Engineered interleukin-6-derived cytokines recruit artificial receptor complexes and disclose CNTF signaling via the OSMR.

Ciliary neurotrophic factor (CNTF) activates cells via the non-signaling α-receptor CNTF receptor (CNTFR) and the two signaling ß-receptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). The CNTF derivate, Axokine, was protective against obesity and insulin resistance, but clinical development was halted by the emergence of CNTF antibodies. The chimeric cytokine IC7 used the framework of interleukin (IL-)6 with the LIFR-binding site from CNTF to activate cells via IL-6R:gp130:LIFR complexes. Similar to CNTF/Axokine, IC7 protected mice from obesity and insulin resistance. Here, we developed CNTF-independent chimeras that specifically target the IL-6R:gp130:LIFR complex. In GIL-6 and GIO-6, we transferred the LIFR binding site from LIF or OSM to IL-6, respectively. While GIO-6 signals via gp130:IL-6R:LIFR and gp130:IL-6R:OSMR complexes, GIL-6 selectively activates the IL-6R:gp130:LIFR receptor complex. By re-evaluation of IC7 and CNTF, we discovered the Oncostatin M receptor (OSMR) as an alternative non-canonical high-affinity receptor leading to IL-6R:OSMR:gp130 and CNTFR:OSMR:gp130 receptor complexes, respectively. The discovery of OSMR as an alternative high-affinity receptor for IC7 and CNTF designates GIL-6 as the first truly selective IL-6R:gp130:LIFR cytokine, whereas GIO-6 is a CNTF-free alternative for IC7.

Acute and short-term fluctuations in gravity are associated with changes in circulatory plasma protein levels.

Gravitational changes between micro- and hypergravity cause several adaptations and alterations in the human body. Besides muscular atrophy and immune system impairment, effects on the circulatory system have been described, which can be associated with a wide range of blood biomarker changes. This study examined nine individuals (seven males, two females) during a parabolic flight campaign (PFC). Thirty-one parabolas were performed in one flight day, resulting in ~22 s of microgravity during each parabola. Each participant was subjected to a single flight day with a total of 31 parabolas, totaling 11 min of microgravity during one parabolic flight. Before and after (1 hour (h) and 24 h), the flights blood was sampled to examine potential gravity-induced changes of circulating plasma proteins. Proximity Extension Assay (PEA) offers a proteomic solution, enabling the simultaneous analysis of a wide variety of plasma proteins. From 2925 unique proteins analyzed, 251 (8.58%) proteins demonstrated a differential regulation between baseline, 1 h and 24 h post flight. Pathway analysis indicated that parabolic flights led to altered levels of proteins associated with vesicle organization and apoptosis up to 24 h post microgravity exposure. Varying gravity conditions are associated with poorly understood physiological changes, including stress responses and fluid shifts. We provide a publicly available library of gravity-modulated circulating protein levels illustrating numerous changes in cellular pathways relevant for inter-organ function and communication.

SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling.

Cellular responses leading to development, proliferation, and differentiation depend on RAF/MEK/ERK signaling, which integrates and amplifies signals from various stimuli for downstream cellular responses. C-RAF activation has been reported in many types of tumor cell proliferation and developmental disorders, necessitating the discovery of potential C-RAF protein regulators. Here, we identify a novel and specific protein interaction between C-RAF among the RAF kinase paralogs, and SIRT4 among the mitochondrial sirtuin family members SIRT3, SIRT4, and SIRT5. Structurally, C-RAF binds to SIRT4 through the N-terminal cysteine-rich domain, whereas SIRT4 predominantly requires the C-terminus for full interaction with C-RAF. Interestingly, SIRT4 specifically interacts with C-RAF in a pre-signaling inactive (serine 259-phosphorylated) state. Consistent with this finding, the expression of SIRT4 in HEK293 cells results in an up-regulation of pS259-C-RAF levels and a concomitant reduction in MAPK signaling as evidenced by strongly decreased phospho-ERK signals. Thus, we propose an additional extra-mitochondrial function of SIRT4 as a cytosolic tumor suppressor of C-RAF-MAPK signaling, besides its metabolic tumor suppressor role of glutamate dehydrogenase and glutamate levels in mitochondria.

