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  • 1. Adiels, Martin
    et al.
    Mardinoglu, Adil
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Taskinen, Marja-Riitta
    Boren, Jan
    Kinetic Studies to Elucidate Impaired Metabolism of Triglyceride-rich Lipoproteins in Humans2015In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, article id 342Article, review/survey (Refereed)
    Abstract [en]

    To develop novel strategies for prevention and treatment of dyslipidemia, it is essential to understand the pathophysiology of dyslipoproteinemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion, and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labeled with stable isotopes and mathematical modeling, provides us with a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering our understanding of the pathogenesis of dyslipoproteinemia.

  • 2.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Spazzini, Pier Giorgio
    Mechanics Division, National Institute of Metrological Research, Turin, Italy.
    Swedenborg, Jesper
    Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Gasser, T. Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    An Integrated Fluid-Chemical Model Toward Modeling the Formation of Intra-Luminal Thrombus in Abdominal Aortic Aneurysms2012In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 3, no 266Article in journal (Refereed)
    Abstract [en]

    Abdominal Aortic Aneurysms (AAAs) are frequently characterized by the presence of an Intra-Luminal Thrombus (ILT) known to influence their evolution biochemically and biomechanically. The ILT progression mechanism is still unclear and little is known regarding the impact of the chemical species transported by blood flow on this mechanism. Chemical agonists and antagonists of platelets activation, aggregation, and adhesion and the proteins involved in the coagulation cascade (CC) may play an important role in ILT development. Starting from this assumption, the evolution of chemical species involved in the CC, their relation to coherent vortical structures (VSs) and their possible effect on ILT evolution have been studied. To this end a fluid-chemical model that simulates the CC through a series of convection-diffusion-reaction (CDR) equations has been developed. The model involves plasma-phase and surface-bound enzymes and zymogens, and includes both plasma-phase and membrane-phase reactions. Blood is modeled as a non-Newtonian incompressible fluid. VSs convect thrombin in the domain and lead to the high concentration observed in the distal portion of the AAA. This finding is in line with the clinical observations showing that the thickest ILT is usually seen in the distal AAA region. The proposed model, due to its ability to couple the fluid and chemical domains, provides an integrated mechanochemical picture that potentially could help unveil mechanisms of ILT formation and development.

  • 3.
    Bidkhori, Gholamreza
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Elmas, Ezgi
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kararoudi, Meisam Naeimi
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Arif, Muhammad
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Metabolic Network-Based Identification and Prioritization o f Anticancer Targets Based on Expression Data in Hepatocellular Carcinoma2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 916Article in journal (Refereed)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with high mortality worldwide. Unfortunately, the large heterogeneity of this disease makes it difficult to develop effective treatment strategies. Cellular network analyses have been employed to study heterogeneity in cancer, and to identify potential therapeutic targets. However, the existing approaches do not consider metabolic growth requirements, i.e., biological network functionality, to rank candidate targets while preventing toxicity to non-cancerous tissues. Here, we developed an algorithm to overcome these issues based on integration of gene expression data, genome-scale metabolic models, network controllability, and dispensability, as well as toxicity analysis. This method thus predicts and ranks potential anticancer non-toxic controlling metabolite and gene targets. Our algorithm encompasses both objective-driven and-independent tasks, and uses network topology to finally rank the predicted therapeutic targets. We employed this algorithm to the analysis of transcriptomic data for 50 HCC patients with both cancerous and non-cancerous samples. We identified several potential targets that would prevent cell growth, including 74 anticancer metabolites, and 3 gene targets (PRKACA, PGS1, and CRLS1). The predicted anticancer metabolites showed good agreement with existing FDA-approved cancer drugs, and the 3 genes were experimentally validated by performing experiments in HepG2 and Hep3B liver cancer cell lines. Our observations indicate that our novel approach successfully identifies therapeutic targets for effective treatment of cancer. This approach may also be applied to any cancer type that has tumor and non-tumor gene or protein expression data.

  • 4.
    Bjorklund, Glenn
    et al.
    Mid Sweden Univ, Dept Hlth Sci, Swedish Winter Sports Res Ctr, Ostersund, Sweden.;Swedish Sports Confederat, Stockholm, Sweden..
    Svarén, Mikael
    KTH, School of Engineering Sciences (SCI).
    Born, Dennis-Peter
    Swiss Fed Inst Sport, Dept Elite Sport, Magglingen, Switzerland..
    Stoeggl, Thomas
    Univ Salzburg, Dept Sport & Exercise Sci, Salzburg, Austria..
    Biomechanical Adaptations and Performance Indicators in Short Trail Running2019In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 10, article id 506Article in journal (Refereed)
    Abstract [en]

