcome Measures in Effectiveness Trials (COMET) guide and use modified Delphi methods, including collating outcomes reported in social prescribing publications, online surveys, and discussion with our team to finalize the core outcome set. We intentionally center this work on people who deliver and receive social prescribing and include methods to evaluate collaboration. Our three-part process includes: (1) identifying published systematic reviews on social prescribing for adults to extract reported outcomes; and (2) up to three rounds of online surveys to rate the importance of outcomes for social prescribing. For this part, we will invite people (n = 240) who represent the population experienced in social prescribing, including researchers, members of social prescribing organizations, and people who receive social prescribing and their caregivers. Finally, we will (3) convene a virtual team meeting to discuss and rank the findings and finalize the core outcome set and our knowledge mobilization plan.ConclusionTo our knowledge, this is the first study designed to use a modified Delphi method to co-create core outcomes for social prescribing. Development of a core outcome set contributes to improved knowledge synthesis via consistency in measures and terminology. We aim to develop guidance for future research, and specifically on the use of core outcomes for social prescribing at the person/patient, provider, program, and societal-level

International Consensus Statement on Obstructive Sleep Apnea

Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy

International consensus statement on obstructive sleep apnea

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea is needed to consolidate and summarize key factors important for clinical management of the OSA adult patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA and treatment on the multiple comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature in OSA consolidates the available knowledge and identifies the limitations of the current evidence. This effort aims to highlight the basis of OSA evidence-based practice and identify future research needs. Knowledge gaps and opportunities for improvement include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy