High-throughput phenotyping is becoming increasingly available thanks to analytical and bioinformatics approaches that enable the use of very high-dimensional data and to the availability of dynamic ...models that link phenomena across levels: from genes to cells, from cells to organs, and through the whole organism. The combination of phenomics, deep learning, and machine learning represents a strong potential for the phenotypical investigation, leading the way to a more embracing approach, called machine learning phenomics (MLP). In particular, in this work we present a novel MLP platform for phenomics investigation of cancer-cells response to therapy, exploiting and combining the potential of time-lapse microscopy for cell behavior data acquisition and robust deep learning software architectures for the latent phenotypes extraction. A two-step proof of concepts is designed. First, we demonstrate a strict correlation among gene expression and cell phenotype with the aim to identify new biomarkers and targets for tailored therapy in human colorectal cancer onset and progression. Experiments were conducted on human colorectal adenocarcinoma cells (DLD-1) and their profile was compared with an isogenic line in which the expression of LOX-1 transcript was knocked down. In addition, we also evaluate the phenotypic impact of the administration of different doses of an antineoplastic drug over DLD-1 cells. Under the omics paradigm, proteomics results are used to confirm the findings of the experiments.
•ZrB2-based UHTCMC with carbon fibers tested in supersonic arc-jet wind tunnel.•Temperature jump on the front surfaces, at specific total enthalpies over 18 MJ/kg.•Excellent erosion resistance, ...despite formation of a porous oxide layer.•Jump related to increase in surface catalycity and reduction of thermal conductivity.
An experimental campaign has been carried out to characterize a new class of Ultra-High-Temperature Ceramic Matrix Composites for near-zero ablation Thermal Protection Systems. Small-sized specimens, with ZrB2-based matrix and different carbon fiber architectures, were exposed to a simulated air supersonic flow generated by an arc-jet wind tunnel, achieving specific total enthalpies up to 20 MJ/kg and cold wall fully catalytic heat fluxes over 5 MW/m2, in an aero-thermo-chemical environment representative of atmospheric re-entry. Ablation rates were estimated by means of mass and thickness measurements before and after testing, demonstrating an excellent performance of the developed materials. Surface temperatures were monitored by means of infrared pyrometers and a thermo-camera, and during all the tests a spontaneous temperature jump was observed, with temperatures that reached values over 2800 K at the steady state. Post-test microstructural analyses revealed the formation of a porous oxide layer with a thickness of few hundred microns, mainly consisting of zirconia, with substantial removal of both SiC and carbon fibers. Below the oxide, the bulk material was unaffected. Computational Fluid Dynamics simulations allowed rebuilding the thermo-fluid-dynamic and chemical flow field. Moreover, it was possible to propose an innovative correlation of the temperature jump with an increased catalytic activity and a dramatic reduction of the thermal conductivity of the oxide layers forming on the exposed part of the sample, which anyway had a key role in preserving the unoxidized bulk materials at reasonable temperatures.
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We describe a novel method to achieve a universal, massive, and fully automated analysis of cell motility behaviours, starting from time-lapse microscopy images. The approach was inspired by the ...recent successes in application of machine learning for style recognition in paintings and artistic style transfer. The originality of the method relies i) on the generation of atlas from the collection of single-cell trajectories in order to visually encode the multiple descriptors of cell motility, and ii) on the application of pre-trained Deep Learning Convolutional Neural Network architecture in order to extract relevant features to be used for classification tasks from this visual atlas. Validation tests were conducted on two different cell motility scenarios: 1) a 3D biomimetic gels of immune cells, co-cultured with breast cancer cells in organ-on-chip devices, upon treatment with an immunotherapy drug; 2) Petri dishes of clustered prostate cancer cells, upon treatment with a chemotherapy drug. For each scenario, single-cell trajectories are very accurately classified according to the presence or not of the drugs. This original approach demonstrates the existence of universal features in cell motility (a so called "motility style") which are identified by the DL approach in the rationale of discovering the unknown message in cell trajectories.
