TY  - JOUR
AB  - INTRODUCTION: Genetic manipulation of murine retinal tissue through ocular administration of adeno-associated viruses (AAVs) has become a standard technique to investigate a multitude of mechanisms underlying retinal physiology. Resultantly, developments of recombinant viral vectors with improved transduction efficiency and further methodological improvements have mostly focused on murine tissue, whereas AAVs successfully targeting avian retinae have remained scarce. METHODOLOGY: Using a custom-designed injection setup, we identified a viral serotype with the capability to successfully induce widespread transduction of the bird retina. RESULTS: Intravitreal administration of an AAV type 2/9 encoding for enhanced green fluorescent protein (EGFP) in night-migratory European robins (Erithacus rubecula) resulted in transduction coverages of up to 60% within retinal tissue. Subsequent immunohistochemical analyses revealed that the AAV2/9-EGFP serotype almost exclusively targeted photoreceptors: rods, various single cones (UV, blue, green, and red cones), and both (accessory and principal) members of double cones. DISCUSSION: The consistently high and photoreceptor-specific transduction efficiency makes the AAV2/9 serotype a powerful tool for carrying out genetic manipulations in avian retinal photoreceptors, thus opening a wealth of opportunities to investigate physiological aspects underlying retinal processing in birds, such as physiological recordings and/or post-transductional behavioural readouts for future vision-related research.
AU  - Seth, P.K.*
AU  - Heyers, D.*
AU  - Satish, B.*
AU  - Mendoza, E.*
AU  - Haase, K.*
AU  - Borowsky, L.*
AU  - Musielak, I.*
AU  - Koch, K.W.*
AU  - Feederle, R.
AU  - Scharff, C.*
AU  - Dedek, K.*
AU  - Mouritsen, H.*
C1  - 73978
C2  - 57255
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - AAV-mediated transduction of songbird retina.
JO  - Front. Physiol.
VL  - 16
PB  - Frontiers Media Sa
PY  - 2025
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Hereditary angioedema (HAE) is characterized by recurrent localized edema in various organs, which can be potentially fatal. There are different types of hereditary angioedema, which include genetic deficiency of C1 inhibitor (C1-INH) and hereditary angioedema with normal C1-INH (HAEnCI). In HAEnCI patients mutations have been identified in the F12, PLG, KNG1, ANGPT1, MYOF, and HS3ST6 genes. The release of bradykinin from kininogen via the kallikrein-kinin system (KKS) has been shown to be the main mediator in HAE-FXII, but for HAE-PLG there are only first indications how the PLG mutations can result in bradykinin release. Here we identified in a multi-generation HAE-PLG family an additional F12 mutation, resulting in the loss of one F12 allele. There were no differences in the clinical presentation between HAE-PLG patients with and without the additional F12 mutation, thus we concluded that the kallikrein-kinin system is bypassed in HAE-PLG. Structural modeling and in vitro assays using purified proteins confirmed the PLG mutation c.988A>G; p.K330E to be a gain of function mutation resulting in an increased bradykinin release by direct cleavage of high molecular weight kininogen (HMWK). Thus, we can provide clinical and experimental evidence that mutant plasminogen in HAE-PLG is bypassing FXII/kallikrein to generate bradykinin.
AU  - Hintze, S.*
AU  - Möhl, B.S.
AU  - Beyerl, J.*
AU  - Wulff, K.*
AU  - Wieser, A.*
AU  - Bork, K.*
AU  - Meinke, P.*
C1  - 67255
C2  - 54198
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin.
JO  - Front. Physiol.
VL  - 13
PB  - Frontiers Media Sa
PY  - 2023
SN  - 1664-042X
ER  - 

TY  - JOUR
AU  - Najjar, S.M.*
AU  - Ghadieh, H.E.*
AU  - Sekar, R.
AU  - Carraro, R.*
AU  - Noriega, L.G.*
AU  - Paes, A.M.d.A.*
C1  - 68322
C2  - 54732
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Editorial: Metabolism in nonalcoholic fatty liver disease.
JO  - Front. Physiol.
VL  - 14
PB  - Frontiers Media Sa
PY  - 2023
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Introduction: Hematologists analyze microscopic images of red blood cells to study their morphology and functionality, detect disorders and search for drugs. However, accurate analysis of a large number of red blood cells needs automated computational approaches that rely on annotated datasets, expensive computational resources, and computer science expertise. We introduce RedTell, an AI tool for the interpretable analysis of red blood cell morphology comprising four single-cell modules: segmentation, feature extraction, assistance in data annotation, and classification. Methods: Cell segmentation is performed by a trained Mask R-CNN working robustly on a wide range of datasets requiring no or minimum fine-tuning. Over 130 features that are regularly used in research are extracted for every detected red blood cell. If required, users can train task-specific, highly accurate decision tree-based classifiers to categorize cells, requiring a minimal number of annotations and providing interpretable feature importance. Results: We demonstrate RedTell's applicability and power in three case studies. In the first case study we analyze the difference of the extracted features between the cells coming from patients suffering from different diseases, in the second study we use RedTell to analyze the control samples and use the extracted features to classify cells into echinocytes, discocytes and stomatocytes and finally in the last use case we distinguish sickle cells in sickle cell disease patients. Discussion: We believe that RedTell can accelerate and standardize red blood cell research and help gain new insights into mechanisms, diagnosis, and treatment of red blood cell associated disorders.
