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1.
Response to Comments on "Soybean photosynthesis and crop yield is improved by accelerating recovery from photoprotection".
De Souza, AP, Burgess, SJ, Doran, L, Manukyan, L, Hansen, J, Maryn, N, Leonelli, L, Niyogi, KK, Stephen, SP, Gotarkar, D
Science (New York, N.Y.). 2023;(6634):eadf2189
Abstract
We recently demonstrated that accelerating the relaxation of nonphotochemical quenching leads to higher soybean photosynthetic efficiency and yield. In response, Sinclair et al. assert that improved photosynthesis cannot improve crop yields and that there is only one valid experimental design for proving a genetic improvement in yield. We explain here why neither assertion is valid.
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2.
Ketone Body Infusion Abrogates Growth Hormone-Induced Lipolysis and Insulin Resistance.
Høgild, ML, Hjelholt, AJ, Hansen, J, Pedersen, SB, Møller, N, Wojtaszewski, JFP, Johannsen, M, Jessen, N, Jørgensen, JOL
The Journal of clinical endocrinology and metabolism. 2023;(3):653-664
Abstract
CONTEXT Exogenous ketone body administration lowers circulating glucose levels but the underlying mechanisms are uncertain. OBJECTIVE We tested the hypothesis that administration of the ketone body β-hydroxybutyrate (βOHB) acutely increases insulin sensitivity via feedback suppression of circulating free fatty acid (FFA) levels. METHODS In a randomized, single-blinded crossover design, 8 healthy men were studied twice with a growth hormone (GH) infusion to induce lipolysis in combination with infusion of either βOHB or saline. Each study day comprised a basal period and a hyperinsulinemic-euglycemic clamp combined with a glucose tracer and adipose tissue and skeletal muscle biopsies. RESULTS βOHB administration profoundly suppressed FFA levels concomitantly with a significant increase in glucose disposal and energy expenditure. This was accompanied by a many-fold increase in skeletal muscle content of both βOHB and its derivative acetoacetate. CONCLUSION Our data unravel an insulin-sensitizing effect of βOHB, which we suggest is mediated by concomitant suppression of lipolysis.
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3.
Central Serotonin/Noradrenaline Transporter Availability and Treatment Success in Patients with Obesity.
Griebsch, NI, Kern, J, Hansen, J, Rullmann, M, Luthardt, J, Helfmeyer, S, Dekorsy, FJ, Soeder, M, Hankir, MK, Zientek, F, et al
Brain sciences. 2022;(11)
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [11C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [11C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m2) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.
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4.
Pancreatic enzyme supplementation versus placebo for improvement of gastrointestinal symptoms in non-responsive celiac disease: A cross-over randomized controlled trial.
Yoosuf, S, Barrett, CG, Papamichael, K, Madoff, SE, Kurada, S, Hansen, J, Silvester, JA, Therrien, A, Singh, P, Dennis, M, et al
Frontiers in medicine. 2022;:1001879
Abstract
BACKGROUND Pancreatic Exocrine Insufficiency (PEI) is a possible cause of recurrent/persistent symptoms in celiac disease. Although pancreatic enzyme supplementation may be used to treat non-responsive celiac disease (NRCD) in clinical practice, clinical outcomes are variable and there is limited and low quality evidence to support this practice. The aim of this study was to assess the efficacy of pancreatic enzyme supplements (PES) for improvement of gastrointestinal symptoms in NRCD. METHODS Prospective, randomized, placebo-controlled, double-blind, cross-over trial in adults with NRCD examining Celiac Disease-Gastrointestinal Symptom Rating Scale (CeD-GSRS) scores on PES (pancrelipase co-administered with omeprazole) versus placebo (omeprazole only) during a 10-day treatment period. The study was registered under the clinical trials registry (https://clinicaltrials.gov/ number, NCT02475369) on 18 Jun 2015. RESULTS Twelve participants (nine female) were included in the per-protocol analysis; one participant had low fecal elastase-1. Pancrelipase was not associated with significant change in CeD-GSRS compared to placebo (-0.03 versus -0.26; P = 0.366). There was a significant decrease in mean values of total CeD-GSRS scores (3.58 versus 2.90, P = 0.004), abdominal pain (2.92 versus 2.42, P = 0.009), and diarrhea sub-scores (3.44 versus 2.92, P = 0.037) during the run-in period with omeprazole. CONCLUSION In this prospective, cross-over randomized, placebo-controlled study, PES did not improve symptoms in patients with NRCD. It is unclear whether this is a trial effect or related to administration of omeprazole.
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5.
MRI-Detected Brain Lesions and Cognitive Function in Patients With Atrial Fibrillation Undergoing Left Atrial Catheter Ablation in the Randomized AXAFA-AFNET 5 Trial.