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•ZrB2-SiC-WC was tested in supersonic arc-jet wind tunnel.•Flows with different chemical composition, simulated air and pure nitrogen, were studied.•Surface temperatures achieved ...2650–2800 K at specific total enthalpies up to 20 MJ/kg.•Oxygen in the high-enthalpy flow is beneficial in retarding the material consumption.•5 vol% of W-compounds is sufficient to govern the composite subscale oxide configuration.
A super-strong ZrB2 ceramic containing WC and SiC was tested in a supersonic arc-jet wind tunnel by exposure to flows with two chemical compositions, simulated air or pure nitrogen, at temperatures of 2650 and 2800 K. Temperature jumps of 500–600 K were observed in both environments at constant flow conditions. SEM analyses revealed that oxygen in the high-enthalpy flow retards the material consumption owing to the formation of partially protective glass. Then, it appears that even 5 vol% of W-compounds is sufficient to modify the subscale oxide configuration and form a cell-like multi-layered architecture typical of tungsten, rather than that typical of ZrB2.
An analytical model to predict the longitudinal acoustic modes of hybrid rocket combustion chambers is presented. In the classical motor configuration, a dump plenum and an aft-mixing chamber are ...mated to the solid fuel grain; this arrangement produces cross-sectional discontinuities that vary over the motor firing because of the widening of the fuel port. This feature mainly, in conjunction with mixture-ratio shift in the motor operation to a much lesser degree, usually induces a change of the frequency of longitudinal modes during combustion. Furthermore, in the combustion chamber there is an axial gradient of the speed of sound, which has an influence on the mode characteristics. The model developed here accounts for both the cross-sectional area discontinuities and the axial variations of temperature and gas composition, assuming a linear trend of the squared speed of sound from the injection head to the exhaust nozzle entrance, and zero mean flow. Comparison with the results computed with a comprehensive one-dimensional model, which considers also the effects of the vaporizing fuel mass injection and of the actual temperature variation in the chamber, reveals maximum deviations around 3%. Finally, the model has been employed to predict the first longitudinal acoustic mode frequency measured versus time in a couple of firing tests of a laboratory-scale rocket showing fairly good agreement.
•Two novel test set-ups for high-temperature testing of materials for rocket nozzles.•ZrB2-based UHTCMCs with carbon fibers tested in high heat flux environment.•Temperature exceeded 2900 K for ...samples with higher erosion rates.•Excellent erosion resistance with respect to state-of-art materials.•Optimized manufacturing process favors thermal shock resistance.
This paper presents the results of experimental tests for the characterization of Ultra-High-Temperature Ceramic Matrix Composite (UHTCMC) materials for near-zero erosion rocket nozzles. Two dedicated test set-ups were developed for preliminary screening of material candidates in a representative environment, characterized by relevant heat flux and temperature. The experimental set-up was based on a lab-scale 200N-class hybrid rocket engine, employing gaseous oxygen as the oxidizer and High-Density PolyEthylene as fuel; the configurations included free-jet test, in which small button-like samples were exposed to the supersonic exhaust jet of the rocket nozzle; and chamber inserts, in the shape and size of an annular element, placed inside the rocket combustion chamber. Computational Fluid Dynamic simulations, for modeling heat transfer and combustion chemical reactions, complemented the experimental observations and supported the characterization of test conditions. Samples with ZrB2-SiC matrix and continuous or chopped carbon fibers, sintered by either Hot Pressing or Spark Plasma Sintering were tested. Free-jet test samples demonstrated a substantially improved erosion resistance with respect to conventional graphite and in one case a negligible material recession. UHTCMC samples erosion was associated to the occurrence of a rapid rise in surface temperature, which achieved values over 2900 K. Chamber inserts, besides confirming the outstanding erosion resistance of UHTCMCs with respect to traditional materials (i.e. C/SiC), proved that long-fibers samples with sufficient porosity are more likely to withstand thermal shocks typical of the rocket combustion environment.
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Longitudinal clinical registry-infrastructures such as Anti-Rheumatic Therapies in Sweden (ARTIS) allow simultaneous comparison of the safety of individual immunomodulatory drugs used in clinical ...practice, with consistent definitions of treatment cohorts, follow-up and outcomes. Our objective was to assess and compare incidence rates of key safety outcomes for individual targeted synthetic or biological disease-modifying antirheumatic drugs (b/ts DMARDs) in rheumatoid arthritis (RA), updating previous reports and including newer treatments including Janus Kinase inhibitors (JAKi).
Nationwide register-based cohort study including all patients with RA in Sweden registered as starting any b/tsDMARD 1 January 2010 through 31 December 2020, followed until 30 June 2021 (N=20 117). The incidence rates of selected outcomes, identified through national healthcare registers, were compared between individual b/tsDMARDs, adjusted for confounding by demographics, RA disease characteristics and comorbidity.
There were marked differences in treatment discontinuations due to adverse events (rates per 1000 person-years ranged from 18 on rituximab to 57 on tofacitinib), but few significant differences were observed for the serious adverse events under study. Neither cardiovascular events nor general serious infections were more frequent on baricitinib or tofacitinib versus bDMARDs, but JAKi were associated with higher rates of hospital-treated herpes zoster (HR vs etanercept, 3.82 (95% CI 2.05 to 7.09) and 4.00 (1.59 to 10.06)). Low number of events limited some comparisons, in particular for sarilumab and tofacitinib.
Data from ARTIS supports that the b/tsDMARDs currently used to treat RA have acceptable and largely similar safety profiles, but differences exist in particular concerning tolerability and specific infection risks.
Cell-cell interactions are an observable manifestation of underlying complex biological processes occurring in response to diversified biochemical stimuli. Recent experiments with microfluidic ...devices and live cell imaging show that it is possible to characterize cell kinematics via computerized algorithms and unravel the effects of targeted therapies. We study the influence of spatial and temporal resolutions of time-lapse videos on motility and interaction descriptors with computational models that mimic the interaction dynamics among cells. We show that the experimental set-up of time-lapse microscopy has a direct impact on the cell tracking algorithm and on the derived numerical descriptors. We also show that, when comparing kinematic descriptors in two diverse experimental conditions, too low resolutions may alter the descriptors' discriminative power, and so the statistical significance of the difference between the two compared distributions. The conclusions derived from the computational models were experimentally confirmed by a series of video-microscopy acquisitions of co-cultures of unlabelled human cancer and immune cells embedded in 3D collagen gels within microfluidic devices. We argue that the experimental protocol of acquisition should be adapted to the specific kind of analysis involved and to the chosen descriptors in order to derive reliable conclusions and avoid biasing the interpretation of results.
We aimed to describe the uptake of newer biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in psoriatic arthritis (PsA) in the Nordic countries and to compare their ...retention and effectiveness.
Patients with PsA starting a b/tsDMARD in 2012-2020 in five Nordic rheumatology registers were included. Uptake and patient characteristics were described, with comorbidities identified from linkages to national patient registries. One-year retention and 6-month effectiveness (proportions achieving low disease activity (LDA) on the Disease Activity Index for PSoriatic Arthritis based on 28-joint evaluation) for the newer b/tsDMARDs (abatacept/apremilast/ixekizumab/secukinumab/tofacitinib/ustekinumab) were compared with adalimumab through adjusted regression models stratified by treatment course (first, second/third, and fourth or more).
In total, 5659 treatment courses with adalimumab (56% biologic-naïve) and 4767 courses with a newer b/tsDMARD (21% biologic-naïve) were included. The uptake of newer b/tsDMARDs increased from 2014 and plateaued in 2018. Patient characteristics appeared similar across treatments at treatment start. Adalimumab was more often used as the first course and newer b/tsDMARDs more often in biologic-experienced patients. Used as a second/third b/tsDMARD, the retention rate and the proportion achieving LDA were significantly better for adalimumab (rate 65%, proportion 59%) compared with abatacept (45%, 37%), apremilast (43%, 35%), ixekizumab (LDA only, 40%) and ustekinumab (LDA only, 40%), but not significantly different from other b/tsDMARDs.
Uptake of newer b/tsDMARDs occurred mainly in biologic-experienced patients. Regardless of mode of action, only a minority of patients starting a second or later b/tsDMARD course remained on drug and achieved LDA. Superior outcomes for adalimumab indicate that the positioning of newer b/tsDMARDs in the PsA treatment algorithm remains to be established.
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