AU  - Sadafi, A.
AU  - Bordukova, M.
AU  - Makhro, A.*
AU  - Navab, N.*
AU  - Bogdanova, A.*
AU  - Marr, C.
C1  - 67830
C2  - 54308
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - RedTell: An AI tool for interpretable analysis of red blood cell morphology.
JO  - Front. Physiol.
VL  - 14
PB  - Frontiers Media Sa
PY  - 2023
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - COVID-19 is a disease caused by a new coronavirus SARS-CoV-2, primarily impacting the respiratory system. COVID-19 can result in mild illness or serious disease leading to critical illness and requires admission to ICU due to respiratory failure. There is intense discussion around potential factors predisposing to and protecting from COVID-19. The immune response and the abnormal respiratory function with a focus on respiratory function testing in COVID-19 patients will be at the center of this Perspective article of the Frontiers in Physiology Series on "The Tribute of Physiology for the Understanding of COVID-19 Disease." We will discuss current advances and provide future directions and present also our perspective in this field.
AU  - Laveneziana, P.*
AU  - Straus, C.*
AU  - Meiners, S.
C1  - 62568
C2  - 50948
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - How and to what extent immunological responses to SARS-CoV-2 shape pulmonary function in COVID-19 patients.
JO  - Front. Physiol.
VL  - 12
PB  - Frontiers Media Sa
PY  - 2021
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Physical activity (PA) and nutrition are the essential components of a healthy lifestyle, as they can influence energy balance, promote functional ability of various systems and improve immunity. Infections and their associated symptoms are the common and frequent challenges to human health that are causing severe economic and social consequences around the world. During aging, human immune system undergoes dramatic aging-related changes/dysfunctions known as immunosenescence. Clinically, immunosenescence refers to the gradual deterioration of immune system that increases exposure to infections, and reduces vaccine efficacy. Such phenomenon is linked to impaired immune responses that lead to dysfunction of multiple organs, while lack of physical activity, progressive loss of muscle mass, and concomitant decline in muscle strength facilitate immunosenescence and inflammation. In the present review, we have discussed the role of nutrition and PA, which can boost the immune system alone and synergistically. Evidence suggests that long-term PA is beneficial in improving immune system and preventing various infections. We have further discussed several nutritional strategies for improving the immune system. Unfortunately, the available evidence shows conflicting results. In terms of interaction with food intake, PA does not tend to increase energy intake during a short time course. However, overcoming nutritional deficiencies appears to be the most practical recommendation. Through the balanced nutritious diet intake one can fulfill the bodily requirement of optimal nutrition that significantly impacts the immune system. Supplementation of a single nutrient as food is generally not advisable. Rather incorporating various fruits and vegetables, whole grains, proteins and probiotics may ensure adequate nutrient intake. Therefore, multi-nutrient supplements may benefit people having deficiency in spite of sufficient diet. Along with PA, supplementation of probiotics, bovine colostrum, plant-derived products and functional foods may provide additional benefits in improving the immune system.
AU  - Shao, T.*
AU  - Verma, H.K.
AU  - Pande, B.*
AU  - Costanzo, V.*
AU  - Ye, W.*
AU  - Cai, Y.*
AU  - Bhaskar, L.V.K.S.*
C1  - 63361
C2  - 51421
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Physical activity and nutritional influence on immune function: An important strategy to improve immunity and health status.
JO  - Front. Physiol.
VL  - 12
PB  - Frontiers Media Sa
PY  - 2021
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - So far, surface electromyography (sEMG) has been the method of choice to detect and evaluate muscle fatigue. However, recent advancements in non-cryogenic quantum sensors, such as optically pumped magnetometers (OPMs), enable interesting possibilities to flexibly record biomagnetic signals. Yet, a magnetomyographic investigation of muscular fatigue is still missing. Here, we simultaneously used sEMG (4 surface electrode) and OPM-based magnetomyography (OPM-MMG, 4 sensors) to detect muscle fatigue during a 3 × 1-min isometric contractions of the left rectus femoris muscle in 7 healthy participants. Both signals exhibited the characteristic spectral compression distinctive for muscle fatigue. OPM-MMG and sEMG slope values, used to quantify the spectral compression of the signals, were positively correlated, displaying similarity between the techniques. Additionally, the analysis of the different components of the magnetic field vector enabled speculations regarding the propagation of the muscle action potentials (MAPs). Altogether these results show the feasibility of the magnetomyographic approach with OPMs and propose a potential alternative to sEMG for the study of muscle fatigue.
AU  - Sometti, D.*
AU  - Semeia, L.
AU  - Baek, S.*
AU  - Chen, H.*
AU  - Righetti, G.*
AU  - Dax, J.*
AU  - Kronlage, C.*
AU  - Kirchgässner, M.*
AU  - Romano, A.*
AU  - Heilos, J.*
AU  - Staber, D.*
AU  - Oppold, J.*
AU  - Middelmann, T.*
AU  - Braun, C.*
AU  - Broser, P.*
AU  - Marquetand, J.*
C1  - 63935
C2  - 51705
TI  - Muscle fatigue revisited - Insights from optically pumped magnetometers.
JO  - Front. Physiol.
