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The article focuses on the author's journey to reconnect with her Cherokee heritage through a visit to Tahlequah, Oklahoma. Topics include her exploration of Native American food culture, personal reflections on family history and identity, and the cultural significance of traditional stories and practices.

ABSTRACTMitochondria are susceptible to damage resulting from their activity as energy providers. Damaged mitochondria can cause harm to the cell and thus mitochondria are subjected to elaborate quality-control mechanisms including elimination via lysosomal degradation in a process termed mitophagy. Basal mitophagy is a house-keeping mechanism fine-tuning the number of mitochondria according to the metabolic state of the cell. However, the molecular mechanisms underlying basal mitophagy remain largely elusive. In this study, we visualized and assessed the level of mitophagy in H9c2 cardiomyoblasts at basal conditions and after OXPHOS induction by galactose adaptation. We used cells with a stable expression of a pH-sensitive fluorescent mitochondrial reporter and applied state-of-the-art imaging techniques and image analysis. Our data showed a significant increase in acidic mitochondria after galactose adaptation. Using a machine-learning approach we also demonstrated increased mitochondrial fragmentation by OXPHOS induction. Furthermore, super-resolution microscopy of live cells enabled capturing of mitochondrial fragments within lysosomes as well as dynamic transfer of mitochondrial contents to lysosomes. Applying correlative light and electron microscopy we revealed the ultrastructure of the acidic mitochondria confirming their proximity to the mitochondrial network, ER and lysosomes. Finally, exploiting siRNA knockdown strategy combined with flux perturbation with lysosomal inhibitors, we demonstrated the importance of both canonical as well as non-canonical autophagy mediators in lysosomal degradation of mitochondria after OXPHOS induction. Taken together, our high-resolution imaging approaches applied on H9c2 cells provide novel insights on mitophagy during physiologically relevant conditions. The implication of redundant underlying mechanisms highlights the fundamental importance of mitophagy.Abbreviations:ATG: autophagy related; ATG7: autophagy related 7; ATP: adenosine triphosphate; BafA1: bafilomycin A1; CLEM: correlative light and electron microscopy; EGFP: enhanced green fluorescent protein; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; OXPHOS: oxidative phosphorylation; PepA: pepstatin A; PLA: proximity ligation assay; PRKN: parkin RBR E3 ubiquitin protein ligase; RAB5A: RAB5A, member RAS oncogene family; RAB7A: RAB7A, member RAS oncogene family; RAB9A: RAB9A, member RAS oncogene family; ROS: reactive oxygen species; SIM: structured illumination microscopy; siRNA: short interfering RNA; SYNJ2BP: synaptojanin 2 binding protein; TEM: transmission electron microscopy; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like kinase 1.

TNF inhibitors have improved treatment of Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis, but are expensive therapies. The aim of NOR-SWITCH was to examine switching from originator infliximab to the less expensive biosimilar CT-P13 regarding efficacy, safety, and immunogenicity.

Objective.To examine the frequency of 6 definitions for remission and 4 definitions for low disease activity (LDA) after starting a disease-modifying antirheumatic drug (DMARD) in patients with rheumatoid arthritis (RA) in clinical practice, and to study whether predictors for achieving remission after 6 months are similar for these definitions.Methods.Remission and LDA were calculated according to the 28-joint Disease Activity Score (DAS28), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), the Routine Assessment of Patient Index Data (RAPID3), and both the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission definitions 3 and 6 months after 4992 DMARD prescriptions for patients enrolled in the NOR-DMARD, a 5-center Norwegian register. Prediction of remission after 6 months was also studied.Results.After 3 months, remission rates varied between definitions from 8.7% to 22.5% and for LDA from 35.5% to 42.7%, and increased slightly until 6 months of followup. DAS28 and RAPID3 gave the highest and ACR/EULAR, SDAI, and CDAI the lowest proportions for remission. Positive predictors for remission after 6 months were similar across the definitions and included lower age, male sex, short disease duration, high level of education, current nonsmoking, nonerosive disease, treatment with a biological DMARD, being DMARD-naive, good physical function, little fatigue, and LDA.Conclusion.In daily clinical practice, the DAS28 and RAPID3 definitions identified remission about twice as often as the ACR/EULAR Boolean, SDAI, and CDAI. Predictors of remission were similar across remission definitions. These findings provide additional evidence to follow treatment recommendations and treat RA early with a DMARD.