    Our aims were to measure anthropometric and oxygen uptake ((V)over dot O-2) variables in the laboratory, to measure kinetic and stride characteristics during a trail running time trial, and then analyse the data for correlations with trail running performance. Runners (13 men, 4 women: mean age: 29 +/- 5 years; stature: 179.5 +/- 0.8 cm; body mass: 69.1 +/- 7.4 kg) performed laboratory tests to determine (V)over dot O-2 (max), running economy (RE), and anthropometric characteristics. On a separate day they performed an outdoor trail running time trial (two 3.5 km laps, total climb: 486 m) while we collected kinetic and time data. Comparing lap 2 with lap 1 (19:40 +/- 1:57 min vs. 21:08 +/- 2:09 min, P < 0.001), runners lost most time on the uphill sections and least on technical downhills (-2.5 +/- 9.1 s). Inter-individual performance varied most for the downhills (CV > 25%) and least on flat terrain (CV < 10%). Overall stride cycle and ground contact time (GCT) were shorter in downhill than uphill sections (0.64 +/- 0.03 vs. 0.84 +/- 0.09 s; 0.26 +/- 0.03 vs. 0.46 +/- 0.90 s, both P < 0.001). Force impulse was greatest on uphill (248 +/- 46 vs. 175 +/- 24 Ns, P < 0.001) and related to GCT (r = 0.904, P < 0.001). Peak force was greater during downhill than during uphill running (1106 +/- 135 vs. 959 +/- 104 N, P < 0.01). Performance was related to absolute and relative (V)over dot O-2 (max) (P < 0.01), vertical uphill treadmill speed (P < 0.001) and fat percent (P < 0.01). Running uphill involved the greatest impulse per step due to longer GCT while downhill running generated the highest peak forces. (V)over dot O-2 (max), vertical running speed and fat percent are important predictors for trail running performance. Performance between runners varied the most on downhills throughout the course, while pacing resembled a reversed J pattern. Future studies should focus on longer competition distances to verify these findings and with application of measures of 3D kinematics.

  • 5. Bjornson, Elias
    et al.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. Chalmers University, Sweden.
    Personalized Cardiovascular Disease Prediction and Treatment-A Review of Existing Strategies and Novel Systems Medicine Tools2016In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, article id 2Article, review/survey (Refereed)
    Abstract [en]

    Cardiovascular disease (CVD) continues to constitute the leading cause of death globally. CVD risk stratification is an essential tool to sort through heterogeneous populations and identify individuals at risk of developing CVD. However, applications of current risk scores have recently been shown to result in considerable misclassification of high-risk subjects. In addition, despite long standing beneficial effects in secondary prevention, current CVD medications have in a primary prevention setting shown modest benefit in terms of increasing life expectancy. A systems biology approach to CVD risk stratification may be employed for improving risk-estimating algorithms through addition of high-throughput derived omics biomarkers. In addition, modeling of personalized benefit-of-treatment may help in guiding choice of intervention. In the area of medicine, realizing that CVD involves perturbations of large complex biological networks, future directions in drug development may involve moving away from a reductionist approach toward a system level approach. Here, we review current CVD risk scores and explore how novel algorithms could help to improve the identification of risk and maximize personalized treatment benefit. We also discuss possible future directions in the development of effective treatment strategies for CVD through the use of genome-scale metabolic models (GEMs) as well as other biological network-based approaches.

  • 6. Debevec, T.
    et al.
    Ganse, B.
    Mittag, U.
    Eiken, Ola
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Environmental Physiology. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Swedish Aerospace Physiology Centre, SAPC.
    Mekjavic, I. B.
    Rittweger, J.
    Hypoxia aggravates inactivity-Related muscle wasting2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, no May, article id 494Article in journal (Refereed)
    Abstract [en]

    Poor musculoskeletal state is commonly observed in numerous clinical populations such as chronic obstructive pulmonary disease (COPD) and heart failure patients. It, however, remains unresolved whether systemic hypoxemia, typically associated with such clinical conditions, directly contributes to muscle deterioration. We aimed to experimentally elucidate the effects of systemic environmental hypoxia upon inactivity-related muscle wasting. For this purpose, fourteen healthy, male participants underwent three 21-day long interventions in a randomized, cross-over designed manner: (i) bed rest in normoxia (NBR; PiO2 = 133.1 ± 0.3 mmHg), (ii) bed rest in normobaric hypoxia (HBR; PiO2 = 90.0 ± 0.4 mmHg) and ambulatory confinement in normobaric hypoxia (HAmb; PiO2 = 90.0 ± 0.4 mmHg). Peripheral quantitative computed tomography and vastus lateralis muscle biopsies were performed before and after the interventions to obtain thigh and calf muscle cross-sectional areas and muscle fiber phenotype changes, respectively. A significant reduction of thigh muscle size following NBR (-6.9%, SE 0.8%; P &lt; 0.001) was further aggravated following HBR (-9.7%, SE 1.2%; P = 0.027). Bed rest-induced muscle wasting in the calf was, by contrast, not exacerbated by hypoxic conditions (P = 0.47). Reductions in both thigh (-2.7%, SE 1.1%, P = 0.017) and calf (-3.3%, SE 0.7%, P &lt; 0.001) muscle size were noted following HAmb. A significant and comparable increase in type 2× fiber percentage of the vastus lateralis muscle was noted following both bed rest interventions (NBR = +3.1%, SE 2.6%, HBR = +3.9%, SE 2.7%, P &lt; 0.05). Collectively, these data indicate that hypoxia can exacerbate inactivity-related muscle wasting in healthy active participants and moreover suggest that the combination of both, hypoxemia and lack of activity, as seen in COPD patients, might be particularly harmful for muscle tissue.

  • 7.
    Dillon-Murphy, Desmond
    et al.
    Kings Coll London, Sch Biomed Engn & Imaging Sci, London, England..
    Marlevi, David
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Ruijsink, Bram
    Kings Coll London, Sch Biomed Engn & Imaging Sci, London, England..
    Qureshi, Ahmed
    Kings Coll London, Sch Biomed Engn & Imaging Sci, London, England..
    Chubb, Henry
    Stanford Univ, Dept Cardiothorac Surg, Palo Alto, CA 94304 USA..
    Kerfoot, Eric
    Kings Coll London, Sch Biomed Engn & Imaging Sci, London, England..
    O'Neill, Mark
    Kings Coll London, Sch Biomed Engn & Imaging Sci, London, England..
    Nordsleffen, David
    Kings Coll London, Sch Biomed Engn & Imaging Sci, London, England..
    Aslanidi, Oleg
    Kings Coll London, Sch Biomed Engn & Imaging Sci, London, England..
    de Vecchi, Adelaide
    Kings Coll London, Sch Biomed Engn & Imaging Sci, London, England..
    Modeling Left Atrial Flow, Energy, Blood Heating Distribution in Response to Catheter Ablation Therapy2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1757Article in journal (Refereed)
    Abstract [en]