VL  - 12
PY  - 2021
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - The ability of red blood cells (RBCs) to transport gases, their lifespan as well as their rheological properties invariably depend on the deformability, hydration, and membrane stability of these cells, which can be measured by Laser optical rotational red cell analyser (Lorrca® Maxsis, RR Mechatronics). The osmoscan mode of Lorrca is currently used in diagnosis of rare anemias in clinical laboratories. However, a broad range of normal values for healthy subjects reduces the sensitivity of this method for diagnosis of mild disease phenotype. In this pilot study, we explored the impact of age and gender of 45 healthy donors, as well as RBC age on the Lorrca indices. Whereas gender did not affect the Lorrca indices in our study, the age donors had a profound effect on the O_hyper parameter. To study the impact of RBC age on the osmoscan parameters, we have isolated low (L)-, medium (M)-, or high (H)- density fractions enriched with young, mature, and senescent RBCs, respectively, and evaluated the influence of RBC age-related properties, such as density, morphology, and redox state, on the osmoscan indices. As before, O_hyper was the most sensitive parameter, dropping markedly with an increase in RBC density and age. Senescence was associated with a decrease in deformability (EI_max) and tolerability to low and high osmolatites (Area). L-fraction was enriched with reticulocytes and cells with high projected area and EMA staining, but also contained a small number of cells small in projected area and most likely, terminally senescent. L-fraction was on average slightly less deformable than mature cells. The cells from the L-fraction produced more oxidants and NO than all other fractions. However, RBCs from the L-fraction contained maximal levels of reduced thiols compared to other fractions. Our study suggests that reference values for O_hyper should be age-stratified, and, most probably, corrected for the average RBC age. Further multi-center study is required to validate these suggestions before implementing them into clinical practice.
AU  - van Cromvoirt, A.M.*
AU  - Fenk, S.*
AU  - Sadafi, A.
AU  - Melnikova, E.V.*
AU  - Lagutkin, D.A.*
AU  - Dey, K.*
AU  - Petrushanko, I.Y.*
AU  - Hegemann, I.*
AU  - Goede, J.S.*
AU  - Bogdanova, A.*
C1  - 61645
C2  - 50366
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Donor age and red cell age contribute to the variance in lorrca indices in healthy donors for next generation ektacytometry: A pilot study.
JO  - Front. Physiol.
VL  - 12
PB  - Frontiers Media Sa
PY  - 2021
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - BackgroundMelatonin modulates circadian rhythms in physiology and sleep initiation. Genetic variants of the MTNR1B locus, encoding the melatonin MT2 receptor, have been associated with increased type 2 diabetes (T2D) risk. Carriers of the common intronic MTNR1B rs10830963 T2D risk variant have modified sleep and circadian traits such as changes of the melatonin profile. However, it is currently unknown whether rare variants in the MT2 coding region are also associated with altered sleep and circadian phenotypes, including meal timing. Materials and MethodsIn this pilot study, 28 individuals [50% male; 46-82 years old; 50% with rare MT2 mutations (T2D MT2)] wore actigraphy devices and filled out daily food logs for 4 weeks. We computed circadian, sleep, and caloric intake phenotypes, including sleep duration, timing, and regularity [assessed by the Sleep Regularity Index (SRI)]; composite phase deviations (CPD) as well a sleep timing-based proxy for circadian misalignment; and caloric intake patterns throughout the day. Using regression analyses, we estimated age- and sex-adjusted mean differences (MD) and 95% confidence intervals (95%CI) between the two patient groups. Secondary analyses also compare T2D MT2 to 15 healthy controls. ResultsPatients with rare MT2 mutations had a later sleep onset (MD = 1.23, 95%CI = 0.42;2.04), and midsleep time (MD = 0.91, 95%CI = 0.12;1.70), slept more irregularly (MD in SRI = -8.98, 95%CI = -16.36;-1.60), had higher levels of behavioral circadian misalignment (MD in CPD = 1.21, 95%CI = 0.51;1.92), were more variable in regard to duration between first caloric intake and average sleep offset (MD = 1.08, 95%CI = 0.07;2.08), and had more caloric episodes in a 24 h day (MD = 1.08, 95%CI = 0.26;1.90), in comparison to T2D controls. Secondary analyses showed similar patterns between T2D MT2 and non-diabetic controls. ConclusionThis pilot study suggests that compared to diabetic controls, T2D MT2 patients display a number of adverse sleep, circadian, and caloric intake phenotypes, including more irregular behavioral timing. A prospective study is needed to determine the role of these behavioral phenotypes in T2D onset and severity, especially in view of rare MT2 mutations.
AU  - Imam, A.*
AU  - Winnebeck, E.C.*
AU  - Buchholz, N.*
AU  - Froguel, P.*
AU  - Bonnefond, A.*
AU  - Solimena, M.
AU  - Ivanova, A.
AU  - Bouvier, M.*
AU  - Plouffe, B.*
AU  - Charpentier, G.*
AU  - Karamitri, A.*
AU  - Jockers, R.*
AU  - Roenneberg, T.*
AU  - Vetter, C.*
C1  - 60439
C2  - 49457
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Circadian, sleep and caloric intake phenotyping in type 2 diabetes patients with rare melatonin receptor 2 mutations and controls: A pilot study.
JO  - Front. Physiol.