Haeusler, KG, Eichner, FA, Heuschmann, PU, Fiebach, JB, Engelhorn, T, Blank, B, Callans, D, Elvan, A, Grimaldi, M, Hansen, J, et al
Circulation. 2022;(12):906-915
Abstract
BACKGROUND We aimed to assess the prevalence of ischemic brain lesions detected by magnetic resonance imaging and their association with cognitive function 3 months after first-time ablation using continuous oral anticoagulation in patients with paroxysmal atrial fibrillation (AF). METHODS We performed a prespecified analysis of the AXAFA-AFNET 5 trial (Anticoagulation Using the Direct Factor Xa Inhibitor Apixaban During Atrial Fibrillation Catheter Ablation: Comparison to Vitamin K Antagonist Therapy), which randomized 674 patients with AF 1:1 to uninterrupted apixaban or vitamin K antagonist therapy before first-time ablation. Brain magnetic resonance imaging using fluid-attenuated inversion recovery and high-resolution diffusion-weighted imaging was obtained within 3 to 48 hours after AF ablation in all eligible patients enrolled in 25 study centers in Europe and the United States. Patients underwent cognitive assessment 3 to 6 weeks before ablation and 3 months after ablation using the Montreal Cognitive Assessment (MoCA). RESULTS In 84 (26.1%) of 321 patients with analyzable magnetic resonance imaging, high-resolution diffusion-weighted imaging detected at least 1 acute brain lesion, including 44 (27.2%) patients treated with apixaban and 40 (24.8%) patients treated with vitamin K antagonist (P=0.675). Median MoCA score was similar in patients with or without acute brain lesions at 3 months after ablation (28 [interquartile range (IQR), 26-29] versus 28 [IQR, 26-29]; P=0.948). Cerebral chronic white matter damage (defined as Wahlund score ≥4 points) detected by fluid-attenuated inversion recovery was present in 130 (40.5%) patients and associated with lower median MoCA scores before ablation (27 [IQR, 24-28] versus 27 [IQR, 25-29]; P=0.026) and 3 months after ablation (27 [IQR, 25-29] versus 28 [IQR, 26-29]; P=0.011). This association was no longer significant when adjusted for age and sex. Age was associated with lower MoCA scores before ablation (relative risk, 1.02 per 10 years [95% CI, 1.01-1.03]) and 3 months after ablation (relative risk, 1.02 per 10 years [95% CI, 1.01-1.03]). CONCLUSIONS Chronic white matter damage as well as acute ischemic lesions detected by brain magnetic resonance imaging were found frequently after first-time ablation for paroxysmal AF using uninterrupted oral anticoagulation. Acute ischemic brain lesions detected by high-resolution diffusion-weighted imaging were not associated with cognitive function at 3 months after ablation. Lower MoCA scores before and after ablation were associated only with older age, highlighting the safety of AF ablation on uninterrupted oral anticoagulation. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT02227550.
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6.
SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, but Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes: A Randomized Double-Blind, Placebo-Controlled Crossover Trial.
Lauritsen, KM, Nielsen, BRR, Tolbod, LP, Johannsen, M, Hansen, J, Hansen, TK, Wiggers, H, Møller, N, Gormsen, LC, Søndergaard, E
Diabetes. 2021;(3):800-808
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation, and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. Thirteen individuals with type 2 diabetes were studied after 4 weeks' treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with 11C-palmitate and 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT). Oxygen consumption and myocardial external efficiency (MEE) were measured with 11C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using 15O-H2O PET/CT. Empagliflozin did not affect myocardial free fatty acids (FFAs) uptake but reduced myocardial glucose uptake by 57% (P < 0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (P < 0.01), but did not significantly affect stress MBF or MFR. In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose toward other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition.
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7.
Interactions in protein solutions close to liquid-liquid phase separation: ethanol reduces attractions via changes of the dielectric solution properties.
Hansen, J, Uthayakumar, R, Pedersen, JS, Egelhaaf, SU, Platten, F
Physical chemistry chemical physics : PCCP. 2021;(39):22384-22394
Abstract
Ethanol is a common protein crystallization agent, precipitant, and denaturant, but also alters the dielectric properties of solutions. While ethanol-induced unfolding is largely ascribed to its hydrophobic parts, its effect on protein phase separation and inter-protein interactions remains poorly understood. Here, the effects of ethanol and NaCl on the phase behavior and interactions of protein solutions are studied in terms of the metastable liquid-liquid phase separation (LLPS) and the second virial coefficient B2 using lysozyme solutions. Determination of the phase diagrams shows that the cloud-point temperatures are reduced and raised by the addition of ethanol and salt, respectively. The observed trends can be explained using the extended law of corresponding states as changes of B2. The results for B2 agree quantitatively with those of static light scattering and small-angle X-ray scattering experiments. Furthermore, B2 values calculated based on inter-protein interactions described by the Derjaguin-Landau-Verwey-Overbeek (DLVO) potential and considering the dielectric solution properties and electrostatic screening due to the ethanol and salt content quantitatively agree with the experimentally observed B2 values.
