| 1. |
- Trac, Quang Thinh, et al.
(författare)
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Prediction model for drug response of acute myeloid leukemia patients
- 2023
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Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Despite some encouraging successes, predicting the therapy response of acute myeloid leukemia (AML) patients remains highly challenging due to tumor heterogeneity. Here we aim to develop and validate MDREAM, a robust ensemble-based prediction model for drug response in AML based on an integration of omics data, including mutations and gene expression, and large-scale drug testing. Briefly, MDREAM is first trained in the BeatAML cohort (n = 278), and then validated in the BeatAML (n = 183) and two external cohorts, including a Swedish AML cohort (n = 45) and a relapsed/refractory acute leukemia cohort (n = 12). The final prediction is based on 122 ensemble models, each corresponding to a drug. A confidence score metric is used to convey the uncertainty of predictions; among predictions with a confidence score >0.75, the validated proportion of good responders is 77%. The Spearman correlations between the predicted and the observed drug response are 0.68 (95% CI: [0.64, 0.68]) in the BeatAML validation set, -0.49 (95% CI: [-0.53, -0.44]) in the Swedish cohort and 0.59 (95% CI: [0.51, 0.67]) in the relapsed/refractory cohort. A web-based implementation of MDREAM is publicly available at https://www.meb.ki.se/shiny/truvu/MDREAM/.
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| 2. |
- Akhtar, Monira, et al.
(författare)
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Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity
- 2012
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 41:6, s. 1959-1966
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Tidskriftsartikel (refereegranskat)abstract
- The fetal transcription factor PLAG1 is found to be overexpressed in cancers, and has been suggested to bind the insulin like growth factor 2 (IGF2) P3 promoter, and to activate the IGF2 gene. The expression of IGF2 has partly been linked to loss of CTCF-dependent chromatin insulator function at the H19 imprinting control region (ICR). We investigated the role of PLAG1 for IGF2 regulation in Hep3B and JEG-3 cell lines. Chromatin immunoprecipitation revealed cell type-specific binding of PLAG1 to the IGF2 P3 promoter, which was substantially insensitive to recombinant PLAG1 overexpression in the endogenous context. We hypothesized that the H19 chromatin insulator may be involved in the cell type-specific PLAG1 response. By using a GFP reporter gene/insulator assay plasmid construct with and without the H19 ICR and/or an SV40 enhancer, we confirm that the effect of the insulator is specifically associated with the activity of the IGF2 P3 promoter in the GFP reporter system, and furthermore, that the reporter insulator is functional in JEG-3 but not in Hep3B cells. FACS analysis was used to assess the function of PLAG1 in low endogenously expressing, but Zn-inducible stable PLAG1 expressing JEG-3 cell clones. Considerable increase in IGF2 expression upon PLAG1 induction with a partial insulator overriding activity was found using the reporter constructs. This is in contrast to the effect of the endogenous IGF2 gene which was insensitive to PLAG1 expression in JEG-3, while modestly induced the already highly expressed IGF2 gene in Hep3B cells. We suggest that the PLAG1 binding to the IGF2 P3 promoter and IGF2 expression is cell type-specific, and that the PLAG1 transcription factor acts as a transcriptional facilitator that partially overrides the insulation by the H19 ICR.
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| 3. |
- Brännvall, Rickard, et al.
(författare)
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Data center excess heat recovery : A case study of apple drying
- 2020
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Ingår i: ECOS 2020 - Proceedings of the 33rd International Conference on Efficiency, Cost, Optimization, Simulation and Environmental Impact of Energy Systems. - : ECOS 2020 Local Organizing Committee. ; , s. 2165-2174, s. 2165-2174
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Konferensbidrag (refereegranskat)abstract
- Finding synergies between heat producing and heat consuming actors in an economy provides opportunity for more efficient energy utilization and reduction of overall power consumption. We propose to use low-grade heat recovered from data centers directly in food processing industries, for example for the drying of fruit and berries. This study analyses how the heat output of industrial IT-load on servers can dry apples in a small-scale experimental set up. To keep the temperatures of the server exhaust airflow near a desired set-point we use a model predictive controller (MPC) re-purposed to the drying experiment set-up from a previous work that used machine learning models for cluster thermal management. Thus, conditions with for example 37 C for 8 hours drying can be obtained with results very similar to conventional drying of apples. The proposed solution increases the value output of the electricity used in a data center by capturing and using the excess heat that would otherwise be exhausted. The results from our experiments show that drying foods with excess heat from data center is possible with potential of strengthening the food processing industry and contribute to food self-sufficiency in northern Sweden.