VL  - 11
PB  - Frontiers Media Sa
PY  - 2020
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Endurance is not only a key factor in many sports but endurance-related variables are also associated with good health and low mortality. Twin and family studies suggest that several endurance-associated traits are ≈50% inherited. However, we still poorly understand what DNA sequence variants contribute to endurance heritability. To address this issue, we conducted a systematic review to identify genes whose experimental loss or gain-of-function increases endurance capacity in mice. We found 31 genes including two isoforms of Ppargc1a whose manipulation increases running or swimming endurance performance by up to 1800%. Genes whose gain-of-function increases endurance are Adcy5, Adcy8, Hk2, Il15, Mef2c, Nr4a3, Pck1 (Pepck), Ppard, Ppargc1a (both the a and b isoforms of the protein Pgc-1α), Ppargc1b, Ppp3ca (calcineurin), Scd1, Slc5a7, Tfe3, Tfeb, Trib3 & Trpv1. Genes whose loss-of-function increases endurance in mice are Actn3, Adrb2, Bdkrb2, Cd47, Crym, Hif1a, Myoz1, Pappa, Pknox1, Pten, Sirt4, Thbs1, Thra, and Tnfsf12. Of these genes, human DNA sequence variants of ACTN3, ADCY5, ADRB2, BDKRB2, HIF1A, PPARD, PPARGC1A, PPARGC1B, and PPP3CA are also associated with endurance capacity and/or VO2max trainability suggesting evolutionary conservation between mice and humans. Bioinformatical analyses show that there are numerous amino acid or copy number-changing DNA variants of endurance genes in humans, suggesting that genetic variation of endurance genes contributes to the variation of human endurance capacity, too. Moreover, several of these genes/proteins change their expression or phosphorylation in skeletal muscle or the heart after endurance exercise, suggesting a role in the adaptation to endurance exercise.
AU  - Nezhad, F.Y.*
AU  - Verbrugge, S.A.J.*
AU  - Schönfelder, M.*
AU  - Becker, L.
AU  - Hrabě de Angelis, M.
AU  - Wackerhage, H.*
C1  - 55726
C2  - 46460
TI  - Genes whose gain or loss-of-function increases endurance performance in mice: a systematic literature review.
JO  - Front. Physiol.
VL  - 10
PY  - 2019
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Introduction: Beside positive effects on athlete's health, competitive sport can be linked with an increased risk of illness and injury. Because of high relative increases in training, additional physical and psychological strains, and an earlier specialization and professionalization, adolescent athletes needs an increased attention. Training can alter the immune system by inducing a temporary immunosuppression, finally developing infection symptoms. Previous studies identified Epstein Barr Virus (EBV) as potential indicator for the immune status. In addition to the identification of triggering risk factors for recurrent infections, the aim was to determine the interaction between training load, stress sense, immunological parameters, and clinical symptoms. Methods: A controlled, prospective, longitudinal study on young athletes (n = 274, mean age: 13.8 +/- 1.5 yrs) was conducted between 2010 and 2014. Also 285 controls (students, who did not perform competitive sports, mean age: 14.5 +/- 1.9 yrs) were recruited. Athletes were examined 3 times each year to determine the effects of stress factors (training load: training hours per week [Th/w]) on selected outcome parameters (clinical [susceptibility to infection, WURSS-21: 21-item Wisconsin Upper Respiratory Symptom Survey], immunological, psychological end points). As part of each visit, EBV serostatus and EBV-specific IgG tiers were studied longitudinally as potential immune markers. Results: Athletes (A) trained 14.9 +/- 5.6 h weekly. Controls (C) showed no lower stress levels compared to athletes (p = 0.387). Twelve percent of athletes reported recurrent infections (C: 8.5%, p = 0.153), the presence of an upper respiratory tract infection (URTI) was achieved in 30.7%. EBV seroprevalence of athletes was 60.3% (C: 56.6%, p = 0.339). Mean EBV-specific IgG titer of athletes was 166 +/- 115 U/ml (C: 137 +/- 112 U/ml, p = 0.030). With increasing Th/w, higher stress levels were observed (p < 0.001). Analyzes of WURSS-21 data revealed no relationship to training load (p = 0.323). Also, training load had no relation to EBV serostatus (p = 0.057) or the level of EBV-specific IgG titers (p = 0.364). Discussion: Young elite athletes showed no increased sense of stress, no higher prevalence of recurrent infections, and no different EBV-specific serological parameters compared to controls. Also, no direct relationship between training loads, clinical complaints, and EBV-specific immune responses was found. With increasing training loads athletes felt more stressed, but significant associations to EBV-specific serological parameters were absent. In summary, EBV serostatus and EBV-specific IgG titers do not allow risk stratification for impaired health. Further investigations are needed to identify additional risk factors and immune markers, with the aim to avoid inappropriate strains by early detection and following intervention.
AU  - Blume, K.*
AU  - Körber, N.
AU  - Hoffmann, D.
AU  - Wolfarth, B.*
C1  - 53345
C2  - 44658
CY  - Lausanne
TI  - Training load, immune status, and clinical outcomes in young athletes: A controlled, prospective, longitudinal study.
JO  - Front. Physiol.