Association of dietary patterns with diabetes-related comorbidities varies among diabetes endotypes.

BACKGROUND AND AIMS: Differences of dietary pattern adherence across the novel diabetes endotypes are unknown. This study assessed adherence to pre-specified dietary patterns and their associations with cardiovascular risk factors, kidney function, and neuropathy among diabetes endotypes. METHODS AND RESULTS: The cross-sectional analysis included 765 individuals with recent-onset (67 %) and prevalent diabetes (33 %) from the German Diabetes Study (GDS) allocated into severe autoimmune diabetes (SAID, 35 %), severe insulin-deficient diabetes (SIDD, 3 %), severe insulin-resistant diabetes (SIRD, 5 %), mild obesity-related diabetes (MOD, 28 %), and mild age-related diabetes (MARD, 29 %). Adherence to a Mediterranean diet score (MDS), Dietary Approaches to Stop Hypertension (DASH) score, overall plant-based diet (PDI), healthful (hPDI) and unhealthful plant-based diet index (uPDI) was derived from a food frequency questionnaire and associated with cardiovascular risk factors, kidney function, and neuropathy using multivariable linear regression analysis. Differences in dietary pattern adherence between endotypes were assessed using generalized mixed models. People with MARD showed the highest, those with SIDD and MOD the lowest adherence to the hPDI. Adherence to the MDS, DASH, overall PDI, and hPDI was inversely associated with high-sensitivity C-reactive protein (hsCRP) among people with MARD (ß (95%CI): -9.18 % (-15.61; -2.26); -13.61 % (-24.17; -1.58); -19.15 % (-34.28; -0.53); -16.10 % (-28.81; -1.12), respectively). Adherence to the PDIs was associated with LDL cholesterol among people with SAID, SIRD, and MOD. CONCLUSIONS: Minor differences in dietary pattern adherence (in particular for hPDI) and associations with markers of diabetes-related complications (e.g. hsCRP) were observed between endotypes. So far, evidence is insufficient to derive endotype-specific dietary recommendations. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01055093.

Ultra-processed food consumption and human health: an umbrella review of systematic reviews with meta-analyses.

Recently, ultra-processed foods received a lot of attention, but also criticism. Our aim was to provide an overview of the existing evidence of ultra-processed food consumption on human health. We conducted a systematic search in four databases until January 5th, 2024. Systematic reviews with meta-analyses on ultra-processed food consumption as defined by the NOVA classification system were included. The certainty of evidence was evaluated by the GRADE approach. We identified 16 publications. Moderate certainty of evidence was found for all-cause mortality (Summary Risk Ratio per 50 g: 1.02; 95% confidence Interval (CI): 1.01, 1.03), cardiovascular disease incidence and mortality (per 50 g/d: 1.04; 95% CI: 1.02, 1.06, and 1.05; 95% CI: 1.01, 1.08), type 2 diabetes incidence (per 10%: 1.12; 95% CI: 1.10, 1.13) and colorectal cancer (per 10%: 1.04; 95% CI: 1.01, 1.07). For several outcomes such as inflammatory bowel diseases, obesity, metabolic syndrome, nonalcoholic fatty liver disease, mental health as well as nutrient quality, similar estimates were observed, but certainty of evidence was limited. Discussing the NOVA concept, it remains unclear whether the processing of foods leads to increased health risks or if ultra-processed food consumption is only a measure for poor diet quality.

Application and challenges of TCR and BCR sequencing to investigate T- and B-cell clonality in elastase-induced experimental murine abdominal aortic aneurysm.

