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The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.
Aim of the study: Investigation, whether water-filtered infrared-A (wIRA) irradiation during moderate bicycle ergometer endurance exercise has effects especially on local fat reduction and on weight reduction beyond the effects of ergometer exercise alone.
Methods: Randomised controlled study with 40 obese females (BMI 30-40 (median: 34.5), body weight 76-125 (median: 94.9) kg, age 20-40 (median: 35.5) years, isocaloric nutrition), 20 in the wIRA group and 20 in the control group. In both groups each participant performed 3 times per week over 4 weeks for 45 minutes bicycle ergometer endurance exercise with a constant load according to a lactate level of 2 mmol/l (aerobic endurance load, as determined before the intervention period). In the wIRA group in addition large parts of the body (including waist, hip, and thighs) were irradiated during all ergometries of the intervention period with visible light and a predominant part of water-filtered infrared-A (wIRA), using the irradiation unit “Hydrosun® 6000” with 10 wIRA radiators (Hydrosun® Medizintechnik, Müllheim, Germany, radiator type 500, 4 mm water cuvette, yellow filter, water-filtered spectrum 500-1400 nm) around a speed independent bicycle ergometer.
Main variable of interest: change of “the sum of circumferences of waist, hip, and both thighs of each patient” over the intervention period (4 weeks). Additional variables of interest: body weight, body mass index BMI, body fat percentage, fat mass, fat-free mass, water mass (analysis of body composition by tetrapolar bioimpedance analysis), assessment of an arteriosclerotic risk profile by blood investigation of variables of lipid metabolism (cholesterol, triglycerides, high density lipoproteins HDL, low density lipoproteins LDL, apolipoprotein A1, apolipoprotein B), clinical chemistry (fasting glucose, alanin-aminotransferase ALT (= glutamyl pyruvic transaminase GPT), gamma-glutamyl-transferase GGT, creatinine, albumin), endocrinology (leptin, adiponectin (= adipo Q), homocysteine, insulin). All variables were at least measured before and after the intervention period. Ergometry (ECG, blood pressure behaviour, lactate curve with power at 2, 3 and 4 mmol/l) before the intervention period. In addition: nutrition training ahead of and during the intervention period with a nutrition protocol over one week for assessment of the daily energy intake; calculation of basic metabolic rate and total energy requirement. Assessment of undesired effects.
Only methods of non-parametric statistics were used, both descriptive (median, percentiles of 25 and 75 (= interquartile range), minimum, maximum) and confirmatory (two-sided Mann-Whitney U test for unpaired samples for the only one main variable of interest). Total error probability: .05 (5%). An intention to treat analysis ITT with last observed carry forward method was used preferably (presented results) and in addition an on treatment analysis OT. Only 2 (treatment group) and 4 (control group) drop-outs occurred (mostly due to lack of time).
Results: The “sum of circumferences of waist, hip, and both thighs of each patient” decreased during the 4 weeks significantly more (p<.001) in the wIRA group than in the control group: medians and interquartile ranges: -8.0 cm (-10.5 cm/-4.1 cm) vs. -1.8 cm (-4.4 cm/0.0 cm).
As well “body weight of each patient” decreased during the 4 weeks markedly more in the wIRA group than in the control group: medians and interquartile ranges: -1.9 kg (-4.0 kg/0.0 kg) vs. 0.0 kg (-1.5 kg/+0.4 kg); median of body weight changed from 99.3 kg to 95.6 kg (wIRA) vs. 89.9 kg to 89.6 kg (control). A similar effect showed the body mass index BMI.
Blood variables of interest remained unchanged or showed some slight improvements during the treatment period, concerning most variables with no obvious differences between the two groups; insulin showed a slight trend to decrease in the wIRA group and to increase in the control group.
Undesired effects of the treatment were not seen.
