ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC

A shared HLA-DRB1 epitope in the DR beta first domain is associated with Vogt-Koyanagi-Harada syndrome in Indian patients

PURPOSE: Vogt-Koyanagi-Harada (VKH) disease and sympathetic ophthalmia (SO) are two distinct entities that share common clinical and histopathological features; however, it remains unknown whether they have a common genetic susceptibility. Several studies have shown an association of human leukocyte antigen (HLA)-DR4 with VKH disease in patients of different ethnic backgrounds. We present in this paper the HLA-DRB1 genotyping analysis of a large cohort of VKH patients from southern India and compare these patients to patients with SO and to healthy individuals from the same geographic area. METHODS: VKH patients were diagnosed according to the revised criteria of the International Committee on VKH disease. Patients with granulomatous uveitis after ocular trauma or multiple eye surgeries were diagnosed as having SO. Genomic DNA was extracted from all patients and controls. Samples were analyzed for HLA-DRB1 alleles by reverse polymerase chain reaction (PCR) sequence-specific oligonucleotide (SSO) hybridization on microbeads, using the Luminex technology, and by PCR sequence-specific primers (SSP) typing for DRB1*04 allele determination. Strength of associations was estimated by odds ratios (OR) and 95% confidence intervals (CI) and frequencies were compared using the Fisher's exact test. RESULTS: HLA-DRB1 alleles were determined in 94 VKH patients, 39 SO patients, and 112 healthy controls. HLA-DRB1*04 frequency was higher in VKH patients (20.2% versus 10.3% in controls; OR=2.2, p=0.005, pc=0.067). This association was lower than the association of HLA-DRB1*04 frequency in cohorts of patients from different origins. No significant DR4 association with SO was detected. HLA-DRB1*0405 and HLA-DRB1*0410 alleles were significantly increased in VKH patients (8.5% versus 0.9% in controls; OR=10.3, 95% CI=2.34-45.5, p<0.001). These two alleles share the epitope S57-LLEQRRAA (67-74) in the third hypervariable region of the HLA-DR molecule. None of the DRB1 alleles was significantly associated with SO. CONCLUSIONS: Based on the association of HLA-DRB1*0405 and HLA-DRB1*0410 alleles with VKH disease, we propose that the epitope S57-LLEQRRAA (67-74) in the third hypervariable region of the HLA-DRbeta1 molecule is the relevant susceptibility epitope. This genetic component seems specific to VKH disease since no correlation could be identified in SO patients. The weaker association with HLA-DR4 in this VKH patient cohort compared to VKH patients from northern India is probably related to the lower frequency of HLA-DRB1*0405 in our study group. The HLA-DRB1 association with susceptibility to VKH syndrome seems weaker in Indian patients compared to Japanese or Hispanic patients, suggesting a different non-HLA immunogenetic background in Indian VKH patients

Performance study of ground-based infrared Bracewell interferometers - Application to the detection of exozodiacal dust disks with GENIE

Nulling interferometry, a powerful technique for high-resolution imaging of the close neighbourhood of bright astrophysical objets, is currently considered for future space missions such as Darwin or the Terrestrial Planet Finder Interferometer (TPF-I), both aiming at Earth-like planet detection and characterization. Ground-based nulling interferometers are being studied for both technology demonstration and scientific preparation of the Darwin/TPF-I missions through a systematic survey of circumstellar dust disks around nearby stars. In this paper, we investigate the influence of atmospheric turbulence on the performance of ground-based nulling instruments, and deduce the major design guidelines for such instruments. End-to-end numerical simulations allow us to estimate the performance of the main subsystems and thereby the actual sensitivity of the nuller to faint exozodiacal disks. Particular attention is also given to the important question of stellar leakage calibration. This study is illustrated in the context of GENIE, the Ground-based European Nulling Interferometer Experiment, to be installed at the VLTI and working in the L' band. We estimate that this instrument will detect exozodiacal clouds as faint as about 50 times the Solar zodiacal cloud, thereby placing strong constraints on the acceptable targets for Darwin/TPF-I.Comment: A&A, accepte