Background: An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. Although its pathogenesis is still poorly understood, recent evidence suggests that AAA displays autoimmune disease characteristics. Particularly, T cells responding to AAA-related antigens in the aortic wall may contribute to an initial immune response. Single-cell RNA (scRNA) T cell receptor (TCR) and B cell receptor (BCR) sequencing is a powerful tool for investigating clonality. However, difficulties such as limited numbers of isolated cells must be considered during implementation and data analysis, making biological interpretation challenging. Here, we perform a representative single-cell immune repertoire analysis in experimental murine AAA and show a reliable bioinformatic processing pipeline highlighting opportunities and limitations of this approach. Methods: We performed scRNA TCR and BCR sequencing of isolated lymphocytes from the infrarenal aorta of male C57BL/6J mice 3, 7, 14, and 28 days after AAA induction via elastase perfusion of the aorta. Sham-operated mice at days 3 and 28 and non-operated mice served as controls. Results: Comparison of complementarity-determining region (CDR3) length distribution of 179 B cells and 796 T cells revealed neither differences between AAA and control nor between the disease stages. We found no clonal expansion of B cells in AAA. For T cells, we identified several clones in 11 of 16 AAA samples and one of eight control samples. Immune receptor repertoire comparison indicated that only a few clones were shared between the individual AAA samples. The most frequently used V-genes in the TCR beta chain in AAA were TRBV3, TRBV19, and the splicing variant TRBV12-2 + TRBV13-2. Conclusion: We found no clonal expansion of B cells but evidence for clonal expansion of T cells in elastase-induced AAA in mice. Our findings imply that a more precise characterization of TCR and BCR distribution requires a more extensive number of lymphocytes to prevent undersampling and potentially detect rare clones. Thus, further experiments are necessary to confirm our findings. In summary, this paper examines TCR and BCR sequencing results, identifies limitations and pitfalls, and offers guidance for future studies.

CoCl2 -triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299.

SIRT4, together with SIRT3 and SIRT5, comprises the mitochondrially localized subgroup of sirtuins. SIRT4 regulates mitochondrial bioenergetics, dynamics (mitochondrial fusion), and quality control (mitophagy) via its NAD+ -dependent enzymatic activities. Here, we address the regulation of SIRT4 itself by characterizing its protein stability and degradation upon CoCl2 -induced pseudohypoxic stress that typically triggers mitophagy. Interestingly, we observed that of the mitochondrial sirtuins, only the protein levels of SIRT4 or ectopically expressed SIRT4-eGFP decrease upon CoCl2 treatment of HEK293 cells. Co-treatment with BafA1, an inhibitor of autophagosome-lysosome fusion required for autophagy/mitophagy, or the use of the proteasome inhibitor MG132, prevented CoCl2 -induced SIRT4 downregulation. Consistent with the proteasomal degradation of SIRT4, the lysine mutants SIRT4(K78R) and SIRT4(K299R) showed significantly reduced polyubiquitination upon CoCl2 treatment and were more resistant to pseudohypoxia-induced degradation as compared to SIRT4. Moreover, SIRT4(K78R) and SIRT4(K299R) displayed increased basal protein stability as compared to wild-type SIRT4 when subjected to MG132 treatment or cycloheximide (CHX) chase assays. Thus, our data indicate that stress-induced protein degradation of SIRT4 occurs through two mechanisms: (a) via mitochondrial autophagy/mitophagy, and (b) as a separate process via proteasomal degradation within the cytoplasm.

The mediating role of obesity on the prospective association between urinary sucrose and diabetes incidence in a sub-cohort of the EPIC-Norfolk.

BACKGROUND/OBJECTIVES: Findings from epidemiological studies showed controversial findings between dietary sugar intake and the development of diabetes. Most of these studies assessed dietary sugar intake by self-reports which might be prone to bias. Urinary sucrose, an objective biomarker of sucrose intake, might provide better insights into this association. Thus, the aim of this study was to investigate the associations between sucrose intake, measured via self-reports and urinary sucrose, with incident diabetes and to detect the impact of obesity on this association. SUBJECTS/METHODS: Data of a sub-group (n = 2996) from the prospective EPIC-Norfolk cohort were investigated. Sucrose intake was assessed by self-reports (validated food frequency questionnaire (FFQ) and 7-day diet diaries (7DD)) and as an objective urinary sucrose biomarker. Cox proportional hazard models were conducted to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for the associations between urinary and dietary sucrose intake and incident diabetes. Mediation analysis was performed to investigate the mediated percentage of body mass index (BMI) and waist circumference (WC) on this association. RESULTS: The mean age of the participants was 60.6 ± 9.5 years and 53% were women. After a mean follow-up of 11.2 ± 2.9 years, 97 participants developed diabetes. Findings suggested inverse associations regarding incident diabetes for self-reported sucrose intake per 50 g/d via 7DD [HR: 0.63 (95% CI: 0.43, 0.91)], and a tendency via FFQ [HR: 0.81 (95% CI: 0.46, 1.42)]. Urinary sucrose indicated a positive association with incident diabetes for each increase of 100 µM [HR: 1.14 (95% CI: 0.95, 1.36)]. The proportion mediated of BMI and WC for this association was 16 and 22%. CONCLUSIONS: These findings indicate that sucrose measured as objective urinary biomarker points to a positive association with incident diabetes. BMI might partly mediate this association. However, to obtain more precise results, more studies are warranted that consider this objective biomarker.

