| 1. |
- Hojjat-Farsangi, Mohammad
(författare)
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Small-molecule inhibitors of the receptor tyrosine kinases : promising tools for targeted cancer therapies
- 2014
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Ingår i: International Journal of Molecular Sciences. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1422-0067.
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK–TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK–TKIs have been developed for the treatment of cancer patients. Specific/selective RTK–TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK–TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs.
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| 2. |
- Barrozo, Alexandre, et al.
(författare)
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Computational Protein Engineering: Bridging the Gap between Rational Design and Laboratory Evolution
- 2012
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 13:10, s. 12428-12460
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Forskningsöversikt (refereegranskat)abstract
- Enzymes are tremendously proficient catalysts, which can be used as extracellular catalysts for a whole host of processes, from chemical synthesis to the generation of novel biofuels. For them to be more amenable to the needs of biotechnology, however, it is often necessary to be able to manipulate their physico-chemical properties in an efficient and streamlined manner, and, ideally, to be able to train them to catalyze completely new reactions. Recent years have seen an explosion of interest in different approaches to achieve this, both in the laboratory, and in silico. There remains, however, a gap between current approaches to computational enzyme design, which have primarily focused on the early stages of the design process, and laboratory evolution, which is an extremely powerful tool for enzyme redesign, but will always be limited by the vastness of sequence space combined with the low frequency for desirable mutations. This review discusses different approaches towards computational enzyme design and demonstrates how combining newly developed screening approaches that can rapidly predict potential mutation “hotspots” with approaches that can quantitatively and reliably dissect the catalytic step can bridge the gap that currently exists between computational enzyme design and laboratory evolution studies.
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| 3. |
- Blom, Hans, et al.
(författare)
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Electrostatic Interactions of Fluorescent Molecules with Dielectric Interfaces Studied by Total Internal Reflection Fluorescence Correlation Spectroscopy
- 2010
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 11:2, s. 368-406
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Tidskriftsartikel (refereegranskat)abstract
- Electrostatic interactions between dielectric surfaces and different fluorophoresused in ultrasensitive fluorescence microscopy are investigated using objective-based TotalInternal Reflection Fluorescence Correlation Spectroscopy (TIR-FCS). The interfacialdynamics of cationic rhodamine 123 and rhodamine 6G, anionic/dianionic fluorescein,zwitterionic rhodamine 110 and neutral ATTO 488 are monitored at various ionic strengthsat physiological pH. As analyzed by means of the amplitude and time-evolution of theautocorrelation function, the fluorescent molecules experience electrostatic attraction orrepulsion at the glass surface depending on their charges. Influences of the electrostaticinteractions are also monitored through the triplet-state population and triplet relaxationtime, including the amount of detected fluorescence or the count-rate-per-moleculeparameter. These TIR-FCS results provide an increased understanding of how fluorophoresare influenced by the microenvironment of a glass surface, and show a promising approachfor characterizing electrostatic interactions at interfaces.
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| 4. |
- Fuvesi, J., et al.
(författare)
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Proteomic Analysis of Cerebrospinal Fluid in a Fulminant Case of Multiple Sclerosis
- 2012
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 13:6, s. 7676-7693
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Tidskriftsartikel (refereegranskat)abstract
- Multiple Sclerosis (MS) is a chronic disease, but in rare fulminant cases rapid progression may lead to death shortly after diagnosis. Currently there is no diagnostic test to predict disease course. The aim of this study was to identify potential biomarkers/proteins related to rapid progression. We present the case history of a 15-year-old male MS patient. Cerebrospinal fluid (CSF) was taken at diagnosis and at the time of rapid progression leading to the patient's death. Using isobaric tag labeling and nanoflow liquid chromatography in conjunction with matrix assisted laser desorption/ionization time of flight tandem mass spectrometry we quantitatively analyzed the protein content of two CSF samples from the patient with fulminant MS as well as one relapsing-remitting (RR) MS patient and one control headache patient, whose CSF analysis was normal. Seventy-eight proteins were identified and seven proteins were found to be more abundant in both fulminant MS samples but not in the RR MS sample compared to the control. These proteins are involved in the immune response, blood coagulation, cell proliferation and cell adhesion. In conclusion, in this pilot study we were able to show differences in the CSF proteome of a rapidly progressing MS patient compared to a more typical clinical form of MS and a control subject.
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| 5. |
- Mohsenzadeh, Abas, et al.
(författare)
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The Effect of Carbon Monoxide Co-Adsorption on Ni-Catalysed Water Dissociation
- 2013
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Ingår i: International Journal of Molecular Sciences. - : M D P I AG. - 1661-6596 .- 1422-0067. ; 14:12, s. 23301-23314
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Tidskriftsartikel (refereegranskat)abstract
- The effect of carbon monoxide (CO) co-adsorption on the dissociation of water on the Ni(111) surface has been studied using density functional theory. The structures of the adsorbed water molecule and of the transition state are changed by the presence of the CO molecule. The water O–H bond that is closest to the CO is lengthened compared to the structure in the absence of the CO, and the breaking O–H bond in the transition state structure has a larger imaginary frequency in the presence of CO. In addition, the distances between the Ni surface and H2O reactant and OH and H products decrease in the presence of the CO. The changes in structures and vibrational frequencies lead to a reaction energy that is 0.17 eV less exothermic in the presence of the CO, and an activation barrier that is 0.12 eV larger in the presence of the CO. At 463 K the water dissociation rate constant is an order of magnitude smaller in the presence of the CO. This reveals that far fewer water molecules will dissociate in the presence of CO under reaction conditions that are typical for the water-gas-shift reaction.