VL  - 9
IS  - MAR
PB  - Frontiers Media Sa
PY  - 2018
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Intrauterine growth restriction (IUGR), which is already known to be a risk factor for pathological intrauterine development, perinatal mortality, and morbidity, is now also assumed to cause both physical and cognitive alterations in later child development. In the current study, effects of IUGR on infantile brain function were investigated during the fetal period and in a follow-up developmental assessment during early childhood. During the fetal period, visual and auditory event-related responses (VER and AER) were recorded using fetal magnetoencephalography (fMEG). VER latencies were analyzed in 73 fetuses (14 IUGR fetuses) while AER latencies were analyzed in 66 fetuses (11 IUGR fetuses). Bayley Scales of Infant Development, Second Edition (BSID-II) were used to assess the developmental status of the infants at the age of 24 months. The Mental Development Index (MDI) was available from 66 children (8 IUGR fetuses) and the Psychomotor Development Index (PDI) from 63 children (7 IUGR fetuses). Latencies to visual stimulation were more delayed in IUGR than in small for gestational age (SGA) or appropriate for gestational age (AGA) fetuses, albeit not to any significant extent (p = 0.282). The MDI in former IUGR infants was significantly lower (p = 0.044) than in former SGA and AGA infants. However, IUGR had no impact on PDI (p = 0.213). These findings support the hypothesis that IUGR may constitute a risk factor for neurodevelopmental delay. Further investigation of the possible underlying mechanisms, as well as continued long-term developmental research, is therefore necessary.
AU  - Hartkopf, J.
AU  - Schleger, F.
AU  - Keune, J.*
AU  - Wiechers, C.*
AU  - Pauluschke-Froehlich, J.*
AU  - Weiss, M.*
AU  - Conzelmann, A.*
AU  - Brucker, S.*
AU  - Preissl, H.
AU  - Kiefer-Schmidt, I.*
C1  - 54408
C2  - 45527
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Impact of intrauterine growth restriction on cognitive and motor development at 2 years of age.
JO  - Front. Physiol.
VL  - 9
PB  - Frontiers Media Sa
PY  - 2018
SN  - 1664-042X
ER  - 

TY  - JOUR
AU  - Polymeropoulos, E.T.*
AU  - Oelkrug, R.*
AU  - Jastroch, M.
C1  - 53969
C2  - 45158
TI  - Editorial: The evolution of endothermy-from patterns to mechanisms.
JO  - Front. Physiol.
VL  - 9
IS  - JUL
PY  - 2018
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - We explored the metagenomic, metabolomic and trace metal makeup of intestinal microbiota and environment in healthy male participants during the run-in (5 day) and the following three 21-day interventions: normoxic bedrest (NBR), hypoxic bedrest (HBR) and hypoxic ambulation (HAmb) which were carried out within a controlled laboratory environment (circadian rhythm, fluid and dietary intakes, microbial bioburden, oxygen level, exercise). The fraction of inspired O(FO) and partial pressure of inspired O(PO) were 0.209 and 133.1 ± 0.3 mmHg for the NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg (~4,000 m simulated altitude) for HBR and HAmb interventions, respectively. Shotgun metagenomes were analyzed at various taxonomic and functional levels,H- andC -metabolomes were processed using standard quantitative and human expert approaches, whereas metals were assessed using X-ray fluorescence spectrometry. Inactivity and hypoxia resulted in a significant increase in the genusin HBR, in genes coding for proteins involved in iron acquisition and metabolism, cell wall, capsule, virulence, defense and mucin degradation, such as beta-galactosidase (EC3.2.1.23), α-L-fucosidase (EC3.2.1.51), Sialidase (EC3.2.1.18), and α-N-acetylglucosaminidase (EC3.2.1.50). In contrast, the microbial metabolomes, intestinal element and metal profiles, the diversity of bacterial, archaeal and fungal microbial communities were not significantly affected. The observed progressive decrease in defecation frequency and concomitant increase in the electrical conductivity (EC) preceded or took place in absence of significant changes at the taxonomic, functional gene, metabolome and intestinal metal profile levels. The fact that the genusand proteins involved in iron acquisition and metabolism, cell wall, capsule, virulence and mucin degradation were enriched at the end of HBR suggest that both constipation and EC decreased intestinal metal availability leading to modified expression of co-regulated genes ingenomes. Bayesian network analysis was used to derive the first hierarchical model of initial inactivity mediated deconditioning steps over time. The PlanHab wash-out period corresponded to a profound life-style change (i.e., reintroduction of exercise) that resulted in stepwise amelioration of the negative physiological symptoms, indicating that exercise apparently prevented the crosstalk between the microbial physiology, mucin degradation and proinflammatory immune activities in the host.
AU  - Šket, R.*
AU  - Debevec, T.*
AU  - Kublik, S.
AU  - Schloter, M.
AU  - Schöler, A.
AU  - Murovec, B.*
AU  - Mikuš, K.V.*
AU  - Makuc, D.*
AU  - Pečnik, K.*
AU  - Plavec, J.*
AU  - Mekjavić, I.B.*
AU  - Eiken, O.*
AU  - Prevoršek, Z.*
AU  - Stres, B.*
C1  - 53301
C2  - 44663
CY  - Lausanne
TI  - Intestinal metagenomes and metabolomes in healthy young males: Inactivity and hypoxia generated negative physiological symptoms precede microbial dysbiosis.
JO  - Front. Physiol.