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| 4. |
- Brännvall, Rickard, et al.
(författare)
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EDGE : Microgrid Data Center with Mixed Energy Storage
- 2020
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Ingår i: e-Energy 2020 - Proceedings of the 11th ACM International Conference on Future Energy Systems. - New York, NY, USA : Association for Computing Machinery, Inc. - 9781450380096 ; , s. 466-473, s. 466-473
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Konferensbidrag (refereegranskat)abstract
- Low latency requirements are expected to increase with 5G telecommunications driving data and compute to EDGE data centers located in cities near to end users. This article presents a testbed for such data centers that has been built at RISE ICE Datacenter in northern Sweden in order to perform full stack experiments on load balancing, cooling, micro-grid interactions and the use of renewable energy sources. This system is described with details on both hardware components and software implementations used for data collection and control. A use case for off-grid operation is presented to demonstrate how the test lab can be used for experiments on edge data center design, control and autonomous operation. © 2020 Author.
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| 5. |
- Chan, Sherwin, et al.
(författare)
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Regulation of PfEMP1-VAR2CSA translation by a Plasmodium translation-enhancing factor
- 2017
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Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 2:7
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Tidskriftsartikel (refereegranskat)abstract
- Pregnancy-associated malaria commonly involves the binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate A (CSA) through the PfEMP1-VAR2CSA protein. VAR2CSA is translationally repressed by an upstream open reading frame. In this study, we report that the P. falciparum translation enhancing factor (PTEF) relieves upstream open reading frame repression and thereby facilitates VAR2CSA translation. VAR2CSA protein levels in var2csa-transcribing parasites are dependent on the expression level of PTEF, and the alleviation of upstream open reading frame repression requires the proteolytic processing of PTEF by PfCalpain. Cleavage generates a C-terminal domain that contains a sterile-alpha-motif-like domain. The C-terminal domain is permissive to cytoplasmic shuttling and interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence. It also enhances translation in a heterologous translation system and thus represents the first non-canonical translation enhancing factor to be found in a protozoan. Our results implicate PTEF in regulating placental CSA binding of infected erythrocytes.
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| 6. |
- Forsgren, Henrik, et al.
(författare)
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Homomorphic Encryption Enables Data and Algorithm Confidentiality for Remote Monitoring and Control : An Application to Data Center Systems
- 2023
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Ingår i: Companion Proceedings of the 14th ACM International Conference on Future Energy Systems. - : Association for Computing Machinery. ; , s. 85-90
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Konferensbidrag (refereegranskat)abstract
- The design of intelligent algorithms used for device monitoring and control can be costly and is an investment that must be protected against reverse engineering by competitors. An algorithm can be safeguarded by running remotely from the cloud instead of locally on the equipment hardware. However, such a setup requires that sensitive data is sent from the device to the cloud. Fully Homomorphic Encryption (FHE) is an emerging technology that offers a solution to this problem since it enables computation on encrypted data. A cloud service using FHE can protect its proprietary algorithms while simultaneously offering customer data confidentiality. The computational overhead for the technology is, however, still very high. This work reports on a practical investigation of using FHE for data center remote control problems: What applications are feasible today? And at what cost?
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| 7. |
- Fotouhi, Omid, et al.
(författare)
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Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
- 2019
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Ingår i: Oncogene. - : NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 38:43, s. 6881-6897
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Tidskriftsartikel (refereegranskat)abstract
- Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.
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| 8. |
- Galkin, Nikolai, et al.
