Chemical screening identifies the β-Carboline alkaloid harmine to be synergistically lethal with doxorubicin.

Despite being an invaluable chemotherapeutic agent for several types of cancer, the clinical utility of doxorubicin is hampered by its age-related and dose-dependent cardiotoxicity. Co-administration of dexrazoxane as a cardioprotective agent has been proposed, however recent studies suggest that it attenuates doxorubicin-induced antitumor activity. Since compounds of natural origin present a rich territory for drug discovery, we set out to identify putative natural compounds with the view to mitigate or minimize doxorubicin cardiotoxicity. We identify the DYRK1A kinase inhibitor harmine, which phosphorylates Tau that is deregulated in Alzheimer's disease, as a potentiator of cell death induced by non-toxic doses of doxorubicin. These observations suggest that harmine or other compounds that target the DYRK1A kinase my offer a new therapeutic opportunity to suppress doxorubicin age-related and dose-dependent cardiotoxicity

Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical–induced DNA damage

Breakage of one strand of DNA is the most common form of DNA damage. Most damaged DNA termini require end-processing in preparation for ligation. The importance of this step is highlighted by the association of de- fects in the 3′-end processing enzyme tyrosyl DNA phosphodiesterase 1 (TDP1) and neurodegeneration and by the cytotoxic induction of protein-linked DNA breaks (PDBs) and oxidized nucleic acid intermediates during chemotherapy and radiotherapy. Although much is known about the repair of PDBs in the nucleus, little is known about this process in the mitochondria. We reveal that TDP1 resolves mitochondrial PDBs (mtPDBs), thereby promoting mitochondrial gene transcription. Overexpression of a toxic form of mitochondrial topo- isomerase I (TOP1mt*), which generates excessive mtPDBs, results in a TDP1-dependent compensatory up- regulation of mitochondrial gene transcription. In the absence of TDP1, the imbalance in transcription of mitochondrial- and nuclear-encoded electron transport chain (ETC) subunits results in misassembly of ETC complex III. Bioenergetics profiling further reveals that TDP1 promotes oxidative phosphorylation under both basal and high energy demands. It is known that mitochondrial dysfunction results in free radical leakage and nuclear DNA damage; however, the detection of intermediates of radical damage to DNA is yet to be shown. Consequently, we report an increased accumulation of carbon-centered radicals in cells lacking TDP1, using electron spin resonance spectroscopy. Overexpression of the antioxidant enzyme superoxide dismutase 1 (SOD1) reduces carbon-centered adducts and protects TDP1-deficient cells from oxidative stress. Conversely, overexpression of the amyotrophic lateral sclerosis–associated mutant SOD1G93A leads to marked sensitivity. Whereas Tdp1 knockout mice develop normally, overexpression of SOD1G93A suggests early embryonic lethal- ity. Together, our data show that TDP1 resolves mtPDBs, thereby regulating mitochondrial gene transcription and oxygen consumption by oxidative phosphorylation, thus conferring cellular protection against reactive oxygen species–induced damage

Visualization as a guidance to classification for large datasets

Data visualization has gained a lot of attention after the stressing need to make sense of the huge amounts of data that we collect every day. Lower dimensional embedding techniques such as IsoMap, Locally Linear Embedding and t-SNE help us visualize high dimensional data by projecting it on a two or three-dimensional space. t-SNE, or t-Distributed Stochastic Neighbor Embedding proved to be successful in providing lower dimensional data mappings that makes interpreting the underlying structure of data easier for our human brains. We wanted to test the hypothesis that this simple visualization that human beings can easily understand will also simplify the job of the classification models and boost their performance. In order to test this hypothesis, we reduce the dimensionality of a student performance dataset using t-SNE into 2D and 3D and feed the calculated 2D and 3D feature vectors into a classifier to classify students according to their predicted performance. We compare the classifier performance before and after the dimensionality reduction. Our experiments showed that t-SNE helps improve classification accuracy of NN and KNN on a benchmarking dataset as well as a user-curated dataset on performance of students at our home institution. We also visually compared the 2D and 3D mapping of t-SNE and PCA. Our comparison favored t-SNE\u27s visualization over PC\u27s. This was also reflected in the classification accuracy of all classifiers used, scoring higher on t-SNE\u27s mapping than on the PCA\u27s mapping

Role of quercetin and arginine in ameliorating nano zinc oxide-induced nephrotoxicity in rats