VL  - 9
IS  - MAR
PB  - Frontiers Media Sa
PY  - 2018
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Skeletal muscle mass differs greatly in mice and humans and this is partially inherited. To identify muscle hypertrophy candidate genes we conducted a systematic review to identify genes whose experimental loss or gain-of-function results in significant skeletal muscle hypertrophy in mice. We found 47 genes that meet our search criteria and cause muscle hypertrophy after gene manipulation. They are from high to small effect size: Ski, Fst, Acvr2b, Akt1, Mstn, Klf10, Rheb, Igf1, Pappa, Ppard, Ikbkb, Fstl3, Atgr1a, Ucn3, Mcu, Junb, Ncor1, Gprasp1, Grb10, Mmp9, Dgkz, Ppargc1a (specifically the Ppargc1a4 isoform), Smad4, Ltbp4, Bmpr1a, Crtc2, Xiap, Dgat1, Thra, Adrb2, Asb15, Cast, Eif2b5, Bdkrb2, Tpt1, Nr3c1, Nr4a1, Gnas, Pld1, Crym, Camkk1, Yap1, Inhba, Tp53inp2, Inhbb, Nol3, Esr1. Knock out, knock down, overexpression or a higher activity of these genes causes overall muscle hypertrophy as measured by an increased muscle weight or cross sectional area. The mean effect sizes range from 5 to 345% depending on the manipulated gene as well as the muscle size variable and muscle investigated. Bioinformatical analyses reveal that Asb15, Klf10, Tpt1 are most highly expressed hypertrophy genes in human skeletal muscle when compared to other tissues. Many of the muscle hypertrophy-regulating genes are involved in transcription and ubiquitination. Especially genes belonging to three signaling pathways are able to induce hypertrophy: (a) Igf1-Akt-mTOR pathway, (b) myostatin-Smad signaling, and (c) the angiotensin-bradykinin signaling pathway. The expression of several muscle hypertrophy-inducing genes and the phosphorylation of their protein products changes after human resistance and high intensity exercise, in maximally stimulated mouse muscle or in overloaded mouse plantaris.
AU  - Verbrugge, S.A.J.*
AU  - Schönfelder, M.*
AU  - Becker, L.
AU  - Nezhad, F.Y.*
AU  - Hrabě de Angelis, M.
AU  - Wackerhage, H.*
C1  - 53555
C2  - 44634
TI  - Genes whose gain or loss-of-function increases skeletal muscle mass in mice: A systematic literature review.
JO  - Front. Physiol.
VL  - 9
IS  - MAY
PY  - 2018
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Skeletal muscle mass is a result of the balance between protein breakdown and protein synthesis. It has been shown that multiple conditions of muscle atrophy are characterized by the common regulation of a specific set of genes, termed atrogenes. It is not known whether various models of muscle hypertrophy are similarly regulated by a common transcriptional program. Here, we characterized gene expression changes in three different conditions of muscle growth, examining each condition during acute and chronic phases. Specifically, we compared the transcriptome of Extensor Digitorum Longus (EDL) muscles collected (1) during the rapid phase of postnatal growth at 2 and 4 weeks of age, (2) 24 h or 3 weeks after constitutive activation of AKT, and (3) 24 h or 3 weeks after overload hypertrophy caused by tenotomy of the Tibialis Anterior muscle. We observed an important overlap between significantly regulated genes when comparing each single condition at the two different timepoints. Furthermore, examining the transcriptional changes occurring 24 h after a hypertrophic stimulus, we identify an important role for genes linked to a stress response, despite the absence of muscle damage in the AKT model. However, when we compared all different growth conditions, we did not find a common transcriptional fingerprint. On the other hand, all conditions showed a marked increase in mTORC1 signaling and increased ribosome biogenesis, suggesting that muscle growth is characterized more by translational, than transcriptional regulation.
AU  - Pereira, M.G.*
AU  - Dyar, K.A.
AU  - Nogara, L.*
AU  - Solagna, F.*
AU  - Marabita, M.*
AU  - Baraldo, M.*
AU  - Chemello, F.*
AU  - Germinario, E.*
AU  - Romanello, V.*
AU  - Nolte, H.*
AU  - Blaauw, B.*
C1  - 52575
C2  - 44054
CY  - Lausanne
TI  - Comparative analysis of muscle hypertrophy models reveals divergent gene transcription profiles and points to translational regulation of muscle growth through increased mTOR signaling.
JO  - Front. Physiol.
VL  - 8
PB  - Frontiers Media Sa
PY  - 2017
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - The lesser hedgehog tenrec (Echinops telfairi) displays reptile-like thermoregulatory behavior with markedly high variability in body temperature and metabolic rate. To understand how energy metabolism copes with this flexibility, we studied the bioenergetics of isolated liver mitochondria from cold (20°C) and warm (27°C) acclimated tenrecs. Different acclimation temperatures had no impact on mitochondrial respiration using succinate as the substrate. Mimicking the variation of body temperature by changing assay temperatures from 22 to 32°C highlighted temperature-sensitivity of respiration. The 40% reduction of respiratory control ratio (RCR) at 22°C compared to 32°C, a common estimate for mitochondrial efficiency, was caused by reduced substrate oxidation capacity. The simultaneous measurement of mitochondrial membrane potential enabled the precise assessment of efficiency with corrected respiration rates. Using this method, we show that proton leak respiration at the highest common membrane potential was not affected by acclimation temperature but was markedly decreased by assay temperature. Using membrane potential corrected respiration values, we show that the fraction of ATP-linked respiration (coupling efficiency) was maintained (70-85%) at lower temperatures. Collectively, we demonstrate that compromised substrate oxidation was temperature-compensated by the reduction of proton leak, thus maintaining the efficiency of mitochondrial energy conversion. Therefore, membrane potential data suggest that adjustments of mitochondrial proton leak contribute to energy homeostasis during thermoregulatory flexibility of tenrecs.