Non-Invasive Zinc Protoporphyrin Screening Offers Opportunities for Secondary Prevention of Iron Deficiency in Blood Donors.

Background: Frequent blood donors are at high risk of developing iron deficiency. Currently, there is no potent screening during blood donation to detect iron deficient erythropoiesis (IDE) before anemia develops and deferral from donation is inevitable. Study Design and Methods: In addition to capillary and venous hemoglobin, the iron status of 99 frequent blood donors was assessed by various venous blood parameters and zinc protoporphyrin IX (ZnPP). ZnPP was determined by high-performance liquid chromatography (HPLC) and a new prototype fiber-optic device was employed for non-invasive measurements of ZnPP through the blood collection tubing (NI-tubing) and on lip tissue (NI-lip). We aimed to evaluate the feasibility and diagnostic value of the NI-tubing measurement for early detection of severe iron deficiency in blood donors. Results: NI-tubing and HPLC reference measurements of ZnPP showed narrow limits of agreement of 12.2 µmol ZnPP/mol heme and very high correlation (Spearman's Rho = 0.938). Using a cutoff of 65 µmol ZnPP/mol heme, NI-tubing measurements (n = 93) identified 100% of donors with iron deficiency anemia (IDA) and an additional 38% of donors with IDE. Accordingly, NI-tubing measurements would allow detection and selective protection of particularly vulnerable donors. Conclusion: NI-tubing measurements are an accurate and simple method to implement ZnPP determination into the routine blood donation process. ZnPP was able to identify the majority of subjects with IDE and IDA and might therefore be a valuable tool to provide qualified information to donors about dietary measures and adjustments of the donation interval and thereby help to prevent IDA and hemoglobin deferral in the future.

Mediation Analysis in Medical Research.

BACKGROUND: Mediation analysis addresses the question of the mechanisms by which an exposure causes an outcome. This article is intended to convey basic knowledge of statistical mediation analysis. METHODS: Selected articles and examples are used to explain the principle of mediation analysis. RESULTS: The goal of mediation analysis is to express an overall exposure effect as a combination of an indirect and a direct effect. For example, it might be of interest whether the increased risk of diabetes (outcome) due to obesity (exposure) is mediated by insulin resistance (indirect effect), and, if so, how much of a direct effect remains. In this example, insulin resistance is a potential mediator of the effect of obesity on the risk of diabetes. In general, for a mediation analysis to be valid, more confounders must be taken into account than in the estimation of the overall effect size. A regression-based approach can be used to ensure the consideration of all relevant confounders in a mediation analysis. CONCLUSION: By decomposing the overall exposure effect into indirect and direct components, a mediation analysis can reveal not just whether an exposure causes an outcome, but also how. For a mediation analysis to be valid, however, multiple assumptions must be satisfied that cannot easily be checked, potentially compromising such analyses as compared to the estimation of an overall effect.

Association of a lifestyle score with cardiometabolic markers among individuals with diabetes: a cross-sectional study.