BACKGROUND: Nanoparticles are small-scale substances (<100 nm) with unique properties. Therefore, nanoparticles pose complex health risk implications. The objective of this study was to detect whether treatment with quercetin (Qur) and/or arginine (Arg) ameliorated nephrotoxicity induced by two different doses of nano zinc oxide (n-ZnO) particles. METHOD: ZnO nanoparticles were administered orally in two doses (either 600 mg or 1 g/Kg body weight/day for 5 conscutive days) to Wister albino rats. In order to detect the protective effects of the studied antioxidants against n-ZnO induced nepherotoxicity, different biochemical parameters were investigated. Moreover, histopathological examination of kidney tissue was performed. RESULTS: Nano zinc oxide-induced nephrotoxicity was confirmed by the elevation in serum inflammatory markers including: tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6); and C-reactive protein (CRP). Moreover, immunoglobulin (IGg), vascular endothelium growth factor (VEGF), and nitric oxide (NO) were significantly increased in rat serum. Serum urea and creatinine levels were also significantly increased in rats intoxicated with n-ZnO particles compared with the control group. Additionally, a significant decrease in the non-enzymatic antioxidant reduced glutathione (GSH) was shown in kidney tissues and serum glucose levels were increased. These biochemical findings were supported by a histopathological examination of kidney tissues, which showed that in the animals that received a high dose of n-ZnO, numerous kidney glomeruli underwent atrophy and fragmentation. Moreover, the renal tubules showed epithelial desquamation, degeneration and necrosis. Some renal tubules showed casts in their lumina. Severe congestion was also observed in renal interstitium. These effects were dose dependent. Cotreatment of rats with Qur and/or Arg along with n-ZnO significantly improved most of the deviated tested parameters. CONCLUSIONS: The data show that Qur has a beneficial effect against n-ZnO oxidative stress and related vascular complications. Also, its combination with Arg proved to be even more effective in ameliorating nano zinc oxide nephrotoxicity

Modelling real-world renewable hydrogen energy systems for enabling Scotland zero-carbon ambition.

Hydrogen is described as one of the most indicative scenarios for meeting Scotland Net-Zero carbon ambition set out for 2045. According to the 2021 Scottish Government’s hydrogen policy statement, the target is to invest 5 GW of renewable and low-carbon hydrogen by 2030 and to boost the planned capacity to 25 GW by 2045 to transform Scotland into a hydrogen nation. To enable meeting such ambitious goal and promoting the development of renewable hydrogen, there should be accurate dynamic modelling tools and approaches for simulating the entire operation of real-world renewable hydrogen energy systems and measuring realistic opportunities for decarbonizing miscellaneous energy sectors. This talk will investigate the potential of a precise dynamic model designed for sizing solar-hydrogen energy systems and accurately simulating their real-world dynamic behaviors in charging and discharging on-site hydrogen fuel considering an effective energy management operation that can ensure increased clean energy supply towards decarbonizing the Scottish building sector. The developed model has been tested and validated on a group of grid-connected buildings within a Scottish university and the obtained results have demonstrated effectiveness in planning the integration of renewable-hydrogen energy systems within grid-connected buildings

A comparative suitability study between classification systems for BIM in heritage

The research outlined in this paper is part of a collaborative fund to propose an innovative classification framework for restoration of historical/cultural heritage assets. Most of the previous research/applications in applying BIM to Heritage have focused on the physical or geometric reporting of assets. This typically involves laser scanning for creating as-built models and recording asset components, for operations and maintenance. However to efficiently identify/record general asset component requirements, standardised classification systems must be used which categorise different components, their characteristics, attributes, and maintenance requirements. Furthermore as will be demonstrated, current database, knowledge and classification systems available for new builds might not be suitable to categorise components in historical buildings, which differ according to historical eras and architectural periods, hence might render their restoration process inefficient. There is currently no research dedi- cated towards investigating appropriate classification systems to be used for heritage buildings. This paper provides a comparative study between current international classification systems within the construction industry, and investigates their suitability for heritage buildings. This includes CI/SFB, CAW, SFG20, Omniclass, Uniclass versions etc. Properties of suitability will also be investigated e.g. object types, hierarchy of tables/schedules, depth levels and appropriateness for different archi- tectural styles and parametric geometries (e.g. origin, material, allowed stresses, proportions etc.). This study provides evidence for the lack of appropriate classification systems for Heritage and provides recommendations for a taxonomical representation for suitable classification systems of Heritage assets from different historical and architectural periods. This includes information descriptors of hierarchical classes, historical, social and technological context, allowing usage of standardised Heritage BIM data for documentation, operations, maintenance and restoration management, and also allowing searching for similarities/differences between different buildings in the global heritage domain, replacement components and comparing artefacts, which might impact historical significance