AU  - Polymeropoulos, E.T.*
AU  - Oelkrug, R.*
AU  - Jastroch, M.
C1  - 52362
C2  - 43931
TI  - Mitochondrial proton leak compensates for reduced oxidative power during frequent hypothermic events in a protoendothermic mammal, Echinops telfairi.
JO  - Front. Physiol.
VL  - 8
PY  - 2017
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - Driven by interactions between lipids and proteins, biological membranes display lateral heterogeneity that manifests itself in a mosaic of liquid-ordered (Lo) or raft, and liquid-disordered (Ld) or non-raft domains with a wide range of different properties and compositions. In giant plasma membrane vesicles and giant unilamellar vesicles, specific binding of Cholera Toxin (CTxB) to GM1 glycolipids is a commonly used strategy to label raft domains or Lo membrane environments. However, these studies often use acyl-chain labeled bodipy-GM1 (bdGM1), whose headgroup accessibility and membrane order or phase partitioning may differ from those of GM1, rendering the interpretation of CTxB binding data quite problematic. To unravel the molecular basis of CTxB binding to GM1 and bdGM1, we explored the partitioning and the headgroup presentation of these gangliosides in the Lo and Ld phases using atomistic molecular dynamics simulations complemented by CTxB binding experiments. The conformation of both GM1 and bdGM1 was shown to be largely similar in the Lo and Ld phases. However, bdGM1 showed reduction in receptor availability when reconstituted into synthetic bilayer mixtures, highlighting that membrane phase partitioning of the gangliosides plays a considerable role in CTxB binding. Our results suggest that the CTxB binding is predominately modulated by the partitioning of the receptor to an appropriate membrane phase. Further, given that the Lo and Ld partitioning of bdGM1 differs from those of GM1, usage of bdGM1 for studying GM1 behavior in cells can lead to invalid interpretation of experimental data.
AU  - Rissanen, S.*
AU  - Grzybek, M.
AU  - Orlowski, A.*
AU  - Róg, T.*
AU  - Cramariuc, O.*
AU  - Levental, I.*
AU  - Eggeling, C.*
AU  - Sezgin, E.*
AU  - Vattulainen, I.*
C1  - 51437
C2  - 43072
CY  - Lausanne
TI  - Phase partitioning of GM1 and its bodipy-labeled analog determine their different binding to Cholera Toxin.
JO  - Front. Physiol.
VL  - 8
PB  - Frontiers Media Sa
PY  - 2017
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - We explored the assembly of intestinal microbiota in healthy male participants during the run-in (5 day) and experimental phases [21-day normoxic bed rest (NBR), hypoxic bedrest (HBR)], and hypoxic ambulation (HAmb) in a strictly controlled laboratory environment, balanced fluid, and dietary intakes, controlled circadian rhythm, microbial ambiental burden, and 24/7 medical surveillance. The fraction of inspired O2 (FiO2) and partial pressure of inspired O2 (PiO2) were 0.209 and 133.1 ± 0.3 mmHg for NBR and 0.141 ± 0.004 and 90.0 ± 0.4 mmHg for both hypoxic variants (HBR and HAmb; ~4,000 m simulated altitude), respectively. A number of parameters linked to intestinal transit spanning Bristol Stool Scale, defecation rates, zonulin, α1-antitrypsin, eosinophil derived neurotoxin, bile acids, reducing sugars, short chain fatty acids, total soluble organic carbon, water content, diet composition, and food intake were measured (167 variables). The abundance, structure, and diversity of butyrate producing microbial community were assessed using the two primary bacterial butyrate synthesis pathways, butyryl-CoA: acetate CoA-transferase (but) and butyrate kinase (buk) genes. Inactivity negatively affected fecal consistency and in combination with hypoxia aggravated the state of gut inflammation (p < 0.05). In contrast, gut permeability, various metabolic markers, the structure, diversity, and abundance of butyrate producing microbial community were not significantly affected. Rearrangements in the butyrate producing microbial community structure were explained by experimental setup (13.4%), experimentally structured metabolites (12.8%), and gut metabolite-immunological markers (11.9%), with 61.9% remaining unexplained. Many of the measured parameters were found to be correlated and were hence omitted from further analyses. The observed progressive increase in two immunological intestinal markers suggested that the transition from healthy physiological state toward the developed symptoms of low magnitude obesity-related syndromes was primarily driven by the onset of inactivity (lack of exercise in NBR) that were exacerbated by systemic hypoxia (HBR) and significantly alleviated by exercise, despite hypoxia (HAmb). Butyrate producing community in colon exhibited apparent resilience toward short-term modifications in host exercise or hypoxia. Progressive constipation (decreased intestinal motility) and increased local inflammation marker suggest that changes in microbial colonization and metabolism were taking place at the location of small intestine.
AU  - Šket, R.*
AU  - Treichel, N.
AU  - Debevec, T.*
AU  - Eiken, O.*
AU  - Mekjavic, I.*
AU  - Schloter, M.