    Introduction: Atrial fibrillation (AF) is a widespread cardiac arrhythmia that commonly affects the left atrium (LA), causing it to quiver instead of contracting effectively. This behavior is triggered by abnormal electrical impulses at a specific site in the atrial wall. Catheter ablation (CA) treatment consists of isolating this driver site by burning the surrounding tissue to restore sinus rhythm (SR). However, evidence suggests that CA can concur to the formation of blood clots by promoting coagulation near the heat source and in regions with low flow velocity and blood stagnation. Methods: A patient-specific modeling workflow was created and applied to simulate thermal-fluid dynamics in two patients pre- and post-CA. Each model was personalized based on pre- and post-CA imaging datasets. The wall motion and anatomy were derived from SSFP Cine MRI data, while the trans-valvular flow was based on Doppler ultrasound data. The temperature distribution in the blood was modeled using a modified Pennes bioheat equation implemented in a finite-element based Navier-Stokes solver. Blood particles were also classified based on their residence time in the LA using a particle-tracking algorithm. Results: SR simulations showed multiple short-lived vortices with an average blood velocity of 0.2-0.22 m/s. In contrast, AF patients presented a slower vortex and stagnant flow in the LA appendage, with the average blood velocity reduced to 0.08-0.14 m/s. Restoration of SR also increased the blood kinetic energy and the viscous dissipation due to the presence of multiple vortices. Particle tracking showed a dramatic decrease in the percentage of blood remaining in the LA for longer than one cycle after CA (65.9 vs. 43.3% in patient A and 62.2 vs. 54.8% in patient B). Maximum temperatures of 76 degrees and 58 degrees C were observed when CA was performed near the appendage and in a pulmonary vein, respectively. Conclusion: This computational study presents novel models to elucidate relations between catheter temperature, patient-specific atrial anatomy and blood velocity, and predict how they change from SR to AF. The models can quantify blood flow in critical regions, including residence times and temperature distribution for different catheter positions, providing a basis for quantifying stroke risks.

  • 8.
    Gennser, Mikael
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Environmental Physiology. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Swedish Aerospace Physiology Centre, SAPC.
    Blogg, S. L.
    SLB Consulting, Newbiggin On Lune, Cumbria, England..
    Eiken, Ola
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Environmental Physiology. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Swedish Aerospace Physiology Centre, SAPC.
    Mekjavic, Igor B.
    Jozef Stefan Inst, Dept Automat Biocybernet & Robot, Ljubljana, Slovenia.;Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada..
    Indices of Increased Decompression Stress Following Long-Term Bed Rest2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 442Article in journal (Refereed)
    Abstract [en]

    Human extravehicular activity (EVA) is essential to space exploration and involves risk of decompression sickness (DCS). On Earth, the effect of microgravity on physiological systems is simulated in an experimental model where subjects are confined to a 6 degrees head-down bed rest (HDBR). This model was used to investigate various resting and exercise regimen on the formation of venous gas emboli (VGE), an indicator of decompression stress, post-hyperbaric exposure. Eight healthy male subjects participating in a bed rest regimen also took part in this study, which incorporated five different hyperbaric exposure (HE) interventions made before, during and after the HDBR. Interventions i-iv were all made with the subjects lying in 6 degrees HD position. They included (C1) resting control, (C2) knee-bend exercise immediately prior to HE, (T1) HE during the fifth week of the 35-day HDBR period, (C3) supine cycling exercise during the HE. In intervention (C4), subjects remained upright and ambulatory. The HE protocol followed the Royal Navy Table 11 with 100 min spent at 18 m (280 kPa), with decompression stops at 6 m for 5 min, and at 3 m for 15 min. Post-HE, regular precordial Doppler audio measurements were made to evaluate any VGE produced post-dive. VGE were graded according to the Kisman Masurel scale. The number of bubbles produced was low in comparison to previous studies using this profile [Kisman integrated severity score (KISS) ranging from 0-1], and may be because subjects were young, and lay supine during both the HE and the 2 h measurement period post-HE for interventions i-iv. However, the HE during the end of HDBR produced significantly higher maximum bubble grades and KISS score than the supine control conditions (p < 0.01). In contrast to the protective effect of pre-dive exercise on bubble production, a prolonged period of bed rest prior to a HE appears to promote the formation of post-decompression VGE. This is in contrast to the absence of DCS observed during EVA. Whether this is due to a difference between hypo- and hyperbaric decompression stress, or that the HDBR model is a not a good model for decompression sensitivity during microgravity conditions will have to be elucidated in future studies.

  • 9. Ghaffari, Pouyan
    et al.
    Mardinoglu, Adil
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Nielsen, Jens
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden; Technical University of Denmark, Denmark.
    Cancer Metabolism: A Modeling Perspective2015In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, article id 382Article, review/survey (Refereed)
    Abstract [en]

    Tumor cells alter their metabolism to maintain unregulated cellular proliferation and survival, but this transformation leaves them reliant on constant supply of nutrients and energy. In addition to the widely studied dysregulated glucose metabolism to fuel tumor cell growth, accumulating evidences suggest that utilization of amino acids and lipids contributes significantly to cancer cell metabolism. Also recent progresses in our understanding of carcinogenesis have revealed that cancer is a complex disease and cannot be understood through simple investigation of genetic mutations of cancerous cells. Cancer cells present in complex tumor tissues communicate with the surrounding microenvironment and develop traits which promote their growth, survival, and metastasis. Decoding the full scope and targeting dysregulated metabolic pathways that support neoplastic transformations and their preservation requires both the advancement of experimental technologies for more comprehensive measurement of omics as well as the advancement of robust computational methods for accurate analysis of the generated data. Here, we review cancer-associated reprogramming of metabolism and highlight the capability of genome-scale metabolic modeling approaches in perceiving a system-level perspective of cancer metabolism and in detecting novel selective drug targets.