INTRODUCTION: To investigate the associations of a lifestyle score with various cardiovascular risk markers, indicators for fatty liver disease as well as MRI-determined total, subcutaneous and visceral adipose tissue mass in adults with new-onset diabetes. RESEARCH DESIGN AND METHODS: This cross-sectional analysis included 196 individuals with type 1 (median age: 35 years; median body mass index (BMI): 24 kg/m²) and 272 with type 2 diabetes (median age: 53 years; median BMI: 31 kg/m²) from the German Diabetes Study. A healthy lifestyle score was generated based on healthy diet, moderate alcohol consumption, recreational activity, non-smoking and non-obese BMI. These factors were summed to form a score ranging from 0 to 5. Multivariable linear and non-linear regression models were used. RESULTS: In total, 8.1% of the individuals adhered to none or one, 17.7% to two, 29.7% to three, 26.7% to four, and 17.7% to all five favorable lifestyle factors. High compared with low adherence to the lifestyle score was associated with more favorable outcome measures, including triglycerides (ß (95% CI) -49.1 mg/dL (-76.7; -21.4)), low-density lipoprotein (-16.7 mg/dL (-31.3; -2.0)), and high-density lipoprotein cholesterol (13.5 mg/dL (7.6; 19.4)), glycated hemoglobin (-0.5% (-0.8%; -0.1%)), high-sensitivity C reactive protein (-0.4 mg/dL (-0.6; -0.2)), as well as lower hepatic fat content (-8.3% (-11.9%; -4.7%)), and visceral adipose tissue mass (-1.8 dm³ (-2.9; -0.7)). The dose-response analyses showed that adherence to every additional healthy lifestyle factor was associated with more beneficial risk profiles. CONCLUSIONS: Adherence to each additional healthy lifestyle factor was beneficially associated with cardiovascular risk markers, indicators of fatty liver disease and adipose tissue mass. Strongest associations were observed for adherence to all healthy lifestyle factors in combination. TRIAL REGISTRATION NUMBER: NCT01055093.

Severe COVID-19 associated hyperglycemia is caused by beta cell dysfunction: a prospective cohort study.

BACKGROUND: COVID-19, an infectious disease caused by SARS-CoV-2, was shown to be associated with an increased risk of new-onset diabetes. Mechanisms contributing to the development of hyperglycemia are still unclear. We aimed to study whether hyperglycemia is related to insulin resistance and/or beta cell dysfunction. MATERIALS AND METHODS: Survivors of severe COVID-19 but without a known history of diabetes were examined at baseline (T0) and after 3 (T3) and 6 (T6) months: corticosteroids use, indirect calorimetry, and OGTT. Insulin response and sensitivity (IS) were expressed as insulinogenic (IGI), disposition (DI), and Matsuda insulin sensitivity index (ISI). Resting energy expenditure (REE) and respiratory quotient (RQ) was calculated from the gas exchange and nitrogen losses. RESULTS: 26 patients (out of 37) with complete outcome data were included in the analysis (age ~59.0 years; BMI ~ 30.4, 35% women). Patients were hypermetabolic at T0 (30.3 ± 4.0 kcal/kg lean mass/day, ~120% predicted) but REE declined over 6 months (ΔT6-T0 mean dif. T6-T0 (95% CI): -5.4 (-6.8, -4.1) kcal/kg FFM/day, p < 0.0001). 17 patients at T0 and 13 patients at T6 had hyperglycemia. None of the patients had positive islet autoantibodies. Insulin sensitivity in T0 was similarly low in hyperglycemic (H) and normoglycemic patients (N) (T0 ISIH = 3.12 ± 1.23, ISIN = 3.47 ± 1.78, p = 0.44), whereas insulin response was lower in the H group (DIH = 3.05 ± 1.79 vs DIN = 8.40 ± 5.42, p = 0.003). Over 6 months ISI (ΔT6-T0 mean dif. T6-T0 for ISI (95% CI): 1.84 (0.45, 3.24), p = 0.01)) increased in the H group only. CONCLUSIONS: Patients with severe COVID-19 had increased REE and insulin resistance during the acute phase due to the infection and corticosteroid use, but these effects do not persist during the follow-up period. Only patients with insufficient insulin response developed hyperglycemia, indicating that beta cell dysfunction, rather than insulin resistance, was responsible for its occurrence.

Risk phenotypes of diabetes and association with COVID-19 severity and death: an update of a living systematic review and meta-analysis.