Discussion: The results of the study suggest, that wIRA – during moderate bicycle ergometer endurance exercise as lipolytic stimulus – increases local lipolysis with a local fat reduction (thighs) in the otherwise bradytrophic fatty tissue. The presumably underlying mechanisms of wIRA have already been proven: wIRA acts both by thermal effects and by non-thermal effects. Thermal effects of wIRA are the generation of a therapeutic field of warmth with the increase of tissue temperature, tissue oxygen partial pressure, and tissue blood flow, and by this regional metabolism. As fatty tissue normally has a slow metabolism (bradytrophic and hypothermic tissue) with a low rate of lipolysis, wIRA can increase lipolysis in fatty tissue and the mobilized fats are burned in musculature during the ergometer exercise.
Conclusion: The results of the study indicate, that wIRA irradiation during moderate ergometer endurance exercise can be used – in combination with an appropriate nutrition – to improve body composition, especially local fat distribution, and the reduction of fat and body weight in obese persons.
Keywords: water-filtered infrared-A (wIRA), weight reduction, local fat reduction, bicycle ergometer endurance exercise, lipolysis, randomised controlled study, intervention trial, body weight, body mass index BMI, analysis of body composition, tetrapolar bioimpedance analysis, lactate, lipid metabolism, cholesterol, triglycerides, high density lipoproteins HDL, low density lipoproteins LDL
Aim of the study: Investigation, whether water-filtered infrared-A (wIRA) irradiation during moderate bicycle ergometer endurance exercise has effects especially on local fat reduction and on weight reduction beyond the effects of ergometer exercise alone.
Methods: Randomised controlled study with 40 obese females (BMI 30-40 (median: 34.5), body weight 76-125 (median: 94.9) kg, age 20-40 (median: 35.5) years, isocaloric nutrition), 20 in the wIRA group and 20 in the control group. In both groups each participant performed 3 times per week over 4 weeks for 45 minutes bicycle ergometer endurance exercise with a constant load according to a lactate level of 2 mmol/l (aerobic endurance load, as determined before the intervention period). In the wIRA group in addition large parts of the body (including waist, hip, and thighs) were irradiated during all ergometries of the intervention period with visible light and a predominant part of water-filtered infrared-A (wIRA), using the irradiation unit “Hydrosun® 6000” with 10 wIRA radiators (Hydrosun® Medizintechnik, Müllheim, Germany, radiator type 500, 4 mm water cuvette, yellow filter, water-filtered spectrum 500-1400 nm) around a speed independent bicycle ergometer.
Main variable of interest: change of “the sum of circumferences of waist, hip, and both thighs of each patient” over the intervention period (4 weeks). Additional variables of interest: body weight, body mass index BMI, body fat percentage, fat mass, fat-free mass, water mass (analysis of body composition by tetrapolar bioimpedance analysis), assessment of an arteriosclerotic risk profile by blood investigation of variables of lipid metabolism (cholesterol, triglycerides, high density lipoproteins HDL, low density lipoproteins LDL, apolipoprotein A1, apolipoprotein B), clinical chemistry (fasting glucose, alanin-aminotransferase ALT (= glutamyl pyruvic transaminase GPT), gamma-glutamyl-transferase GGT, creatinine, albumin), endocrinology (leptin, adiponectin (= adipo Q), homocysteine, insulin). All variables were at least measured before and after the intervention period. Ergometry (ECG, blood pressure behaviour, lactate curve with power at 2, 3 and 4 mmol/l) before the intervention period. In addition: nutrition training ahead of and during the intervention period with a nutrition protocol over one week for assessment of the daily energy intake; calculation of basic metabolic rate and total energy requirement. Assessment of undesired effects.
Only methods of non-parametric statistics were used, both descriptive (median, percentiles of 25 and 75 (= interquartile range), minimum, maximum) and confirmatory (two-sided Mann-Whitney U test for unpaired samples for the only one main variable of interest). Total error probability: .05 (5%). An intention to treat analysis ITT with last observed carry forward method was used preferably (presented results) and in addition an on treatment analysis OT. Only 2 (treatment group) and 4 (control group) drop-outs occurred (mostly due to lack of time).