  • 10. Larsdotter-Mellstrom, Helena
    et al.
    Eriksson, Kerstin
    Liblikas, Ilme I.
    Wiklund, Christer
    Borg-Karlson, Anna-Karin
    KTH, School of Chemical Science and Engineering (CHE), Chemistry. University of Tartu, Estonia.
    Nylin, Soren
    Janz, Niklas
    Carlsson, Mikael A.
    It's All in the Mix: Blend-Specific Behavioral Response to a Sexual Pheromone in a Butterfly2016In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, article id 68Article in journal (Refereed)
    Abstract [en]

    Among insects, sexual pheromones are typically mixtures of two to several components, all of which are generally required to elicit a behavioral response. Here we show for the first time that a complete blend of sexual pheromone components is needed to elicit a response also in a butterfly. Males of the Green-veined White, Pieris napi, emit an aphrodisiac pheromone, citral, from wing glands. This pheromone is requisite for females to accept mating with a courting male. Citral is a mixture of the two geometric isomers geranial (E-isomer) and neral (Z-isomer) in an approximate 1:1 ratio. We found that both these compounds are required to elicit acceptance behavior, which indicates synergistic interaction between processing of the isomers. Using functional Ca2+ imaging we found that geranial and neral evoke significantly different but overlapping glomerular activity patterns in the antennal lobe, which suggests receptors with different affinity for the two isomers. However, these glomeruli were intermingled with glomeruli responding to, for example, plant-related compounds, i.e., no distinct subpopulation of pheromone-responding glomeruli as in moths and other insects. In addition, these glomeruli showed lower specificity than pheromone-activated glomeruli in moths. We could, however, not detect any mixture interactions among four identified glomeruli, indicating that the synergistic effect may be generated at a higher processing level. Furthermore, correlations between glomerular activity patterns evoked by the single isomers and the blend did not change over time.

  • 11.
    Liu, Zhengtao
    et al.
    Minist Publ Hlth, Key Lab Combined Multiorgan Transplantat, Hangzhou, Zhejiang, Peoples R China.;Key Lab Organ Transplantat Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China.;Zhejiang Univ, Div Hepatobiliary & Pancreat Surg, Dept Surg, Affiliated Hosp 1,Sch Med, Hangzhou, Zhejiang, Peoples R China..
    Liang, Shuheng
    Women & Childrens Hosp Guangxi, Dept Pediat, Nanning, Peoples R China..
    Que, Shuping
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zhou, Lin
    Minist Publ Hlth, Key Lab Combined Multiorgan Transplantat, Hangzhou, Zhejiang, Peoples R China.;Key Lab Organ Transplantat Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China.;Zhejiang Univ, Div Hepatobiliary & Pancreat Surg, Dept Surg, Affiliated Hosp 1,Sch Med, Hangzhou, Zhejiang, Peoples R China..
    Zheng, Shusen
    Minist Publ Hlth, Key Lab Combined Multiorgan Transplantat, Hangzhou, Zhejiang, Peoples R China.;Key Lab Organ Transplantat Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China.;Zhejiang Univ, Div Hepatobiliary & Pancreat Surg, Dept Surg, Affiliated Hosp 1,Sch Med, Hangzhou, Zhejiang, Peoples R China..
    Mardinogiu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden.;Kings Coll London, Dent Inst, Ctr Host Microbiome Interact, London, England..
    Meta-Analysis of Adiponectin as a Biomarker for the Detection of Metabolic Syndrome2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1238Article, review/survey (Refereed)
    Abstract [en]

    Previous studies revealed the potential significance of circulating adiponectin levels with respect to the diagnosis and prediction of metabolic syndrome, but uncertainty has been noted across different cohorts. Systematic evaluation was performed for diagnostic accuracy and predictivity of adiponectin variation for metabolic syndrome in enrolled studies including 1,248 and 6,020 subjects, respectively. Adiponectin can identify metabolic syndrome with moderate accuracy (area under the curve = 0.81, 95% CI: 0.77-0.84). Heterogeneity analysis revealed that an increasing index of insulin resistance was independently associated with improving the performance of adiponectin upon metabolic syndrome diagnosis (ratio of diagnostic odds ratio = 3.89, 95% CI: 1.13-13.9). In addition, reductions in adiponectin were associated with increasing metabolic syndrome incidence in a linear dose-response manner. The risk of hypoadiponectinemia with metabolic syndrome was especially increased in men (P < 0.05). Further Mendelian randomization analysis identified that the amplified risk could be attributed to increased susceptibility (up to 7%) to insulin resistance compared with women. In conclusion, adiponectin measurement might have potential benefits in the detection of metabolic syndrome. Factors that affect insulin resistance should be considered for adjustment in future assessments.