AIMS/HYPOTHESIS: To provide a systematic overview of the current body of evidence on high-risk phenotypes of diabetes associated with COVID-19 severity and death. METHODS: This is the first update of our recently published living systematic review and meta-analysis. Observational studies investigating phenotypes in individuals with diabetes and confirmed SARS-CoV-2 infection with regard to COVID-19-related death and severity were included. The literature search was conducted from inception up to 14 February 2022 in PubMed, Epistemonikos, Web of Science and the COVID-19 Research Database and updated using PubMed alert to 1 December 2022. A random-effects meta-analysis was used to calculate summary relative risks (SRRs) with 95% CIs. The risk of bias was evaluated using the Quality in Prognosis Studies (QUIPS) tool and the certainty of evidence using the GRADE approach. RESULTS: A total of 169 articles (147 new studies) based on approximately 900,000 individuals were included. We conducted 177 meta-analyses (83 on COVID-19-related death and 94 on COVID-19 severity). Certainty of evidence was strengthened for associations between male sex, older age, blood glucose level at admission, chronic insulin use, chronic metformin use (inversely) and pre-existing comorbidities (CVD, chronic kidney disease, chronic obstructive pulmonary disease) and COVID-19-related death. New evidence with moderate to high certainty emerged for the association between obesity (SRR [95% CI] 1.18 [1.04, 1.34], n=21 studies), HbA1c (53-75 mmol/mol [7-9%]: 1.18 [1.06, 1.32], n=8), chronic glucagon-like peptide-1 receptor agonist use (0.83 [0.71, 0.97], n=9), pre-existing heart failure (1.33 [1.21, 1.47], n=14), pre-existing liver disease (1.40 [1.17, 1.67], n=6), the Charlson index (per 1 unit increase: 1.33 [1.13, 1.57], n=2), high levels of C-reactive protein (per 5 mg/l increase: 1.07 [1.02, 1.12], n=10), aspartate aminotransferase level (per 5 U/l increase: 1.28 [1.06, 1.54], n=5), eGFR (per 10 ml/min per 1.73 m2 increase: 0.80 [0.71, 0.90], n=6), lactate dehydrogenase level (per 10 U/l increase: 1.03 [1.01, 1.04], n=7) and lymphocyte count (per 1×109/l increase: 0.59 [0.40, 0.86], n=6) and COVID-19-related death. Similar associations were observed between risk phenotypes of diabetes and severity of COVID-19, with some new evidence on existing COVID-19  vaccination status (0.32 [0.26, 0.38], n=3), pre-existing hypertension (1.23 [1.14, 1.33], n=49), neuropathy and cancer, and high IL-6 levels. A limitation of this study is that the included studies are observational in nature and residual or unmeasured confounding cannot be ruled out. CONCLUSIONS/INTERPRETATION: Individuals with a more severe course of diabetes and pre-existing comorbidities had a poorer prognosis of COVID-19 than individuals with a milder course of the disease. REGISTRATION: PROSPERO registration no. CRD42020193692. PREVIOUS VERSION: This is a living systematic review and meta-analysis. The previous version can be found at https://link.springer.com/article/10.1007/s00125-021-05458-8 FUNDING: The German Diabetes Center (DDZ) is funded by the German Federal Ministry of Health and the Ministry of Culture and Science of the State North Rhine-Westphalia. This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD).

Cytokimera GIL-11 rescued IL-6R deficient mice from partial hepatectomy-induced death by signaling via non-natural gp130:LIFR:IL-11R complexes.

All except one cytokine of the Interleukin (IL-)6 family share glycoprotein (gp) 130 as the common ß receptor chain. Whereas Interleukin (IL-)11 signal via the non-signaling IL-11 receptor (IL-11R) and gp130 homodimers, leukemia inhibitory factor (LIF) recruits gp130:LIF receptor (LIFR) heterodimers. Using IL-11 as a framework, we exchange the gp130-binding site III of IL-11 with the LIFR binding site III of LIF. The resulting synthetic cytokimera GIL-11 efficiently recruits the non-natural receptor signaling complex consisting of gp130, IL-11R and LIFR resulting in signal transduction and proliferation of factor-depending Ba/F3 cells. Besides LIF and IL-11, GIL-11 does not activate receptor complexes consisting of gp130:LIFR or gp130:IL-11R, respectively. Human GIL-11 shows cross-reactivity to mouse and rescued IL-6R-/- mice following partial hepatectomy, demonstrating gp130:IL-11R:LIFR signaling efficiently induced liver regeneration. With the development of the cytokimera GIL-11, we devise the functional assembly of the non-natural cytokine receptor complex of gp130:IL-11R:LIFR.

