Green-Kubo formula for weakly coupled system with dynamical noise

We study the Green-Kubo (GK) formula $\kappa (\varepsilon, \xi)$ for the heat conductivity of an infinite chain of $d$-dimensional finite systems (cells) coupled by a smooth nearest neighbour potential $\varepsilon V$. The uncoupled systems evolve according to Hamiltonian dynamics perturbed stochastically by an energy conserving noise of strength $\xi$. Noting that $\kappa (\varepsilon, \xi)$ exists and is finite whenever $\xi> 0$, we are interested in what happens when the strength of the noise $\xi \to 0$. For this, we start in this work by formally expanding $\kappa (\varepsilon, \xi)$ in a power series in $\varepsilon$, $\kappa (\varepsilon, \xi) = \varepsilon^2 \sum_{n\ge 2} \varepsilon^{n-2} \kappa_n (\xi)$ and investigating the (formal) equations satisfied by $\kappa_n (\xi$. We show in particular that $\kappa_2 (\xi)$ is well defined when no pinning potential is present, and coincides formally with the heat conductivity obtained in the weak coupling (van Hove) limit, where time is rescaled as $\varepsilon^{-2}t$, for the cases where the latter has been established \cite{LO, DL}. For one-dimensional systems, we investigate $\kappa_2 (\xi)$ as $\xi\to 0$ in three cases: the disordered harmonic chain, the rotor chain and a chain of strongly anharmonic oscillators. Moreover, we formally identify $\kappa_2 (\xi)$ with the conductivity obtained by having the chain between two reservoirs at temperature $T$ and $T+\delta T$, in the limit $\delta T\to 0$, $N \to \infty$, $\varepsilon \to 0$.Comment: New version with many improvement

Diagnostic performance of fractional excretion of urea in the evaluation of critically ill patients with acute kidney injury: a multicenter cohort study

International audienceINTRODUCTION: Several factors, including diuretic use and sepsis, interfere with the fractional excretion of sodium, which is used to distinguish transient from persistent acute kidney injury (AKI). These factors do not affect the fractional excretion of urea (FeUrea). However, there are conflicting data on the diagnostic accuracy of FeUrea. METHODS: We conducted an observational, prospective, multicenter study at three ICUs in university hospitals. Unselected patients, except those with obstructive AKI, were admitted to the participating ICUs during a six-month period. Transient AKI was defined as AKI caused by renal hypoperfusion and reversal within three days. The results are reported as medians (interquartile ranges). RESULTS: A total of 203 patients were included. According to our definitions, 67 had no AKI, 54 had transient AKI and 82 had persistent AKI. FeUrea was 39% (28 to 40) in the no-AKI group, 41% (29 to 54) in the transient AKI group and 32% (22 to 51) in the persistent AKI group (P = 0.12). FeUrea was of little help in distinguishing transient AKI from persistent AKI, with the area under the receiver operating characteristic curve being 0.59 (95% confidence interval, 0.49 to 0.70; P = 0.06). Sensitivity was 63% and specificity was 54% with a cutoff of 35%. In the subgroup of patients receiving diuretics, the results were similar. CONCLUSIONS: FeUrea may be of little help in distinguishing transient AKI from persistent AKI in critically ill patients, including those receiving diuretic therapy. Additional studies are needed to evaluate alternative markers or strategies to differentiate transient from persistent AKI

Identification of a Blood-Based Protein Biomarker Panel for Lung Cancer Detection

Lung cancer is the deadliest cancer worldwide, mainly due to its advanced stage at the time of diagnosis. A non-invasive method for its early detection remains mandatory to improve patients’ survival. Plasma levels of 351 proteins were quantified by Liquid Chromatography-Parallel Reaction Monitoring (LC-PRM)-based mass spectrometry in 128 lung cancer patients and 93 healthy donors. Bootstrap sampling and least absolute shrinkage and selection operator (LASSO) penalization were used to find the best protein combination for outcome prediction. The PanelomiX platform was used to select the optimal biomarker thresholds. The panel was validated in 48 patients and 49 healthy volunteers. A 6-protein panel clearly distinguished lung cancer from healthy individuals. The panel displayed excellent performance: area under the receiver operating characteristic curve (AUC) = 0.999, positive predictive value (PPV) = 0.992, negative predictive value (NPV) = 0.989, specificity = 0.989 and sensitivity = 0.992. The panel detected lung cancer independently of the disease stage. The 6-protein panel and other sub-combinations displayed excellent results in the validation dataset. In conclusion, we identified a blood-based 6-protein panel as a diagnostic tool in lung cancer. Used as a routine test for high- and average-risk individuals, it may complement currently adopted techniques in lung cancer screening.publishedVersio

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

Understanding dental CAD/CAM for restorations--accuracy from a mechanical engineering viewpoint.