  • 12.
    Mardinoglu, Adil
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Editorial: The Impact of Systems Medicine on Human Health and Disease2016In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, article id 552Article in journal (Other academic)
  • 13. Mekjavic, Igor B.
    et al.
    Amon, Mojca
    Kölegård, Roger
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Environmental Physiology.
    Kounalakis, Stylianos N.
    Simpson, Liz
    Eiken, Ola
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Environmental Physiology.
    Keramidas, Michail E.
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Environmental Physiology.
    MacDonald, IanA.
    The effect of normobaric hypoxic confinement on metabolism, gut hormones and body composition2016In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, no 202Article in journal (Refereed)
  • 14. Mekjavic, Igor B.
    et al.
    Ciuha, Ursa
    Grönkvist, Mikael
    KTH, School of Technology and Health (STH), Environmental Physiology.
    Eiken, Ola
    KTH, School of Technology and Health (STH), Environmental Physiology.
    The Effect of Low Ambient Relative Humidity on Physical Performance and Perceptual Responses during Load Carriage2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, no July, article id 451Article in journal (Refereed)
    Abstract [en]

    Introduction: The study evaluated the effect of low ambient relative humidity on physical performance and perceptual responses during load carriage in a hot environment. Methods: Ten heat-unacclimatized male subjects participated in three 130-min trials, during which they walked on a treadmill, carrying a load of similar to 35 kg, at a speed of 3.2 km.h(-1), with an incident wind at the same velocity and ambient temperature at 45 degrees C. Each trial commenced with a 10-min baseline at 20 degrees C and 50% relative humidity (RH), the subjects transferred to a climatic chamber and commenced their simulated hike, comprising two 50-min walks separated by a 20-min rest period. In two, full protective equipment (FP) trials, RH was 10% (partial pressure of water vapor, p(H20) = 7.2 mmHg) in one (FP10), and 20% (p(H20) = 14.4 mmHg; FP20) in the other. In the control trial, subjects were semi-nude (SN) and carried the equipment in their backpacks; RH was 20%. Measurements included oxygen uptake, ventilation, heart rate, rectal and skin temperatures, heat flux, temperature perception, and thermal comfort. Results: In FP20, four subjects terminated the trial prematurely due to signs of heat exhaustion; there were no such signs in FP10 or SN. Upon completion of the trials, pulmonary ventilation, heart rate, and rectal temperature were lower in FP10 (33 5 I/min; 128 +/- 21 bpm; 38.2 +/- 0.4 degrees C) and SN (34 4 I/min; 113 +/- 18 bpm; 38.1 +/- 0.4 degrees C than in FP20 (39 +/- 8 l/min; 145 +/- 12 bpm; 38.6 +/- 0.42 degrees C). Evaporation was significantly greater in the SN compared to FPI and FP20 trials. FP10 was rated thermally more comfortable than FP20. Conclusion: A lower ambient partial pressure of water vapor, reflected in a lower ambient relative humidity, improved cardiorespiratory, thermoregulatory, and perceptual responses during load carriage.

  • 15. Morrison, S. A.
    et al.
    Mirnik, D.
    Korsic, S.
    Eiken, Ola
    KTH, School of Technology and Health (STH), Environmental Physiology. Swedish Aerospace Physiology Centre.
    Mekjavic, I. B.
    Dolenc-Groselj, L.
    Bed rest and hypoxic exposure affect sleep architecture and breathing stability2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, no June, article id 410Article in journal (Refereed)
    Abstract [en]

    Objective: Despite over 50 years of research on the physiological effects of sustained bed rest, data characterizing its effects on sleep macrostructure and breathing stability in humans are scarce. This study was conducted to determine the effects of continuous exposure to hypoxia and sustained best rest, both individually and combined, on nocturnal sleep and breathing stability. Methods: Eleven participants completed three randomized, counter-balanced, 21-days trials of: (1) normoxic bed rest (NBR, PIO2 = 133.1 ± 0.3), (2) hypoxic ambulatory confinement (HAMB, PIO2 = 90.0 ± 0.4) and (3) hypoxic bed rest (HBR, PIO2 = 90.0 ± 0.4; ~4,000 m equivalent altitude). Full objective polysomnography was performed at baseline, on Night 1 and Night 21 in each condition. Results: In NBR Night 1, more time was spent in light sleep (10 ± 2%) compared to baseline (8 ± 2%; p = 0.028); Slow-wave sleep (SWS) was reduced from baseline in the hypoxic-only trial by 18% (HAMB Night 21, p = 0.028) and further reduced by 33% (HBR Night 1, p = 0.010), and 36% (HBR Night 21, p = 0.008) when combined with bed rest. The apnea-hypopnea index doubled from Night 1 to Night 21 in HBR (32-62 events·h-1) and HAMB (31-59 events·h-1; p = 0.002). Those who experienced greatest breathing instability from Night 1 to Night 21 (NBR) were correlated to unchanged or higher (+1%) night SpO2 concentrations (R2 = 0.471, p = 0.020). Conclusion: Bed rest negatively affects sleep macrostructure, increases the apnea-hypopnea index, and worsens breathing stability, each independently exacerbated by continuous exposure to hypoxia.