AU  - Vital, M.*
AU  - Chandler, J.*
AU  - Tiedje, J.M.*
AU  - Murovec, B.*
AU  - Prevoršek, Z.*
AU  - Stres, B.*
C1  - 51150
C2  - 43080
CY  - Lausanne
TI  - Hypoxia and inactivity related physiological changes (constipation, inflammation) are not reflected at the level of gut metabolites and butyrate producing microbial community: The PlanHab study.
JO  - Front. Physiol.
VL  - 8
PB  - Frontiers Media Sa
PY  - 2017
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - IL-6 is a central mediator of the immediate induction of hepatic acute phase proteins (APP) in the liver during infection and after injury, but increased IL-6 activity has been associated with multiple pathological conditions. In hepatocytes, IL-6 activates JAK1-STAT3 signaling that induces the negative feedback regulator SOCS3 and expression of APPs. While different inhibitors of IL-6-induced JAK1-STAT3-signaling have been developed, understanding their precise impact on signaling dynamics requires a systems biology approach. Here we present a mathematical model of IL-6-induced JAK1-STAT3 signaling that quantitatively links physiological IL-6 concentrations to the dynamics of IL-6-induced signal transduction and expression of target genes in hepatocytes. The mathematical model consists of coupled ordinary differential equations (ODE) and the model parameters were estimated by a maximum likelihood approach, whereas identifiability of the dynamic model parameters was ensured by the Profile Likelihood. Using model simulations coupled with experimental validation we could optimize the long-term impact of the JAK-inhibitor Ruxolitinib, a therapeutic compound that is quickly metabolized. Model-predicted doses and timing of treatments helps to improve the reduction of inflammatory APP gene expression in primary mouse hepatocytes close to levels observed during regenerative conditions. The concept of improved efficacy of the inhibitor through multiple treatments at optimized time intervals was confirmed in primary human hepatocytes. Thus, combining quantitative data generation with mathematical modeling suggests that repetitive treatment with Ruxolitinib is required to effectively target excessive inflammatory responses without exceeding doses recommended by the clinical guidelines.
AU  - Sobotta, S.*
AU  - Raue, A.*
AU  - Huang, X.*
AU  - Vanlier, J.*
AU  - Jünger, A.*
AU  - Bohl, S.*
AU  - Albrecht, U.*
AU  - Hahnel, M.J.*
AU  - Wolf, S.*
AU  - Müller, N.S.
AU  - D'Alessandro, L.A.*
AU  - Mueller-Bohl, S.*
AU  - Boehm, M.E.*
AU  - Lucarelli, P.*
AU  - Bonefas, S.*
AU  - Damm, G.*
AU  - Seehofer, D.*
AU  - Lehmann, W.D.*
AU  - Rose-John, S.*
AU  - van der Hoeven, F.*
AU  - Gretz, N.*
AU  - Theis, F.J.
AU  - Ehlting, C.*
AU  - Bode, J.G.*
AU  - Timmer, J.*
AU  - Schilling, M.*
AU  - Klingmüller, U.*
C1  - 52188
C2  - 43828
CY  - Lausanne
TI  - Model based targeting of IL-6-induced inflammatory responses in cultured primary hepatocytes to improve application of the JAK inhibitor ruxolitinib.
JO  - Front. Physiol.
VL  - 8
IS  - OCT
PB  - Frontiers Media Sa
PY  - 2017
SN  - 1664-042X
ER  - 

TY  - JOUR
AB  - XRecently we demonstrated that the capacity of isolated muscle mitochondria to produce reactive oxygen species, measured as H2O2 efflux, is temperature-sensitive in isolated muscle mitochondria of ectothermic fish and the rat, a representative endothermic mammal. However, at physiological temperatures (15 degrees and 37 degrees C for the fish and rat, respectively), the fraction of total mitochondrial electron flux that generated H2O2, the fractional electron leak (FEL), was far lower in the rat than in fish. Those results suggested that the elevated body temperatures associated with endothermy may lead to a compensatory decrease in mitochondrial ROS production relative to respiratory capacity. To test this hypothesis we compare slow twitch (red) muscle mitochondria from the endothermic Pacific bluefin tuna (Thunnus orientalis) with mitochondria from three ectothermic fishes [rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio), and the lake sturgeon (Acipenser fulvescens)] and the rat. At a common assay temperature (25 degrees C) rates of mitochondrial respiration and H2O2 efflux were similar in tuna and the other fishes. The thermal sensitivity of fish mitochondria was similar irrespective of ectothermy or endothermy. Comparing tuna to the rat at a common temperature, respiration rates were similar, or lower depending on mitochondrial substrates. FEL was not different across fish species at a common assay temperature (25 degrees C) but was markedly higher in fishes than in rat. Overall, endothermy and warming of Pacific Bluefin tuna red muscle may increase the potential for ROS production by muscle mitochondria but the evolution of endothermy in this species is not necessarily associated with a compensatory reduction of ROS production relative to the respiratory capacity of mitochondria.
AU  - Wiens, L.*
AU  - Banh, S.*
AU  - Sotiri, E.*
AU  - Jastroch, M.
AU  - Block, B.A.*
AU  - Brand, M.D.*
AU  - Treberg, J.R.*
C1  - 51998
C2  - 43639
CY  - Lausanne
TI  - Comparison of mitochondrial reactive oxygen species production of ectothermic and endothermic fish muscle.
JO  - Front. Physiol.
VL  - 8
PB  - Frontiers Media Sa
PY  - 2017
SN  - 1664-042X
ER  -