International audienceAs is the case in the field of medicine, as well as in most areas of daily life, digital technology is increasingly being introduced into dental practice. Computer-aided design/ computer-aided manufacturing (CAD/CAM) solutions are available not only for chairside practice but also for creating inlays, crowns, fixed partial dentures (FPDs), implant abutments, and other dental prostheses. CAD/CAM dental practice can be considered as the handling of devices and software processing for the almost automatic design and creation of dental restorations. However, dentists who want to use dental CAD/CAM systems often do not have enough information to understand the variations offered by such technology practice. Knowledge of the random and systematic errors in accuracy with CAD/CAM systems can help to achieve successful restorations with this technology, and help with the purchasing of a CAD/CAM system that meets the clinical needs of restoration. This article provides a mechanical engineering viewpoint of the accuracy of CAD/ CAM systems, to help dentists understand the impact of this technology on restoration accuracy

Driving simulator scenarios and measures to faithfully evaluate risky driving behavior: A comparative study of different driver age groups.

To investigate the links between mental workload, age and risky driving, a cross-sectional study was conducted on a driving simulator using several established and some novel measures of driving ability and scenarios of varying complexity. A sample of 115 drivers was divided into three age and experience groups: young inexperienced (18-21 years old), adult experienced (25-55 years old) and older adult (70-86 years old). Participants were tested on three different scenarios varying in mental workload from low to high. Additionally, to gain a better understanding of individuals' ability to capture and integrate relevant information in a highly complex visual environment, the participants' perceptual-cognitive capacity was evaluated using 3-dimensional multiple object tracking (3D-MOT). Results indicate moderate scenario complexity as the best suited to highlight well-documented differences in driving ability between age groups and to elicit naturalistic driving behavior. Furthermore, several of the novel driving measures were shown to provide useful, non-redundant information about driving behavior, complementing more established measures. Finally, 3D-MOT was demonstrated to be an effective predictor of elevated crash risk as well as decreased naturally-adopted mean driving speed, particularly among older adults. In sum, the present experiment demonstrates that in cases of either extreme high or low task demands, drivers can become overloaded or under aroused and thus task measures may lose sensitivity. Moreover, insights from the present study should inform methodological considerations for future driving simulator research. Importantly, future research should continue to investigate the predictive utility of perceptual-cognitive tests in the domain of driving risk assessment

An experimental investigation into the spread and heat transfer dynamics of a train of two concentric impinging droplets over a heated surface

Extensive studies of two concentric droplets consecutively impinging over a thin heated foil surface are carried out to compare the spread and heat transfer dynamics of a single drop, and drop-on-drop configurations using high speed imaging and infrared thermography. Millimeter-sized deionized water droplets (2.80 ± 0.04 mm) are impinged upon a heated Inconel surface (thickness of 25 μm) from a fixed height corresponding to a Weber number (We) of 50 ± 2 and Reynolds number (Re) of 3180 ± 90 with a flow rate of 20 droplets per minute. Surface temperature is chosen as a parameter, and is varied from 22 °C (non-heated) to 175 °C. Temperature and heat flux distributions associated with droplet-surface interactions are obtained, and the outcomes of the process are measured in terms of spread diameter, droplet input heat transfer, dynamic contact angle, and surface mean temperature. A decline in the droplet heat transfer for drop-on-drop impingement is observed for all temperatures investigated in the present work. This is attributed to the surface pre-cooling by the initial droplet and also to the reduced surface area-to-volume ratio i.e., increased spreading film thickness. High heat transfer rates are observed around the three-phase contact line region, especially during the receding phase of the droplet, for both configurations, confirming the significance of contact line evaporation in droplet-hot wall interactions. Theoretical models predicting the maximum spread factor and corresponding input heat transfer into the droplet are identified from the literature, and found to be in good agreement with present experimental observations

A new ALK isoform transported by extracellular vesicles confers drug resistance to melanoma cells

Abstract Background Drug resistance remains an unsolved clinical issue in oncology. Despite promising initial responses obtained with BRAF and MEK kinase inhibitors, resistance to treatment develops within months in virtually all melanoma patients. Methods Microarray analyses were performed in BRAF inhibitor-sensitive and resistant cell lines to identify changes in the transcriptome that might play a role in resistance. siRNA approaches and kinase inhibitors were used to assess the involvement of the identified Anaplastic Lymphoma Kinase (ALK) in drug resistance. The capability of extracellular vesicles (EVs) to transfer drug resistant properties was investigated in co-culture assays. Results Here, we report a new mechanism of acquired drug resistance involving the activation of a novel truncated form of ALK. Knock down or inhibition of ALK re-sensitised resistant cells to BRAF inhibition and induced apoptosis. Interestingly, truncated ALK was also secreted into EVs and we show that EVs were the vehicle for transferring drug resistance. Conclusions To our knowledge, this is the first report demonstrating the functional involvement of EVs in melanoma drug resistance by transporting a truncated but functional form of ALK, able to activate the MAPK signalling pathway in target cells. Combined inhibition of ALK and BRAF dramatically reduced tumour growth in vivo. These findings make ALK a promising clinical target in melanoma patients