Results: The “sum of circumferences of waist, hip, and both thighs of each patient” decreased during the 4 weeks significantly more (p<.001) in the wIRA group than in the control group: medians and interquartile ranges: -8.0 cm (-10.5 cm/-4.1 cm) vs. -1.8 cm (-4.4 cm/0.0 cm).
As well “body weight of each patient” decreased during the 4 weeks markedly more in the wIRA group than in the control group: medians and interquartile ranges: -1.9 kg (-4.0 kg/0.0 kg) vs. 0.0 kg (-1.5 kg/+0.4 kg); median of body weight changed from 99.3 kg to 95.6 kg (wIRA) vs. 89.9 kg to 89.6 kg (control). A similar effect showed the body mass index BMI.
Blood variables of interest remained unchanged or showed some slight improvements during the treatment period, concerning most variables with no obvious differences between the two groups; insulin showed a slight trend to decrease in the wIRA group and to increase in the control group.
Undesired effects of the treatment were not seen.
Discussion: The results of the study suggest, that wIRA – during moderate bicycle ergometer endurance exercise as lipolytic stimulus – increases local lipolysis with a local fat reduction (thighs) in the otherwise bradytrophic fatty tissue. The presumably underlying mechanisms of wIRA have already been proven: wIRA acts both by thermal effects and by non-thermal effects. Thermal effects of wIRA are the generation of a therapeutic field of warmth with the increase of tissue temperature, tissue oxygen partial pressure, and tissue blood flow, and by this regional metabolism. As fatty tissue normally has a slow metabolism (bradytrophic and hypothermic tissue) with a low rate of lipolysis, wIRA can increase lipolysis in fatty tissue and the mobilized fats are burned in musculature during the ergometer exercise.
Conclusion: The results of the study indicate, that wIRA irradiation during moderate ergometer endurance exercise can be used – in combination with an appropriate nutrition – to improve body composition, especially local fat distribution, and the reduction of fat and body weight in obese persons.
A data-driven method was applied to Au+Au collisions at √sNN = 200 GeV made with the STAR detector at RHIC to isolate pseudorapidity distance η-dependent and η-independent correlations by using two- and four-particle azimuthal cumulant measurements. We identified a η-independent component of the correlation, which is dominated by anisotropic flow and flow fluctuations. It was also found to be independent of η within the measured range of pseudorapidity |η| < 1. In 20–30% central Au+Au collisions, the relative flow fluctuation was found to be 34%±2%(stat.)±3%(sys.) for particles with transverse momentum pT less than 2 GeV/c. The η-dependent part, attributed to nonflow correlations, is found to be 5% ± 2%(sys.) relative to the flow of the measured second harmonic cumulant at |η| > 0.7.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Background: There is absence of specific biomarkers and an incomplete understanding of the pathophysiology of exudative age-related macular degeneration (AMD).
Methods and findings: Eighty-eight vitreous samples (73 from patients with treatment naïve AMD and 15 control samples from patients with idiopathic floaters) were analyzed with capillary electrophoresis coupled to mass spectrometry in this retrospective case series to define potential candidate protein markers of AMD. Nineteen proteins were found to be upregulated in vitreous of AMD patients. Most of the proteins were plasma derived and involved in biological (ion) transport, acute phase inflammatory reaction, and blood coagulation. A number of proteins have not been previously associated to AMD including alpha-1-antitrypsin, fibrinogen alpha chain and prostaglandin H2-D isomerase. Alpha-1-antitrypsin was validated in vitreous of an independent set of AMD patients using Western blot analysis. Further systems biology analysis of the data indicated that the observed proteomic changes may reflect upregulation of immune response and complement activity.
Conclusions: Proteome analysis of vitreous samples from patients with AMD, which underwent an intravitreal combination therapy including a core vitrectomy, steroids and bevacizumab, revealed apparent AMD-specific proteomic changes. The identified AMD-associated proteins provide some insight into the pathophysiological changes associated with AMD.
Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity.
Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus.
Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%).
Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.
Conclusion: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients