Low-Velocity Impact Response And Experimental Optimization Of Modified Fiber Metal Laminates With Integrated Mechanical Interlock Bonding System

This paper presents a modified version of fiber metal laminates with integrated mechanical interlock bonding system for aerospace applications. Sheet metals of Al 2024-T3 with surface machined infinitesimal hooks are used along with impregnated glass fiber composites to manufacture a modified version of GLAss REinforced aluminum (GLARE). Low-velocity impact responses of the modified GLARE is examined using a drop weight impact testing machine at an impact energy of 7.5 J. To optimize the geometry of the machined hooks to maximize the modified GLARE low-velocity impact resistance, we developed and tested four configurations of modified GLARE with four variants of hooks’ geometry, including two hook sizes, namely, nano and micro and two hook profiles, namely, curved and straight. Impact tests show that modified GLARE with Straight Nano Hooks (SNH) have comparable dynamic responses to the standard GLARE (without hooks), while experiencing much less delamination and fiber damage. Microscopic inspection of the four configurations of modified GLARE also illustrates that SNHs generate modified GLARE with minimal manufacturing defects. The results obtained indicate that SNH is the optimum hook geometry for the development of modified GLARE. It can be considered as an alternative surface treatment for sheet metals in FML development process as it offers a modified version of the material with comparable impact responses to those manufactured by the industrial standard methodology but at a fraction of production cost

Raman depolarization ratios in RNA and DNA are sensitive for sugar-base coupling

Polarized and depolarized Raman spectra are obtained for a number of synthetic polynucleotides containing adenine, uracil, and thymine bases. The depolarization ratios are determined by two methods: (1) by dividing the -spectrum by the -spectrum and (2) after curve fitting. Overlapping bands, isotope splitting, reorientational broadening, and noncoincidence splitting affect the magnitude of the depolarization ratios over the band-width. For both Lorentz and Gauss curves these influences are simulated. A comparison of the Raman spectra of RNA and DNA molecules shows that the depolarization ratios for a number of similar base vibrations are different. The vibrational modes and the depolarization ratios of sugar vibrations are most sensitive to the structure of the polynucleotide. Base vibrations that have their potential energy distributed over base and sugar atoms also seem to be more sensitive to the structure. For instance the adenine vibrations at 1332 cm-1 and 1344 cm-1 in poly(dA), poly(dA) · poly(dT) and poly(dA-dT) · poly(dA-dT) have different depolarization ratios of, respectively, 0.36 and 0.28. This supports a previous assignment of the 1332 cm-1 band to a different sugar pucker (O4,-endo) than the C2,-endo corresponding with the 1344 cm-1 vibration. Assuming equal Raman scattering coefficients for this vibration, irrespective of the sugar pucker gives rise to the following ratio of the O4,-endo/C2,-endo in poly(dA) of 0.41, in poly(dA) · poly(dT) of 0.37, and in poly(dA-dT) · poly(dA-dT) of 0.41

Identifying and targeting cancer-specific metabolism with network-based drug target prediction

Background Metabolic rewiring allows cancer cells to sustain high proliferation rates. Thus, targeting only the cancer-specific cellular metabolism will safeguard healthy tissues. Methods We developed the very efficient FASTCORMICS RNA-seq workflow (rFASTCORMICS) to build 10,005 high-resolution metabolic models from the TCGA dataset to capture metabolic rewiring strategies in cancer cells. Colorectal cancer (CRC) was used as a test case for a repurposing workflow based on rFASTCORMICS. Findings Alternative pathways that are not required for proliferation or survival tend to be shut down and, therefore, tumours display cancer-specific essential genes that are significantly enriched for known drug targets. We identified naftifine, ketoconazole, and mimosine as new potential CRC drugs, which were experimentally validated. Interpretation The here presented rFASTCORMICS workflow successfully reconstructs a metabolic model based on RNA-seq data and successfully predicted drug targets and drugs not yet indicted for colorectal cancer

Some elements for a history of the dynamical systems theory

Leon Glass would like to thank the Natural Sciences and Engineering Research Council (Canada) for its continuous support of curiosity-driven research for over 40 years starting with the events recounted here. He also thanks his colleagues and collaborators including Stuart Kauffman, Rafael Perez, Ronald Shymko, Michael Mackey for their wonderful insights and collaborations during the times recounted here. R.G. is endebted to the following friends and colleagues, listed in the order encountered on the road described: F. T. Arecchi, L. M. Narducci, J. R. Tredicce, H. G. Solari, E. Eschenazi, G. B. Mindlin, J. L. Birman, J. S. Birman, P. Glorieux, M. Lefranc, C. Letellier, V. Messager, O. E. Rössler, R. Williams. U.P. would like to thank the following friends and colleagues who accompanied his first steps into the world of nonlinear phenomena: U. Dressler, I. Eick, V. Englisch, K. Geist, J. Holzfuss, T. Klinker, W. Knop, A. Kramer, T. Kurz, W. Lauterborn, W. Meyer-Ilse, C. Scheffczyk, E. Suchla and M. Wisenfeldt. The work by L. Pecora and T. Carroll was supported directly by the Office of Naval Research (ONR) and by ONR through the Naval Research Laboratory’s Basic Research Program. C.L. would like to thank Jürgen Kurths for his support to this project.Peer reviewedPostprintPublisher PD