Introduction:Engineered heart tissue (EHT) consisting of beating cardiomyocytes differentiated from human inducible pluripotent stem cells (hiPSCs) has the potential to recapitulate molecular and functional features of the human heart. Cardiac homeostasis is dependent on lysosomal removal of damaged mitochondria through selective autophagy (mitophagy). The level of mitophagy and cardioprotective impact during ischemia and reperfusion remains elusive and demands further investigation.Objective:To assess mitophagy during ischemia-reperfusion simulation in human EHTs.Methods and results:A hiPSC line was genetically modified using CRISPR/Cas9 knock-in to insert a fluorescent tag (mCherry or EGFP) on Translocase of the Outer Mitochondrial Membrane 20(TOMM20)gene resulting in hiPSCs with fluorescent mitochondria. The hiPSCs were differentiated to cardiomyocytes that were embedded in a fibrin hydrogel between two flexible silicone posts to generate EHTs. The EHTs (21 days or older) were subjected to 90 min of ischemia simulation followed by 120 min of simulated reperfusion with and without the lysosomal inhibitor Bafilomycin A1 (BafA1) to measure flux. Time-matched control EHTs remained in normal conditions (with and without BafA1). The EHTs were fixed and sections were immunostained with the lysosomal marker LAMP1A and analyzed by confocal microscopy. Co-localization of fluorescent mitochondria and stained lysosomes was observed after 120 min of reperfusion. To further assess this co-localization we used proximity ligation assay (PLA), an antibody-based assay allowing verification of close proximity (within 40 nm) of two proteins resulting in a single fluorescent signal (PLA dot). We performed the assay using anti-TOMM20 and anti-LAMP1A antibodies to localize mitochondrial content within lysosomes. Notably, there was a significant increase in the number of PLA dots in response to 120 min of reperfusion in the presence of BafA1 (3.41±0.56 fold vs. control, p<0.01; n=4), indicative of induced mitophagy flux.Conclusion:We observed a marked increase in lysosomal degradation of mitochondria in EHTs during reperfusion. The functional impact on EHTs during ischemia and reperfusion needs further research.

Introduction:Low levels of dihomo-gamma-linolenic acid (DGLA) have been shown to predict total death in patients hospitalized with an acute coronary syndrome. DGLA is converted from gamma-linolenic acid (GLA) by the enzyme elongase, following a slower and rate-limiting conversion from linoleic acid (LA) to GLA by the action of delta-6-desaturase. This would suggest that DGLA levels are (strongly) associated with delta-6-desaturase activity. Furthermore, a high ratio of LA to DGLA (LA:DGLA) has been claimed to reflect reduced delta-6-desaturase activity.Hypothesis/Aim:To evaluate the relationship between LA:DGLA ratio and DGLA levels in patients with a recent myocardial infarction (MI).Methods:Baseline samples from the OMEMI (Omega-3 Fatty acids in Elderly with Myocardial Infarction) trial* in which a total of 1027 patients, aged 70 to 82 years, were included 2-8 weeks after an MI, were obtained. The total fatty acid profile was determined in serum phospholipids and relative concentrations (wt%) of LA, GLA and the LA:DGLA ratio (used as a surrogate for delta-6-desaturase activity) were evaluated across quartiles of concentrations of DGLA.Results:Levels of GLA were low compared to other n-6 fatty acids and followed the same trend as DGLA, consistent with a rapid turnover from GLA (Table 1). Furthermore, there was a steady decrease in the LA:DGLA ratio across the quartiles of DGLA, with approximately 50% lower levels in the highest compared to the lowest quartile of DGLA.Conclusion:We found a strong inverse relationship between DGLA and the LA:DGLA ratio in patients with a recent MI, indicating that the LA:DGLA ratio may serve as a measure of delta-6-desaturase activity. * Circulation 2021; 143(6): 528-39.

