| 1. |
|
|
| 2. |
- Zhang, C., et al.
(författare)
-
The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease
- 2020
-
Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 16:4
-
Tidskriftsartikel (refereegranskat)abstract
- The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.
|
|
| 3. |
- Fredenberg, Erik, 1979-
(författare)
-
Spectral Mammography with X-Ray Optics and a Photon-Counting Detector
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Early detection is vital to successfully treating breast cancer, and mammography screening is the most efficient and wide-spread method to reach this goal. Imaging low-contrast targets, while minimizing the radiation exposure to a large population is, however, a major challenge. Optimizing the image quality per unit radiation dose is therefore essential. In this thesis, two optimization schemes with respect to x-ray photon energy have been investigated: filtering the incident spectrum with refractive x-ray optics (spectral shaping), and utilizing the transmitted spectrum with energy-resolved photon-counting detectors (spectral imaging). Two types of x-ray lenses were experimentally characterized, and modeled using ray tracing, field propagation, and geometrical optics. Spectral shaping reduced dose approximately 20% compared to an absorption-filtered reference system with the same signal-to-noise ratio, scan time, and spatial resolution. In addition, a focusing pre-object collimator based on the same type of optics reduced divergence of the radiation and improved photon economy by about 50%. A photon-counting silicon detector was investigated in terms of energy resolution and its feasibility for spectral imaging. Contrast-enhanced tumor imaging with a system based on the detector was characterized and optimized with a model that took anatomical noise into account. Improvement in an ideal-observer detectability index by a factor of 2 to 8 over that obtained by conventional absorption imaging was found for different levels of anatomical noise and breast density. Increased conspicuity was confirmed by experiment. Further, the model was extended to include imaging of unenhanced lesions. Detectability of microcalcifications increased no more than a few percent, whereas the ability to detect large tumors might improve on the order of 50% despite the low attenuation difference between glandular and cancerous tissue. It is clear that inclusion of anatomical noise and imaging task in spectral optimization may yield completely different results than an analysis based solely on quantum noise.
|
|
| 4. |
- Mardinoglu, Adil, 1982, et al.
(författare)
-
Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes
- 2018
-
Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 27, s. 151-155
-
Tidskriftsartikel (refereegranskat)abstract
- Branched-chain amino acids (BCAAs) metabolite, 3-Hydroxyisobutyric acid (3-HIB) has been identified as a secreted mediator of endothelial cell fatty acid transport and insulin resistance (IR) using animal models. To identify if 3-HIB is a marker of human IR and future risk of developing Type 2 diabetes (T2D), we measured plasma levels of 3-HIB and associated metabolites in around 10,000 extensively phenotyped individuals. The levels of 3-HIB were increased in obesity but not robustly associated with degree of IR after adjusting for BMI. Nevertheless, also after adjusting for obesity and plasma BCAA, 3-HIB levels were associated with future risk of incident T2D. We also examined the effect of 3-HIB on fatty acid uptake in human cells and found that both HUVEC and human cardiac endothelial cells respond to 3-HIB whereas human adipose tissue-derived endothelial cells do not respond to 3-HIB. In conclusion, we found that increased plasma level of 3-HIB is a marker of future risk of T2D and 3-HIB may be important for the regulation of metabolic flexibility in heart and muscles.
|
|
| 5. |
- Seoane Martinez, Fernando, 1976
(författare)
-
Electrical Bioimpedance Cerebral Monitoring: Fundamental Steps towards Clinical Application
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neurologically related injuries cause a similar number of deaths as cancer, and brain damage is the second commonest cause of death in the world and probably the leading cause of permanent disability. The devastating effects of most cases of brain damage could be avoided if it were detected and medical treatment initiated in time. The passive electrical properties of biological tissue have been investigated for almost a century and electrical bioimpedance studies in neurology have been performed for more than 50 years. Even considering the extensive efforts dedicated to investigating potential applications of electrical bioimpedance for brain monitoring, especially in the last 20 years, and the specifically acute need for such non-invasive and efficient diagnosis support tools, Electrical Bioimpedance technology has not made the expected breakthrough into clinical application yet. In order to reach this stage in the age of evidence-based medicine, the first essential step is to demonstrate the biophysical basis of the method under study. The present research work confirms that the cell swelling accompanying the hypoxic/ischemic injury mechanism modifies the electrical properties of brain tissue, and shows that by measuring the complex electrical bioimpedance it is possible to detect the changes resulting from brain damage. For the development of a successful monitoring method, after the vital biophysical validation it is critical to have available the proper electrical bioimpedance technology and to implement an efficient protocol of use. Electronic instrumentation is needed for broadband spectroscopy measurements of complex electrical bioimpedance; the selection of the electrode setup is crucial to obtain clinically relevant measurements, and the proper biosignal analysis and processing is the core of the diagnosis support system. This work has focused on all these aspects since they are fundamental for providing the solid medico-technological background necessary to enable the clinical usage of Electrical Bioimpedance for cerebral monitoring.