  • 16.
    Rosario, Dorines
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bidkhori, Gholamreza
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Zhang, Cheng
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Shoaie, Saeed
    Kings Coll London, Ctr Host Microbiome Interact, Dent Inst, London, England.;Karolinska Inst, Ctr Translat Microbiome Res, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Understanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic Modeling2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 775Article in journal (Refereed)
    Abstract [en]

    Dysbiosis in the gut microbiome composition may be promoted by therapeutic drugs such as metformin, the world's most prescribed antidiabetic drug. Under metformin treatment, disturbances of the intestinal microbes lead to increased abundance of Escherichia spp., Akkermansia muciniphila, Subdoligranulum variabile and decreased abundance of Intestinibacter bartlettii. This alteration may potentially lead to adverse effects on the host metabolism, with the depletion of butyrate producer genus. However, an increased production of butyrate and propionate was verified in metformin-treated Type 2 diabetes (T2D) patients. The mechanisms underlying these nutritional alterations and their relation with gut microbiota dysbiosis remain unclear. Here, we used Genomescale Metabolic Models of the representative gut bacteria Escherichia spp., I. bartlettii, A. muciniphila, and S. variabile to elucidate their bacterial metabolism and its effect on intestinal nutrient pool, including macronutrients (e.g., amino acids and short chain fatty acids), minerals and chemical elements (e.g., iron and oxygen). We applied flux balance analysis (FBA) coupled with synthetic lethality analysis interactions to identify combinations of reactions and extracellular nutrients whose absence prevents growth. Our analyses suggest that Escherichia sp. is the bacteria least vulnerable to nutrient availability. We have also examined bacterial contribution to extracellular nutrients including short chain fatty acids, amino acids, and gasses. For instance, Escherichia sp. and S. variabile may contribute to the production of important short chain fatty acids (e.g., acetate and butyrate, respectively) involved in the host physiology under aerobic and anaerobic conditions. We have also identified pathway susceptibility to nutrient availability and reaction changes among the four bacteria using both FBA and flux variability analysis. For instance, lipopolysaccharide synthesis, nucleotide sugar metabolism, and amino acid metabolism are pathways susceptible to changes in Escherichia sp. and A. muciniphila. Our observations highlight important commensal and competing behavior, and their association with cellular metabolism for prevalent gut microbes. The results of our analysis have potential important implications for development of new therapeutic approaches in T2D patients through the development of prebiotics, probiotics, or postbiotics.

  • 17.
    Rouhimoghadam, Milad
    et al.
    Univ Tehran, Sch Biol, Dept Cell & Mol Biol, Coll Sci, Tehran, Iran..
    Safarian, Shahrokh
    Univ Tehran, Sch Biol, Dept Cell & Mol Biol, Coll Sci, Tehran, Iran..
    Carroll, Jason S.
    Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England..
    Sheibani, Nader
    Univ Wisconsin, Dept Ophthalmol & Visual Sci, Biomed Engn & Cell & Regenerat Biol, Sch Med & Publ Hlth, Madison, WI USA..
    Bidkhori, Gholamreza
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Tamoxifen-Induced Apoptosis of MCF-7 Cells via GPR30/PI3K/MAPKs Interactions: Verification by ODE Modeling and RNA Sequencing2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 907Article in journal (Refereed)
    Abstract [en]

    Tamoxifen (Nolvadex) is one of the most widely used and effective therapeutic agent for breast cancer. It benefits nearly 75% of patients with estrogen receptor (ER)-positive breast cancer that receive this drug. Its effectiveness is mainly attributed to its capacity to function as an ER antagonist, blocking estrogen binding sites on the receptor, and inhibiting the proliferative action of the receptor-hormone complex. Although, tamoxifen can induce apoptosis in breast cancer cells via upregulation of pro-apoptotic factors, it can also promote uterine hyperplasia in some women. Thus, tamoxifen as a multifunctional drug could have different effects on cells based on the utilization of effective concentrations or availability of specific co-factors. Evidence that tamoxifen functions as a GPR30 (G-Protein Coupled Receptor 30) agonist activating adenylyl cyclase and EGFR (Epidermal Growth Factor Receptor) intracellular signaling networks, provides yet another means of explaining the multi-functionality of tamoxifen. Here ordinary differential equation (ODE) modeling, RNA sequencing and real time qPCR analysis were utilized to establish the necessary data for gene network mapping of tamoxifen-stimulated MCF7 cells, which express the endogenous ER and GPR30. The gene set enrichment analysis and pathway analysis approaches were used to categorize transcriptionally upregulated genes in biological processes. Of the 2,713 genes that were significantly upregulated following a 48 h incubation with 250 mu M tamoxifen, most were categorized as either growth-related or pro-apoptotic intermediates that fit into the Tp53 and/or MAPK signaling pathways. Collectively, our results display that the effects of tamoxifen on the breast cancer MCF-7 cell line are mediated by the activation of important signaling pathways including Tp53 and MAPKs to induce apoptosis.

  • 18.
    Spühler, Jeannette H.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Jansson, Johan
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Jansson, Niclas
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Hoffman, Johan
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    3D Fluid-Structure Interaction Simulation of Aortic Valves Using a Unified Continuum ALE FEM Model2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 363Article in journal (Refereed)
    Abstract [en]

    Due to advances in medical imaging, computational fluid dynamics algorithms and high performance computing, computer simulation is developing into an important tool for understanding the relationship between cardiovascular diseases and intraventricular blood flow. The field of cardiac flow simulation is challenging and highly interdisciplinary. We apply a computational framework for automated solutions of partial differential equations using Finite Element Methods where any mathematical description directly can be translated to code. This allows us to develop a cardiac model where specific properties of the heart such as fluid-structure interaction of the aortic valve can be added in a modular way without extensive efforts. In previous work, we simulated the blood flow in the left ventricle of the heart. In this paper, we extend this model by placing prototypes of both a native and a mechanical aortic valve in the outflow region of the left ventricle. Numerical simulation of the blood flow in the vicinity of the valve offers the possibility to improve the treatment of aortic valve diseases as aortic stenosis (narrowing of the valve opening) or regurgitation (leaking) and to optimize the design of prosthetic heart valves in a controlled and specific way. The fluid-structure interaction and contact problem are formulated in a unified continuum model using the conservation laws for mass and momentum and a phase function. The discretization is based on an Arbitrary Lagrangian-Eulerian space-time finite element method with streamline diffusion stabilization, and it is implemented in the open source software Unicorn which shows near optimal scaling up to thousands of cores. Computational results are presented to demonstrate the capability of our framework.