Smell and taste changes are early indicators of the COVID-19 pandemic and political decision effectiveness

In response to the COVID-19 pandemic, many governments have taken drastic measures to avoid an overflow of intensive care units. Accurate metrics of disease spread are critical for the reopening strategies. Here, we show that self-reports of smell/taste changes are more closely associated with hospital overload and are earlier markers of the spread of infection of SARS-CoV-2 than current governmental indicators. We also report a decrease in self-reports of new onset smell/taste changes as early as 5 days after lockdown enforcement. Cross-country comparisons demonstrate that countries that adopted the most stringent lockdown measures had faster declines in new reports of smell/taste changes following lockdown than a country that adopted less stringent lockdown measures. We propose that an increase in the incidence of sudden smell and taste change in the general population may be used as an indicator of COVID-19 spread in the population

Relationship Between Mitochondrial Electron Transport Chain Dysfunction, Development, and Life Extension in Caenorhabditis elegans

Prior studies have shown that disruption of mitochondrial electron transport chain (ETC) function in the nematode Caenorhabditis elegans can result in life extension. Counter to these findings, many mutations that disrupt ETC function in humans are known to be pathologically life-shortening. In this study, we have undertaken the first formal investigation of the role of partial mitochondrial ETC inhibition and its contribution to the life-extension phenotype of C. elegans. We have developed a novel RNA interference (RNAi) dilution strategy to incrementally reduce the expression level of five genes encoding mitochondrial proteins in C. elegans: atp-3, nuo-2, isp-1, cco-1, and frataxin (frh-1). We observed that each RNAi treatment led to marked alterations in multiple ETC components. Using this dilution technique, we observed a consistent, three-phase lifespan response to increasingly greater inhibition by RNAi: at low levels of inhibition, there was no response, then as inhibition increased, lifespan responded by monotonically lengthening. Finally, at the highest levels of RNAi inhibition, lifespan began to shorten. Indirect measurements of whole-animal oxidative stress showed no correlation with life extension. Instead, larval development, fertility, and adult size all became coordinately affected at the same point at which lifespan began to increase. We show that a specific signal, initiated during the L3/L4 larval stage of development, is sufficient for initiating mitochondrial dysfunction–dependent life extension in C. elegans. This stage of development is characterized by the last somatic cell divisions normally undertaken by C. elegans and also by massive mitochondrial DNA expansion. The coordinate effects of mitochondrial dysfunction on several cell cycle–dependent phenotypes, coupled with recent findings directly linking cell cycle progression with mitochondrial activity in C. elegans, lead us to propose that cell cycle checkpoint control plays a key role in specifying longevity of mitochondrial mutants

IWGSC Sequence Repository: Moving towards tools to facilitate data integration for the reference sequence of wheat

URGI is a genomics and bioinformatics research unit at INRA (French National institute for Agricultural Research), dedicated to plants and crop parasites. We develop and maintain a genomic and genetic Information System called GnpIS that manages multiple types of wheat data. Under the umbrella of the IWGSC (International Wheat Genome Sequencing Consortium), we have set up a Sequence Repository on the Wheat@URGI website to store, browse and BLAST the data being generated by the wheat genome project: http://wheat-urgi.versailles.inra.fr/Seq-Repository. The repository holds the wheat physical maps, the chromosome survey sequence data for the individual chromosomes of breadwheat, draft sequences for diploid and tetraploid wheats and provides browsable access to the BAC-based reference sequence for chromosome 3B, the first of the chromosomes to be completed by the consortium. I will highlight the new features and data available in the Sequence Repository (e.g., new BLAST functionalities) and, in particular, present what we have done to address needs and concerns raised during the IWGSC S&P workshop last year. In addition, I will open the discussion about the future needs for tools to facilitate the integration of data to produce the reference sequence

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping

Integrated In Vitro and In Silico Modeling Delineates the Molecular Effects of a Synbiotic Regimen on Colorectal-Cancer-Derived Cells

By modulating the human gut microbiome, prebiotics and probiotics (combinations of which are called synbiotics) may be used to treat diseases such as colorectal cancer (CRC). Methodological limitations have prevented determining the potential combina- torial mechanisms of action of such regimens. We expanded our HuMiX gut-on-a-chip model to co-culture CRC-derived epithelial cells with a model probiotic under a simulated prebiotic regimen, and we integrated the multi-omic results with in silico metabolic modeling. In contrast to individual prebi- otic or probiotic treatments, the synbiotic regimen caused downregulation of genes involved in procarci- nogenic pathways and drug resistance, and reduced levels of the oncometabolite lactate. Distinct ratios of organic and short-chain fatty acids were produced during the simulated regimens. Treatment of primary CRC-derived cells with a molecular cocktail reflecting the synbiotic regimen attenuated self-renewal ca- pacity. Our integrated approach demonstrates the potential of modeling for rationally formulating synbi- otics-based treatments in the future