| 1. |
- Bergman, Dan, 1970-
(författare)
-
Computer simulation of topological and spatial structure in water and aqueous solutions
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present thesis concerns molecular-dynamics and expanded-ensemble simulation of topological and spatial structure in water and aqueous solutions.First, methods for analysis of molecular pair configurations using angularly resolved density distributions were considered. It was shown that these distributions expose major features of liquid structure and that they can be used to define the hydrogen bond. Second, a method was developed for analysis of hydrogen-bond network topology. It characterizes networks in terms of the local bond patterns surrounding the water molecules and in terms of loops and chains of directed bonds.The methods developed have been applied to pure water, to water--acetonitrile mixtures and to charged Lennard-Jones spheres dissolved in water. Solvation structures in aqueous solutions of methylamine and tert-butyl alcohol have also been considered. The main results are: (a) In pure water, there is proton ordering around short loops, but not along chains. (b) The hydrogen-bond network in water--acetonitrile mixtures with acetonitrile mole fractions x=0.1, 0.5 and 0.9 have been characterized. As x increases from 0.1 to 0.9, the network is depleted of crosslinks, the proton ordering along chains increases and the most probable loop length decreases. For x=0.5 and 0.9 large water clusters form. (c) The hydration structures surrounding charged Lennard-Jones solutes corresponding to extrema in the solvation entropy have been characterized. Of the two solutes corresponding to the maxima, one acts as a double proton-donor and the other as a double proton-acceptor. The solute corresponding to the minimum enhances the water--water correlations. Further, the orientational and the radial parts of the two-body solute--water entropy have been calculated. The orientational part has a single maximum, whereas the radial part maintains the bimodal form of the full solvation entropy.
|
|
| 2. |
- Chuang, Tzu-Po, et al.
(författare)
-
ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression
- 2023
-
Ingår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:8
-
Tidskriftsartikel (refereegranskat)abstract
- Anaplastic lymphoma kinase (ALK) fusion variants in Non-Small Cell Lung Cancer (NSCLC) consist of numerous dimerizing fusion partners. Retrospective investigations suggest that treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs dependent on the fusion variant present in the patient tumor. Therefore, under -standing the oncogenic signaling networks driven by different ALK fusion variants is important. To do this, we developed controlled inducible cell models expressing either Echinoderm Microtubule Associated Protein Like 4 (EML4)-ALK-V1, EML4-ALK-V3, Kinesin Family Member 5B (KIF5B)-ALK, or TRK-fused gene (TFG)-ALK and investi-gated their transcriptomic and proteomic responses to ALK activity modulation together with patient-derived ALK-positive NSCLC cell lines. This allowed identification of both common and isoform-specific responses downstream of these four ALK fusions. An inflammatory signature that included upregulation of the Serpin B4 serine protease inhibitor was observed in both ALK fusion inducible and patient-derived cells. We show that Signal transducer and activator of transcription 3 (STAT3), Nuclear Factor Kappa B (NF-kappa B) and Activator protein 1 (AP1) are major transcriptional regulators of SERPINB4 downstream of ALK fusions. Upregulation of SERPINB4promotes survival and inhibits natural killer cell-mediated cytotoxicity, which has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.
|
|
| 3. |
- Justice, A. E., et al.
(författare)
-
Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
|
|