Rational and design of the REMOTE trial: An exploratory, pilot study to analyze REtinal MicrOcirculaTion in wEightlessness.

BACKGROUND: "Spaceflight associated neuro-ocular syndrome" (SANS) represents a challenging health condition in modern space medicine. Forty-eight percent of astronauts are diagnosed with SANS after long-term space missions. The pathophysiological mechanism seems to be multifactorial, and yet remains unknown. In this proof-of-concept study we plan to investigate retinal microcirculatory changes in weightlessness and aim to identify their role in the development of SANS. METHODS AND DESIGN: Healthy individuals will take part in a parabolic flight campaign, which recreates fractioned total weightlessness periods. The airplane is specifically equipped, and designed for the execution of parabolic flight maneuvers and scientific research in microgravity. Retinal microcirculation will be assessed with a modified fundus camera, which allows dynamic vessel analysis. We will additionally measure intra-ocular pressure and hemodynamic changes during each phase of the flight. Blood samples will be analyzed at baseline, one hour and 24 hours after exposure to weightlessness. CONCLUSIONS: This pilot study aims to investigate the feasibility of retinal microcirculation assessment during varying gravity. Results of this study may generate insights whether venous stasis in the eye, surrogated by the dilatation of retinal vessels and increase in intraocular pressure as signs of venous insufficiency, may potentially contribute to the development of SANS.

Dietary Factors and All-Cause Mortality in Individuals With Type 2 Diabetes: A Systematic Review and Meta-analysis of Prospective Observational Studies.

BACKGROUND: Type 2 diabetes is a major health concern associated with mortality. Diet may influence the progression of diabetes; however, systematic reviews are lacking. PURPOSE: This study systematically summarized the evidence on diet and all-cause mortality in individuals with type 2 diabetes. DATA SOURCES: PubMed and Web of Science were searched until June 2022. STUDY SELECTION: Prospective observational studies investigating dietary factors in association with all-cause mortality in individuals with type 2 diabetes were selected. DATA SYNTHESIS: We identified 107 studies. Moderate certainty of evidence was found for inverse associations of higher intakes of fish (summary risk ratios per serving/week: 0.95; 95% CI 0.92, 0.99; n = 6 studies), whole grain (per 20 g/day: 0.84; 95% CI 0.71, 0.99; n = 2), fiber (per 5 g/day: 0.86; 95% CI 0.81, 0.91; n = 3), and n-3 polyunsaturated fatty acids (per 0.1 g/day: 0.87; 95% CI 0.82, 0.92; n = 2) and mortality. There was low certainty of evidence for inverse associations of vegetable consumption (per 100 g/day: 0.88; 95% CI 0.82, 0.94; n = 2), plant protein (per 10 g/day: 0.91; 95% CI 0.87, 0.96; n = 3), and for positive associations of egg consumption (per 10 g/day: 1.05; 95% CI 1.03, 1.08; n = 7) and cholesterol intake (per 300 mg/day: 1.19; 95% CI 1.13, 1.26; n = 2). For other dietary factors, evidence was uncertain or no association was observed. CONCLUSIONS: Higher intake of fish, whole grain, fiber, and n-3 polyunsaturated fatty acids were inversely associated with all-cause mortality in individuals with type 2 diabetes. There is limited evidence for other dietary factors, and, thus, more research is needed.