  • 19. Stavrou, Nektarios A. M.
    et al.
    Debevec, Tadej
    Eiken, Ola
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Environmental Physiology. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Swedish Aerospace Physiology Centre, SAPC.
    Mekjavic, Igor B.
    Hypoxia Exacerbates Negative Emotional State during Inactivity: The Effect of 21 Days Hypoxic Bed Rest and Confinement2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 26Article in journal (Refereed)
    Abstract [en]

    Hypoxia and confinement have both been shown to influence emotional state. It is envisaged that the inhabitants of future planetary habitats will be exposed to concomitant confinement, reduced gravity and hypoxia. We examined the independent and combined effects of a 21-day inactivity/unloading and normobaric hypoxia under confined conditions on various psychological factors. Eleven healthy men participated in three 21-day experimental campaigns designed in a cross-over manner (1) Normobaric hypoxic ambulatory confinement, (2) Normobaric hypoxic bed rest and (3) Normobaric normoxic bed rest. The Profile of Mood States, and the Positive and Negative Affect Schedule were employed to assess the participants' psychological responses before (Pre), during (Day 7, Day 14, and Day 21) and after (Post) the confinements. The most negative psychological profile appeared on days 14 and 21 of the hypoxic bed rest campaign. A significant increase in depression, tension, and confusion was noted on days 14 and 21 of the hypoxic bed rest condition. Concomitantly, a decrease, albeit not statistically significant, in positive psychological responses was observed. The psychological profile returned to the initial level at Post following all confinements. These data suggest that the combined effect of hypoxia and bed rest induced the most negative effects on an individual's mood. However, significant intra- and inter-individual differences in psychological responses were noted and should be taken into consideration.

  • 20.
    Turanli, Beste
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Istanbul Medeniyet Univ, Dept Bioengn, Istanbul, Turkey.;Marmara Univ, Dept Bioengn, Istanbul, Turkey..
    Grotli, Morten
    Univ Gothenburg, Dept Chem & Mol Biol, Gothenburg, Sweden..
    Boren, Jan
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden..
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Arga, Kazim Y.
    Marmara Univ, Dept Bioengn, Istanbul, Turkey..
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Drug Repositioning for Effective Prostate Cancer Treatment2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 500Article, review/survey (Refereed)
    Abstract [en]

    Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-kappa B inhibition, Wnt/beta - Catenin pathway inhibition, DNMT1 inhibition, and GSK-3 beta inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.

  • 21.
    Zhang, Cheng
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bidkhori, Gholamreza
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lee, Sunjae
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Arif, Muhammad
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Uhlen, Mathias
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    ESS: A Tool for Genome-Scale Quantification of Essentiality Score for Reaction/Genes in Constraint-Based Modeling2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1355Article in journal (Refereed)
    Abstract [en]

    Genome-scale metabolic models (GEMs) are comprehensive descriptions of cell metabolism and have been extensively used to understand biological responses in health and disease. One such application is in determining metabolic adaptation to the absence of a gene or reaction, i.e., essentiality analysis. However, current methods do not permit efficiently and accurately quantifying reaction/gene essentiality. Here, we present Essentiality Score Simulator (ESS), a tool for quantification of gene/reaction essentialities in GEMs. ESS quantifies and scores essentiality of each reaction/gene and their combinations based on the stoichiometric balance using synthetic lethal analysis. This method provides an option to weight metabolic models which currently rely mostly on topologic parameters, and is potentially useful to investigate the metabolic pathway differences between different organisms, cells, tissues, and/or diseases. We benchmarked the proposed method against multiple network topology parameters, and observed that our method displayed higher accuracy based on experimental evidence. In addition, we demonstrated its application in the wild-type and ldh knock-out E. coli core model, as well as two human cell lines, and revealed the changes of essentiality in metabolic pathways based on the reactions essentiality score. ESS is available without any limitation at https://sourceforge.net/projects/essentiality-score-simulator.

  • 22. Zhang, Cheng
    et al.
    Hua, Qiang
    Applications of Genome-Scale Metabolic Models in Biotechnology and Systems Medicine: Application of GEMs2016In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, no January, article id 413Article in journal (Refereed)
    Abstract [en]

    Genome-scale metabolic models (GEMs) have become a popular tool for systems biology, and they have been used in many fields such as industrial biotechnology and systems medicine. Since more and more studies are being conducted using GEMs, they have recently received considerable attention. In this review, we introduce the basic concept of GEMs and provide an overview of their applications in biotechnology, systems medicine, and some other fields. In addition, we describe the general principle of the applications and analyses built on GEMs. The purpose of this review is to introduce the application of GEMs in biological analysis and to promote its wider use by biologists.

  • 23.
    Zhang, Cheng
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lee, Sunjae
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, Adil
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers, Dept Biol & Biol Engn, Sweden.
    Hua, Qiang
    Investigating the Combinatory Effects of Biological Networks on Gene Co-expression2016In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, article id 160Article in journal (Refereed)
    Abstract [en]

    Co-expressed genes often share similar functions, and gene co-expression networks have been widely used in studying the functionality of gene modules. Previous analysis indicated that genes are more likely to be co-expressed if they are either regulated by the same transcription factors, forming protein complexes or sharing similar topological properties in protein-protein interaction networks. Here, we reconstructed transcriptional regulatory and protein-protein networks for Saccharornyces cerevisiae using well-established databases, and we evaluated their co-expression activities using publically available gene expression data. Based on our network-dependent analysis, we found that genes that were co-regulated in the transcription regulatory networks and shared similar neighbors in the protein-protein networks were more likely to be co-expressed. Moreover, their biological functions were closely related.