Background:Low levels of dihomo-gamma linolenic acid (DGLA) have been related to a bad outcome in patients with acute coronary syndromes. Reduced levels of DGLA may result from reduced conversion of its precursor linoleic acid (LA). An increase in the ratio of LA to DGLA (LA:DGLA) has been shown to reflect reduced delta-6-desaturase activity.Aim:To evaluate the association between the LA:DGLA ratio, reflecting delta-desaturase activity, and the risk of major adverse cardiovascular event (MACE, comprising nonfatal myocardial infarction (MI), unscheduled revascularization, stroke, hospitalization for heart failure, or all-cause death), in patients with a recent MI.Methods:Baseline samples from the OMEMI (Omega-3 Fatty acids in Elderly with Myocardial Infarction) trial* in which a total of 1027 patients, age 70 to 82 years, were included 2-8 weeks after an MI and followed up for 2 years, were used. FAs were measured in serum phospholipids, and the LA:DGLA ratio was calculated at baseline and related to incident MACE by univariate and multivariable Cox regression analyses, adjusted for age, sex, body mass index, omega-3 supplementation at baseline and hypertension.Results:A total of 208 patients experienced MACE during follow-up. The univariate hazard ratio (HR) for MACE in the fourth quartile (Q4) of LA:DGLA compared to the lowest quartile (Q1) was 1.49 (95% confidence interval (CI), 1.00-2.23), p=0.005. After adjustment, the HR for Q4 was weakened [1.47 (0.97-2.25), p=0.072]. The HR for Q2-4 combined as compared to Q1 was borderline significant [1.42 (0.99-2.03)], p=0.055. Although the number of total deaths were more than two-fold higher in Q4 as compared to Q1 [HR 2.30 (1.04-5.06), p=0.038], this did not reach significance in the adjusted models [HR 2.26 (0.95-5.37), p=0.065], and remained non-significant when comparing Q2-4 combined to Q1 [HR 1.74 (0.80-3.77), p=0.16].Conclusion:Higher levels of LA:DGLA ratio were found to be associated with MACE in elderly patients with a recent MI, suggesting a mechanism to why low levels of DGLA may be associated with increased adverse events. * Circulation 2021; 143(6): 528-39.

The rate of side-effects should today be more important for the choice of an agent for treatment of acute urinary tract infections than the cure rate, as this usually is above 90%. The side-effects with co-trimoxazole (trimethoprim-sulphamethoxazol) have been viewed as caused mainly by the sulphonamide component.In this randomized, double-blind trial Group A has been treated with trimethoprim 200 mg x 2 and Group B with nitrofurantoin 50 mg x 4 for a duration of 10 days.There was no difference in cure rate between the two groups.The rate of side-effects was 26% in Group A and 12% in Group B. In Group A 12% had skin eruptions, mostly appearing on Day 7 or later, in Group B 1.3% had eruptions. These differences are statistically significant (p < 0.05). This result, together with a survey of the literature, indicates that the frequency of these rashes might be related both to dosage and duration of treatment. The origin of the side-effects caused by co-trimoxazole should be reconsidered. The in vitro sensitivity against trimethoprim and nitrofurantoin was tested using a disc diffusion method in 98 infecting strains from patients in this study. Two per cent were resistant against trimethoprim and 81% against nitrofurantoin. We found no correlation between the size of the inhibition zone and bacteriological cure rate. This makes the value of the disc diffusion method in out-patients with acute urinary tract infections questionable.

Several letters to the editor are presented in response to articles in previous issues, including "Group Wants DoD to Ban Porn From Bases, Camps" in the June 24, 2013 issue, "Need a Part? Just Press Print" in the June 10, 2013 issue and "Cammies in the Cross Hairs" in the June 17, 2013 issue.

Several letters to the editor are presented in response to articles in previous issues including "Need a Part? Just Press Print" in the June 10, 2013 issue, and another one about the U.S. Department of Defense's (DoD) start of furloughing civilian employees.