Free-energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are ...still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free-energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace, and OpenMM and uses the AMBER 14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset, the average correlation coefficient
was 0.70 ± 0.05 and average Kendall's τ was 0.53 ± 0.05, which are broadly comparable to or better than previously reported results using other methods.
Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying ...cellular and molecular mechanisms remain largely elusive. Here, we identified
miRNAs as potent suppressors for lung adenocarcinoma metastasis.
expression is specifically repressed in mouse metastatic lung adenocarcinomas, and
decrease strongly correlates with poor patient survival. Consistently, deletion of
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in the
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lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer.
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deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells.
regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.
Targeting the activating enzymes (E1) of ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) has emerged as a promising anti-cancer strategy, possibly overcoming the ineffectiveness of proteasome ...inhibitors against solid tumors. Here, we report crystal structures of the yeast ubiquitin E1 (Uba1) with three adenosyl sulfamate inhibitors exhibiting different E1 specificities, which are all covalently linked to ubiquitin. The structures illustrate how the chemically diverse inhibitors are accommodated within the adenylation active site. When compared with the previously reported structures of various E1 enzymes, our structures provide the basis of the preferences of these inhibitors for different Ub/Ubl-activating enzymes. In vitro inhibition assays and molecular dynamics simulations validated the specificities of the inhibitors as deduced from the structures. Taken together, the structures establish a framework for the development of additional compounds targeting E1 enzymes, which will display higher potency and selectivity.
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•Crystal structures define the specificity of adenosyl sulfamates towards Uba1•In vitro assays establish yeast Uba1 as an excellent model for human UBA1•Novel inhibitors can be evaluated with linear interaction energy calculations•Variations in different E1 enzymes can be exploited to develop specific inhibitors
Misra et al. report crystal structures of yeast ubiquitin-activating enzyme (Uba1) in complex with three adenosyl sulfamates covalently linked to ubiquitin. Targeting specific features in the ATP-binding pockets of individual activating (E1) enzymes by rational modulation of the nucleobase extensions of these compounds will yield specific and potent inhibitors.
In FDSOI, sophisticated body biasing schemes can greatly reduce leakage or improve performance as well as efficiency. This paper proposes algorithms to determine body bias domain candidates which ...then merge those to reach a desired number of domains. Domain candidates are determined using an activation based approach, analyzing mapped Verilog netlists to identify which parts of the design are used under specified conditions. Body bias domain partitionings are then determined based on activation and the timing of the partitioned parts. The algorithms include a body bias assignment algorithm to reach given timing goals with multiple domains and cross-domain resource sharing. The approach is compatible with any synthesis optimization and is resource sharing aware. Using an implementation of the proposed algorithms, overall leakage can be significantly reduced in all scenarios while obtaining the same benefits of body biasing. The method is evaluated in STMicro's 28nm FDSOI and Renesas's 65nm SOTB.
To compare anti-VEGF treatments for macular disease in terms of costs and clinical outcomes.
We identified patients suffering from macular disease and treated either with aflibercept, ranibizumab or ...both at the largest public eye clinic in Switzerland between January 1st and December 31st 2016 who were insured in one of the two participating health insurance companies. Clinical data were extracted from the electronic health record system. The health insurers provided the health claim costs for the ophthalmologic care and the total health care costs of each patient in the observation period. Using multivariate regression models, we assessed the monthly ophthalmologic and the monthly total costs of patients with no history of switching (ranibizumab vs. aflibercept), patients with a history of switching from ranibizumab to aflibercept, patients switching during the observation period and a miscellaneous group. We examined baseline differences in age, proportion of males, visual acuity (letters), central retinal thickness (CRT) and treatment history before entering the study. We investigated treatment intensity and compared the changes in letters and CRT.
The analysis involved 488 eyes (361 patients), 182 on ranibizumab treatment, and 63 on aflibercept treatment, 160 eyes with a history of switching from ranibizumab to aflibercept, and 45 switchers during follow-up and 38 eyes of the miscellaneous group. Compared to ranibizumab, monthly costs of ophthalmologic treatment were slightly higher for aflibercept treatment + 175.0 CHF (95%CI: 1.5 CHF to 348.3 CHF; p = 0.048) as were the total monthly costs + 581.0 CHF (95%CI: 159.5 CHF to 1002.4 CHF; p = 0.007). Compared to ranibizumab, the monthly treatment intensity with aflibercept was similar (+ 0.057 injections/month (95%CI -0.023 to 0.137; p = 0.162), corresponding to a projected annual number of 5.4 injections for ranibizumab vs. 6.1 injections for aflibercept. During follow-up, visus dropped by 0.7 letters with ranibizumab and increased by 0.6 letters with aflibercept (p = 0.243). CRT dropped by - 14.9 μm with ranibizumab and by - 19.5 μm with aflibercept (p = 0.708). The monthly costs of all other groups examined were higher.
These real-life data show that aflibercept treatment is equally expensive, and clinical outcomes between the two drugs are similar.