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| 6. |
- Fontes, Magnus
(författare)
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Optimal results for the nonhomogeneous initial-boundary value problem for the two-dimensional Navier-Stokes equations
- 2010
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Ingår i: Journal of Mathematical Fluid Mechanics. - : Springer Science and Business Media LLC. - 1422-6928 .- 1422-6952. ; 12, s. 412-434
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Tidskriftsartikel (refereegranskat)abstract
- In this work we study the fully nonhomogeneous initial boundary value problem for the two-dimensional time-dependent Navier–Stokes equations in a general open space domain in R2 with low regularity assumptions on the initial and the boundary value data. We show that the perturbed Navier–Stokes operator is a diffeomorphism from a suitable function space onto its own dual and as a corollary we get that the Navier–Stokes equations are uniquely solvable in these spaces and that the solution depends smoothly on all involved data. Our source data space and solution space are in complete natural duality and in this sense, without any smallness assumptions on the data, we solve the equations for data with optimally low regularity in both space and time.
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| 7. |
- Almstrand, Robert, et al.
(författare)
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Three-dimensional stratification of bacterial biofilm populations in a moving bed biofilm reactor for nitritation-anammox.
- 2014
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 15:2, s. 2191-206
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Tidskriftsartikel (refereegranskat)abstract
- Moving bed biofilm reactors (MBBRs) are increasingly used for nitrogen removal with nitritation-anaerobic ammonium oxidation (anammox) processes in wastewater treatment. Carriers provide protected surfaces where ammonia oxidizing bacteria (AOB) and anammox bacteria form complex biofilms. However, the knowledge about the organization of microbial communities in MBBR biofilms is sparse. We used new cryosectioning and imaging methods for fluorescence in situ hybridization (FISH) to study the structure of biofilms retrieved from carriers in a nitritation-anammox MBBR. The dimensions of the carrier compartments and the biofilm cryosections after FISH showed good correlation, indicating little disturbance of biofilm samples by the treatment. FISH showed that Nitrosomonas europaea/eutropha-related cells dominated the AOB and Candidatus Brocadia fulgida-related cells dominated the anammox guild. New carriers were initially colonized by AOB, followed by anammox bacteria proliferating in the deeper biofilm layers, probably in anaerobic microhabitats created by AOB activity. Mature biofilms showed a pronounced three-dimensional stratification where AOB dominated closer to the biofilm-water interface, whereas anammox were dominant deeper into the carrier space and towards the walls. Our results suggest that current mathematical models may be oversimplifying these three-dimensional systems and unless the multidimensionality of these systems is considered, models may result in suboptimal design of MBBR carriers.
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| 8. |
- Andersson, Richard L., et al.
(författare)
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Antibacterial Properties of Tough and Strong Electrospun PMMA/PEO Fiber Mats Filled with Lanasol-A Naturally Occurring Brominated Substance
- 2014
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 15:9, s. 15912-15923
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Tidskriftsartikel (refereegranskat)abstract
- A new type of antimicrobial, biocompatible and toughness enhanced ultra-thin fiber mats for biomedical applications is presented. The tough and porous fiber mats were obtained by electrospinning solution-blended poly (methyl methacrylate) (PMMA) and polyethylene oxide (PEO), filled with up to 25 wt % of Lanasol-a naturally occurring brominated cyclic compound that can be extracted from red sea algae. Antibacterial effectiveness was tested following the industrial Standard JIS L 1902 and under agitated medium (ASTM E2149). Even at the lowest concentrations of Lanasol, 4 wt %, a significant bactericidal effect was seen with a 4-log (99.99%) reduction in bacterial viability against S. aureus, which is one of the leading causes of hospital-acquired (nosocomial) infections in the world. The mechanical fiber toughness was insignificantly altered up to the maximum Lanasol concentration tested, and was for all fiber mats orders of magnitudes higher than electrospun fibers based on solely PMMA. This antimicrobial fiber system, relying on a dissolved antimicrobial agent (demonstrated by X-ray diffraction and Infrared (IR)-spectroscopy) rather than a dispersed and "mixed-in" solid antibacterial particle phase, presents a new concept which opens the door to tougher, stronger and more ductile antimicrobial fibers.
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| 9. |
- Ankarloo, Jonas, et al.
(författare)
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Escherichia coli mar and acrAB Mutants Display No Tolerance to Simple Alcohols
- 2010
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 11:4, s. 1403-1412
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Tidskriftsartikel (refereegranskat)abstract
- The inducible Mar phenotype of Escherichia coli is associated with increased tolerance to multiple hydrophobic antibiotics as well as some highly hydrophobic organic solvents such as cyclohexane, mediated mainly through the AcrAB/TolC efflux system. The influence of water miscible alcohols ethanol and 1-propanol on a Mar constitutive mutant and a mar deletion mutant of E. coli K-12, as well as the corresponding strains carrying the additional acrAB deletion, was investigated. In contrast to hydrophobic solvents, all strains were killed in exponential phase by 1-propanol and ethanol at rates comparable to the parent strain. Thus, the Mar phenotype does not protect E. coli from killing by these more polar solvents. Surprisingly, AcrAB does not contribute to an increased alcohol tolerance. In addition, sodium salicylate, at concentrations known to induce the mar operon, was unable to increase 1-propanol or ethanol tolerance. Rather, the toxicity of both solvents was increased in the presence of sodium salicylate. Collectively, the results imply that the resilience of E. coli to water miscible alcohols, in contrast to more hydrophobic solvents, does not depend upon the AcrAB/TolC efflux system, and suggests a lower limit for substrate molecular size and functionality. Implications for the application of microbiological systems in environments containing high contents of water miscible organic solvents, e. g., phage display screening, are discussed.
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| 10. |
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