|
|
| 6. |
- Roswall, Josefine, et al.
(författare)
-
Developmental trajectory of the healthy human gut microbiota during the first 5 years of life
- 2021
-
Ingår i: Cell Host & Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 29:5
-
Tidskriftsartikel (refereegranskat)abstract
- The gut is inhabited by a densely populated ecosystem, the gut microbiota, that is established at birth. However, the succession by which different bacteria are incorporated into the gut microbiota is still relatively unknown. Here, we analyze the microbiota from 471 Swedish children followed from birth to 5 years of age, collecting samples after 4 and 12 months and at 3 and 5 years of age as well as from their mothers at birth using 16S rRNA gene profiling. We also compare their microbiota to an adult Swedish population. Genera follow 4 different colonization patterns during establishment where Methanobrevibacter and Christensenellaceae colonize late and do not reached adult levels at 5 years. These late colonizers correlate with increased alpha diversity in both children and adults. By following the children through age-specific community types, we observe that children have individual dynamics in the gut microbiota development trajectory.
|
|
| 7. |
- Mardinoglu, Adil, 1982, et al.
(författare)
-
An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans
- 2018
-
Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 27:3
-
Tidskriftsartikel (refereegranskat)abstract
- A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum beta-hydroxybutyrate concentrations, reflecting increased mitochondrial beta-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD.
|
|
| 8. |
- Zeybel, M., et al.
(författare)
-
Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients
- 2021
-
Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 17:10
-
Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.
|
|
| 9. |
- Powell, Nelson, et al.
(författare)
-
Patterns in pharyngeal airflow associated with sleep-disordered breathing
- 2011
-
Ingår i: Sleep Medicine. - : Elsevier. - 1389-9457 .- 1878-5506. ; 12:10, s. 966-974
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To establish the feasibility of a noninvasive method to identify pharyngeal airflow characteristics in sleep-disordered breathing.Methods: Four patients with sleep-disordered breathing who underwent surgery or used positive airway pressure devices and four normal healthy controls were studied. Three-dimensional CT imaging and computational fluid dynamics modeling with standard steady-state numerical formulation were used to characterize pharyngeal airflow behavior in normals and pre-and post-treatment in patients. Dynamic flow simulations using an unsteady approach were performed in one patient.Results: The pre-treatment pharyngeal airway below the minimum cross-sectional area obstruction site showed airflow separation. This generated recirculation airflow regions and enhanced turbulence zones where vortices developed. This interaction induced large fluctuations in airflow variables and increased aerodynamic forces acting on the pharyngeal wall. At post-treatment, for the same volumetric flow rate, airflow field instabilities vanished and airflow characteristics improved. Mean maximum airflow velocity during inspiration reduced from 18.3 ± 5.7 m/s pre-treatment to 6.3 ± 4.5 m/s post-treatment (P = 0.002), leading to a reduction in maximum wall shear stress from 4.8 ± 1.7 Pa pre-treatment to 0.9 ± 1.0 Pa post-treatment (P = 0.01). The airway resistance improved from 4.3 ± 1.4 Pa/L/min at pre-treatment to 0.7 ± 0.7 Pa/L/min at post-treatment (P = 0.004). Post-treatment airflow characteristics were not different from normal controls (all P ⩾ 0.39).Conclusions: This study demonstrates that pharyngeal airflow variables may be derived from CT imaging and computational fluid dynamics modeling, resulting in high quality visualizations of airflow characteristics of axial velocity, static pressure, and wall shear stress in sleep-disordered breathing.
|
|
| 10. |
|
|