(författare)
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On Modelling of Edge Datacentre Microgrid for Participation in Smart Energy Infrastructures
- 2022
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Ingår i: IEEE Open Journal of the Industrial Electronics Society. - : Institute of Electrical and Electronics Engineers Inc.. - 2644-1284. ; 3, s. 50-64
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Tidskriftsartikel (refereegranskat)abstract
- Datacentres are becoming a sizable part of the energy system and are one of the biggest consumers of the energy grid. The so-called “Green Datacentre” is capable of not only consuming but also producing power, thus becoming an important kind of prosumers in the electric grid. Green datacentres consist of a microgrid with a backup uninterrupted power supply and renewable generation, e.g., using photovoltaic panels. As such, datacentres could realistically be important participants in demand/response applications. However, this requires reconsidering their currently rigid control and automation systems and the use of simulation models for online estimation of the control actions impact. This paper presents such a microgrid simulation model modelled after a real edge datacentre. A case study consumption scenario is presented for the purpose of validating the developed microgrid model against data traces collected from the green edge datacentre. Both simulation and real-time validation tests are performed to validate the accuracy of the datacentre model. Then the model is connected to the automation environment to be used for the online impact estimation and virtual commissioning purposes.
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| 9. |
- Gao, Yu, et al.
(författare)
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SOCS3 Expression by Thymic Stromal Cells Is Required for Normal T Cell Development
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The suppressor of cytokine signaling 3 (SOCS3) is a major regulator of immune responses and inflammation as it negatively regulates cytokine signaling. Here, the role of SOCS3 in thymic T cell formation was studied in Socs3fl/fl Actin-creER mice (Δsocs3) with a tamoxifen inducible and ubiquitous Socs3 deficiency. Δsocs3 thymi showed a 90% loss of cellularity and altered cortico-medullary organization. Thymocyte differentiation and proliferation was impaired at the early double negative (CD4-CD8-) cell stage and apoptosis was increased during the double positive (CD4+CD8+) cell stage, resulting in the reduction of recent thymic emigrants in peripheral organs. Using bone marrow chimeras, transplanting thymic organoids and using mice deficient of SOCS3 in thymocytes we found that expression in thymic stromal cells rather than in thymocytes was critical for T cell development. We found that SOCS3 in thymic epithelial cells (TECs) binds to the E3 ubiquitin ligase TRIM 21 and that Trim21−/− mice showed increased thymic cellularity. Δsocs3 TECs showed alterations in the expression of genes involved in positive and negative selection and lympho-stromal interactions. SOCS3-dependent signal inhibition of the common gp130 subunit of the IL-6 receptor family was redundant for T cell formation. Together, SOCS3 expression in thymic stroma cells is critical for T cell development and for maintenance of thymus architecture.
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| 10. |
- Herr, Patrick, et al.
(författare)
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Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics
- 2020
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Ingår i: Molecular & Cellular Proteomics. - : Elsevier BV. - 1535-9476 .- 1535-9484. ; 19:4, s. 608-623
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Tidskriftsartikel (refereegranskat)abstract
- The cell cycle is a highly conserved process involving the coordinated separation of a single cell into two daughter cells. To relate transcriptional regulation across the cell cycle with oscillatory changes in protein abundance and activity, we carried out a proteome- and phospho-proteome-wide mass spectrometry profiling. We compared protein dynamics with gene transcription, revealing many transcriptionally regulated G2 mRNAs that only produce a protein shift after mitosis. Integration of CRISPR/Cas9 survivability studies further highlighted proteins essential for cell viability. Analyzing the dynamics of phosphorylation events and protein solubility dynamics over the cell cycle, we characterize predicted phospho-peptide motif distributions and predict cell cycle-dependent translocating proteins, as exemplified by the S-adenosylmethionine synthase MAT2A. Our study implicates this enzyme in translocating to the nucleus after the G1/S-checkpoint, which enables epigenetic histone methylation maintenance during DNA replication. Taken together, this data set provides a unique integrated resource with novel insights on cell cycle dynamics.
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