  • 24. Zhang, Xiang
    et al.
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Joosten, Leo A. B.
    Kuivenhoven, Jan A.
    Li, Yang
    Netea, Mihai G.
    Groen, Albert K.
    Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 139Article in journal (Refereed)
    Abstract [en]

    Immunity and cellular metabolism are tightly interconnected but it is not clear whether different pathogens elicit specific metabolic responses. To address this issue, we studied differential metabolic regulation in peripheral blood mononuclear cells (PBMCs) of healthy volunteers challenged by Candida albicans, Borrelia burgdorferi, lipopolysaccharide, and Mycobacterium tuberculosis in vitro. By integrating gene expression data of stimulated PBMCs of healthy individuals with the KEGG pathways, we identified both common and pathogen-specific regulated pathways depending on the time of incubation. At 4 h of incubation, pathogenic agents inhibited expression of genes involved in both the glycolysis and oxidative phosphorylation pathways. In contrast, at 24 h of incubation, particularly glycolysis was enhanced while genes involved in oxidative phosphorylation remained unaltered in the PBMCs. In general, differential gene expression was less pronounced at 4 h compared to 24 h of incubation. KEGG pathway analysis allowed differentiation between effects induced by Candida and bacterial stimuli. Application of genome-scale metabolic model further generated a Candida-specific set of 103 reporter metabolites (e.g., desmosterol) that might serve as biomarkers discriminating Candida stimulated PBMCs from bacteria-stimuated PBMCs. Our analysis also identified a set of 49 metabolites that allowed discrimination between the effects of Borrelia burgdorferi, lipopolysaccharide and Mycobacterium tuberculosis. We conclude that analysis of pathogen-induced effects on PBMCs by a combination of KEGG pathways and genome-scale metabolic model provides deep insight in the metabolic changes coupled to host defense.

  • 25. Šarabon, N.
    et al.
    Mekjavić, I. B.
    Eiken, Ola
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Environmental Physiology. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Swedish Aerospace Physiology Centre, SAPC.
    Babič, J.
    The effect of bed rest and hypoxic environment on postural balance and trunk automatic (re)actions in young healthy males2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, no January, article id 27Article in journal (Refereed)
    Abstract [en]

    Prolonged inactivity, such as bed rest induces several detrimental changes within a short timeframe. Impaired postural balance and responses of trunk muscles to (un)expected perturbations were both shown to be impaired after bed rest. Certain populations (e.g., astronauts) are exposed to hypoxic environment in addition to inactivity, similar to bed rest. While the isolated negative effects of hypoxia on postural balance have been observed before, no study to date has examined the combined effects of hypoxia and bed rest on postural balance or trunk muscle responses. In this study, we examined the effects of 21-day exposure to three conditions: (i) bed rest in hypoxic environment (HBR), (ii) bed rest in normoxic environment (NBR), and (iii) ambulatory hypoxic environment (HAMB). Fourteen healthy male subjects crossed over between conditions in a randomized order, with a 4-month break between conditions to ensure full recovery. Most body sway parameters indicated a similar deterioration of postural balance following both HBR and NBR. Similarly, both anticipatory and reactive responses of the trunk muscles (m. erector spinae and m. multifidus) were impaired after HBR and NBR to a similar degree and mostly unchanged after HAMB. Certain body sway parameters were impaired after HAMB, confirming that hypoxia alone can undermine postural balance. On the other hand, some trunk responses were improved after HAMB. In conclusion, the results of our study confirmed previous findings on negative effects of bed rest, but showed little or no additional effect of hypoxia during bed rest. Physical activity during bed rest is encouraged to preserve neuromuscular functions of the trunk. While the HBR condition in our study resembled conditions during space missions, our results could be relevant to other populations, such as patients with pulmonary diseases exposed to bed rest.

  • 26. Šket, R.
    et al.
    Debevec, T.
    Kublik, S.
    Schloter, M.
    Schoeller, A.
    Murovec, B.
    Mikuš, K. V.
    Makuc, D.
    Pečnik, K.
    Plavec, J.
    Mekjavić, I. B.
    Eiken, Ola
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Environmental Physiology. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Swedish Aerospace Physiology Centre, SAPC.
    Prevoršek, Z.
    Stres, B.
    Intestinal metagenomes and metabolomes in healthy young males: Inactivity and hypoxia generated negative physiological symptoms precede microbial dysbiosis2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, no Mars, article id 198Article in journal (Refereed)
    Abstract [en]

    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 O2 (FiO2) and partial pressure of inspiredO2 (PiO2) 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, 1H-and 13C-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 genus Bacteroides in 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 genus Bacteroides and 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 in Bacteroides genomes. 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.

  • 27. Šket, Robert
    et al.
    Treichel, Nicole
    Debevec, Tadej
    Eiken, Ola
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Environmental Physiology.
    Mekjavic, Igor
    Schloter, Michael
    Vital, Marius
    Chandler, Jenna
    Tiedje, James M.
    Murovec, Boštjan
    Prevoršek, Zala
    Stres, Blaž
    Hypoxia and Inactivity Related Physiological Changes (Constipation, Inflammation) Are Not Reflected at the Level of Gut Metabolites and Butyrate Producing Microbial Community: The PlanHab Study2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, no 4, article id 250Article in journal (Refereed)
    Abstract [en]

    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.

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