Physical Activity and Risk of Major Diabetes-Related Complications in Individuals With Diabetes: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: Physical activity is a cornerstone in diabetes management; however, evidence synthesis on the association between physical activity and long-term diabetes-related complications is scarce. PURPOSE: To summarize and evaluate findings on physical activity and diabetes-related complications, we conducted a systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Web of Science, and the Cochrane Library for articles published up to 6 July 2021. STUDY SELECTION: We included prospective studies investigating the association between physical activity and incidence of and mortality from diabetes-related complications, i.e., cardiovascular disease (CVD), coronary heart disease, cerebrovascular events, heart failure, major adverse cardiovascular events, and microvascular complications such as retinopathy and nephropathy, in individuals with diabetes. DATA EXTRACTION: Study characteristics and risk ratios with 95% CIs were extracted. Random-effects meta-analyses were performed, and the certainty of evidence and risk of bias were evaluated with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tools. DATA SYNTHESIS: Overall, 31 studies were included. There was moderate certainty of evidence that high versus low levels of physical activity were inversely associated with CVD incidence, CVD mortality (summary risk ratio 0.84 [95% CI 0.77, 0.92], n = 7, and 0.62 [0.55, 0.69], n = 11), and microvascular complications (0.76 [0.67, 0.86], n = 8). Dose-response meta-analyses showed that physical activity was associated with lower risk of diabetes-related complications even at lower levels. For other outcomes, similar associations were observed but certainty of evidence was low or very low. LIMITATIONS: Limitations include residual confounding and misclassification of exposure. CONCLUSIONS: Physical activity, even below recommended amounts, was associated with reduced incidence of diabetes-related complications.

Inhibition of Arp2/3 Complex after ADP-Ribosylation of Arp2 by Binary Clostridioides Toxins.

Clostridioides bacteria are responsible for life threatening infections. Here, we show that in addition to actin, the binary toxins CDT, C2I, and Iota from Clostridioides difficile, botulinum, and perfrigens, respectively, ADP-ribosylate the actin-related protein Arp2 of Arp2/3 complex and its additional components ArpC1, ArpC2, and ArpC4/5. The Arp2/3 complex is composed of seven subunits and stimulates the formation of branched actin filament networks. This activity is inhibited after ADP-ribosylation of Arp2. Translocation of the ADP-ribosyltransferase component of CDT toxin into human colon carcinoma Caco2 cells led to ADP-ribosylation of cellular Arp2 and actin followed by a collapse of the lamellipodial extensions and F-actin network. Exposure of isolated mouse colon pieces to CDT toxin induced the dissolution of the enterocytes leading to luminal aggregation of cellular debris and the collapse of the mucosal organization. Thus, we identify the Arp2/3 complex as hitherto unknown target of clostridial ADP-ribosyltransferases.

Effects of the Population-Based "10,000 Steps Duesseldorf" Intervention for Promoting Physical Activity in Community-Dwelling Adults: Protocol for a Nonrandomized Controlled Trial.

BACKGROUND: The World Health Organization recommends 150 minutes of moderate to vigorous physical activity (PA), which translates to approximately 7000 to 10,000 steps per day for adults. In Germany, less than half of the population in this age range meets this recommendation, highlighting the need for population-based intervention approaches for promoting daily PA. OBJECTIVE: The complex community-based PA intervention "10,000 Steps Ghent," which was originally developed in Belgium and was shown to be effective for PA promotion, has been adapted for implementation and evaluation in 2 German cities. The original Belgian study is currently being replicated, and we aim to examine the effectiveness of the adapted intervention among adults living in intervention city districts in Duesseldorf when compared with those living in control city districts in Wuppertal, over the course of 1 year. METHODS: A controlled intervention trial examining the effects of an intervention addressing multiple levels (eg, individual level: website; organizational level: PA promotion in companies; community level: media campaigns and environmental changes) is being conducted. PA and various secondary outcomes will be assessed in 2 random samples of adults aged 25 to 75 years (n=399 in each city) at baseline and after 1 year. RESULTS: Funding for this study was obtained in March 2020. Recruitment for this study and baseline data collection were conducted from May 2021 to March 2022 (as of March 2022, 626 participants were enrolled in the study). The intervention will be implemented in Duesseldorf for 1 year from April 2022 onward, and follow-up assessments will be conducted, starting in May 2023 (until September 2023). Data analysis will be performed in fall 2023, and the results will be published in spring 2024. CONCLUSIONS: To our knowledge, this is the first research project (currently underway in Germany) that is aimed at replicating the effects of a complex intervention for PA promotion that was previously shown to be effective in another European country. TRIAL REGISTRATION: German Clinical Trials Register DRKS00024873; https://tinyurl.com/4c9e8azh. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39175.