Body bias control is a fundamental technique widely used to provide an efficient tradeoff between leakage power and performance in ultralow-power systems. Therefore, a lot of research about power ...optimization which provides optimal power supply and body bias voltages has been carried out. However, considering the actual voltage sources, the conventional approaches suffer from limited performance/power control granularity and may lead to degradation in terms of the energy efficiency. Therefore, in this paper, a power optimization method that improves the performance/power control granularity is proposed and evaluated with real processor chips. In the proposed optimization, the body biases for nMOSFET and pMOSFET are controlled independently, while the conventional methods control them uniformly. This increases the number of possible voltage combinations and allows finer target frequency selection leading to lower power consumption than the conventional methods at the cost of the optimization complexity. In order to ease this complexity, the proposed optimization is based on simple power and delay models. The model-based optimization does not require brute force search in the phase of real chip testing; thus, the testing time and cost can be significantly reduced. Since the coefficients of the models are extracted with real chip measurements, the error of the model can be suppressed to a few percent in average. The proposed approach is validated by real chips implemented with a 65-nm fully depleted silicon on insulator technology. The evaluation results show that the proposed optimization is an efficient mean of power reduction for a leakage current dominant chip. In fact, when compared with the conventional method, the proposed approach achieves 9.617% of average power reduction reaching up to 22.77% in the case of the V850 microcontroller.
The prevailing production and consumption patterns mostly follow a linear logic: produce, consume and dispose. This orientation of the economic system is highly resource-intensive and exceeds ...planetary boundaries. In order to decouple the economic growth from resource consumption circular economy is an important enabler by creating and closing resource loops. The goal of a circular economy is the sustainable return of resources into the value chain. Thereby, the design of the products plays a decisive role. Ecodesign is a systematic design approach for products in order to reduce environmental impacts over the entire life cycle by defining design principles. Therefore, ecodesign has the potential to allow the implementation of a circular economy by identifying design principles that enable critical resources to be preserved in cycles. For this reason, a framework with nine fields of action for the realization of circular economy by ecodesign was derived. The fields of action are based on the circular economy strategies "Closing the Loop" and "Slowing the Loop" as well as the product lifecycle phases addressed by ecodesign “production”, “use” and “recycling”. Practical use cases deal with the impact of the various design principles at the material, component and product levels of analysis.
In the product development of manufacturing companies, an increasing trend can be observed over the last few years that the number of projects is on the rise. The complexity of the project landscape ...likewise continues to increase due to the number of and interdependency between projects. If more and more activities of a company are carried out in the form of projects and these projects become more and more complex, a successful multi-project management becomes crucial for companies. For this reason, the objective of this paper is to analyze scientific literature as well as reports and studies from practice in order to derive success factors and fields of action for multi-project management.
The frontline anti-malarial drug artemisinin and its derivatives have also been implicated in modulating multiple mammalian cellular pathways, including the recent identification of targeting ...γ-aminobutyric acid type A receptor (GABAAR) signaling in the pancreas. Their molecular mechanism of action, however, remains elusive. Here, we present crystal structures of gephyrin, the central organizer at inhibitory postsynapses, in complex with artesunate and artemether at 1.5-Å resolution. These artemisinins target the universal inhibitory neurotransmitter receptor-binding epitope of gephyrin, thus inhibiting critical interactions between gephyrin and glycine receptors (GlyRs) as well as GABAARs. Electrophysiological recordings reveal a significant inhibition of gephyrin-mediated neurotransmission by artemisinins. Furthermore, clustering analyses in primary neurons demonstrate a rapid inhibition and a time-dependent regulation of gephyrin and GABAAR cluster parameters. Our data not only provide a comprehensive model for artemisinin-mediated modulation of inhibitory neurotransmission but also establish artemisinins as potential lead compounds to pharmacologically interfere with this process.
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•First structure of the anti-malarial drug artemisinin bound to a target protein•Artemisinins target the glycine and GABAA receptor binding pocket in gephyrin•Artemisinins modulate inhibitory neurotransmission with a dependence on gephyrin•Gephyrin-receptor clusters are targeted by artemisinins in a time-dependent manner
Crystal structures of the C-terminal domain of the principal inhibitory postsynaptic scaffolding protein gephyrin in complex with artemisinins together with biochemical and cellular analyses by Kasaragod et al. provide a comprehensive model for the regulation of inhibitory neurotransmission by artemisinins.
Manufacturing companies are confronted with increasing demands regarding product functionality and individualization. To meet these requirements, product variants are increasingly created by linking ...physical and virtual objects forming “cyber-physical systems” (CPS). Nevertheless, connecting a large number of different elements in a system results in increasing complexity which lead to higher complexity cost. In order to control complexity, the objective of this paper is to optimize the cost-benefit ratio of CPS by means of an appropriate complexity design. The cost- and benefit-based classification of a CPS allows the derivation of design recommendations for complexity-oriented product development of CPS.
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