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8.
Circadian misalignment disturbs the skeletal muscle lipidome in healthy young men.
Harmsen, JF, van Polanen, N, van Weeghel, M, Wefers, J, Hoeks, J, Vaz, FM, Pras-Raves, ML, van Kampen, AHC, Schaart, G, van Moorsel, D, et al
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2021;(6):e21611
Abstract
Circadian misalignment, as seen in shift work, is associated with an increased risk to develop type 2 diabetes. In an experimental setting, we recently showed that a rapid day-night shift for 3 consecutive nights leads to misalignment of the core molecular clock, induction of the PPAR pathway, and insulin resistance in skeletal muscle of young, healthy men. Here, we investigated if circadian misalignment affects the skeletal muscle lipidome and intramyocellular lipid droplet characteristics, explaining the misalignment-induced insulin resistance. Fourteen healthy men underwent one aligned and one circadian misalignment period, both consisting of ~3.5 days. In the misaligned condition, day and night were rapidly shifted by 12 hours leading to opposite eating, sleep, and activity times compared with the aligned condition. For each condition, two muscle biopsies were taken from the m. vastus lateralis in the morning and evening and subjected to semi-targeted lipidomics and confocal microscopy analysis. We found that only 2% of detected lipids were different between morning and evening in the aligned condition, whereas 12% displayed a morning-evening difference upon misalignment. Triacylglycerols, in particular species of a carbon length ≥55, were the most abundant lipid species changed upon misalignment. Cardiolipins were decreased upon misalignment, whereas phosphatidylcholines consistently followed the same morning-evening pattern, suggesting regulation by the circadian clock. Cholesteryl esters adjusted to the shifted behavior. Lipid droplet characteristics remained unaltered upon misalignment. Together, these findings show that simulated shift work disturbs the skeletal muscle lipidome, which may contribute to misalignment-induced insulin resistance.
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9.
Resveratrol improves ex vivo mitochondrial function but does not affect insulin sensitivity or brown adipose tissue in first degree relatives of patients with type 2 diabetes.
de Ligt, M, Bruls, YMH, Hansen, J, Habets, MF, Havekes, B, Nascimento, EBM, Moonen-Kornips, E, Schaart, G, Schrauwen-Hinderling, VB, van Marken Lichtenbelt, W, et al
Molecular metabolism. 2018;:39-47
Abstract
OBJECTIVE Resveratrol supplementation improves metabolic health in healthy obese men, but not in patients with type 2 diabetes (T2D) when given as add-on therapy. Therefore, we examined whether resveratrol can enhance metabolic health in men at risk of developing T2D. Additionally, we examined if resveratrol can stimulate brown adipose tissue (BAT). METHODS Thirteen male first degree relatives (FDR) of patients with T2D received resveratrol (150 mg/day) and placebo for 30 days in a randomized, placebo controlled, cross-over trial. RESULTS Resveratrol significantly improved ex vivo muscle mitochondrial function on a fatty acid-derived substrate. However, resveratrol did not improve insulin sensitivity, expressed as the rate of glucose disposal during a two-step hyperinsulinemic-euglycemic clamp. Also, intrahepatic and intramyocellular lipid content, substrate utilization, energy metabolism, and cold-stimulated 18F-FDG glucose uptake in BAT (n = 8) remained unaffected by resveratrol. In vitro experiments in adipocytes derived from human BAT confirmed the lack of effect on BAT. CONCLUSIONS Resveratrol stimulates muscle mitochondrial function in FDR males, which is in concordance with previous results. However, no other metabolic benefits of resveratrol were found in this group. This could be attributed to subject characteristics causing alterations in metabolism of resveratrol and thereby affecting resveratrol's effectiveness. CLINICALTRIALS. GOV ID NCT02129595.
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10.
[Neurogenic autonomic dysfunction in adults].
Terkelsen, AJ, Hansen, J, Klostergaard, A, Otto, M, Mølgaard, H, Hvas, CL, Krogh, K, Kirkeby, HJ, Andersen, H, Jensen, TS
Ugeskrift for laeger. 2018;(18)
Abstract
Neurogenic autonomic dysfunction (NAD) is underdiagnosed, and it is likely in patients, who have orthostatic hypotension and symptoms from multiple organ systems as well as abnormal results from a neurological examination. A clinical and neurophysiological examination of the autonomic nervous system combined with a standardised paraclinical evaluation should be performed. NAD may be present in neurodegenerative disorders, vitamin deficiency, toxicity, infection, and in paraneoplastic, metabolic, hereditary and immune-mediated conditions.