A Concurrent Tuple Set Architecture for Call Level Interfaces

Call Level Interfaces (CLI) are low level API aimed at providing services to connect two main components in database applications: client applications and relational databases. Among their functionalities, the ability to manage data retrieved from databases is emphasized. The retrieved data is kept in local memory structures that may be permanently connected to the host database. Client applications, beyond the ability to read their contents, may also execute Insert, Update and Delete actions over the local memory structures, following specific protocols. These protocols are row (tuple) oriented and, while being executed, cannot be preempted to start another protocol. This restriction leads to several difficulties when applications need to deal with several tuples at a time. The most paradigmatic case is the impossibility to cope with concurrent environments where several threads need to access to the same local memory structure instance, each one pointing to a different tuple and executing its particular protocol. To overcome the aforementioned fragility, a Concurrent Tuple Set Architecture (CTSA) is proposed to manage local memory structures. A performance assessment of a Java component based on JDBC (CLI) is also carried out and compared with a common approach. The main outcome of this research is the evidence that in concurrent environments, components relying on the CTSA may significantly improve the overall performance when compared with solutions based on standard JDBC API.(undefined

On the Linearization of the First and Second Painleve' Equations

We found Fuchs--Garnier pairs in 3X3 matrices for the first and second Painleve' equations which are linear in the spectral parameter. As an application of our pairs for the second Painleve' equation we use the generalized Laplace transform to derive an invertible integral transformation relating two its Fuchs--Garnier pairs in 2X2 matrices with different singularity structures, namely, the pair due to Jimbo and Miwa and the one found by Harnad, Tracy, and Widom. Together with the certain other transformations it allows us to relate all known 2X2 matrix Fuchs--Garnier pairs for the second Painleve' equation with the original Garnier pair.Comment: 17 pages, 2 figure

Mechanical Translation

Contains research objectives and reports on two research objectives.National Science Foundation (Grant GN-244

Evaluation of data-based estimates of anthropogenic carbon in the Arctic Ocean

The Arctic Ocean is particularly vulnerable to ocean acidification, a process that is mainly driven by the uptake of anthropogenic carbon (Cant) from the atmosphere. Although Cant concentrations cannot be measured directly in the ocean, they have been estimated using data-based methods such as the transient time distribution (TTD) approach, which characterizes the ventilation of water masses with inert transient tracers, such as CFC-12. Here, we evaluate the TTD approach in the Arctic Ocean using an eddying ocean model as a test bed. When the TTD approach is applied to simulated CFC-12 in that model, it underestimates the same model's directly simulated Cant concentrations by up to 12%, a bias that stems from its idealized assumption of gas equilibrium between atmosphere and surface water, both for CFC-12 and anthropogenic CO2. Unlike the idealized assumption, the simulated partial pressure of CFC-12 (pCFC-12) in Arctic surface waters is undersaturated relative to that in the atmosphere in regions and times of deep-water formation, while the simulated equivalent for Cant is supersaturated. After accounting for the TTD approach's negative bias, the total amount of Cant in the Arctic Ocean in 2005 increases by 8% to 3.3 ± 0.3 Pg C. By combining the adjusted TTD approach with scenarios of future atmospheric CO2, it is estimated that all Arctic waters, from surface to depth, would become corrosive to aragonite by the middle of the next century even if atmospheric CO2 could be stabilized at 540 ppm

Microconstriction Arrays for High-Throughput Quantitative Measurements of Cell Mechanical Properties

AbstractWe describe a method for quantifying the mechanical properties of cells in suspension with a microfluidic device consisting of a parallel array of micron-sized constrictions. Using a high-speed charge-coupled device camera, we measure the flow speed, cell deformation, and entry time into the constrictions of several hundred cells per minute during their passage through the device. From the flow speed and the occupation state of the microconstriction array with cells, the driving pressure across each constriction is continuously computed. Cell entry times into microconstrictions decrease with increased driving pressure and decreased cell size according to a power law. From this power-law relationship, the cell elasticity and fluidity can be estimated. When cells are treated with drugs that depolymerize or stabilize the cytoskeleton or the nucleus, elasticity and fluidity data from all treatments collapse onto a master curve. Power-law rheology and collapse onto a master curve are predicted by the theory of soft glassy materials and have been previously shown to describe the mechanical behavior of cells adhering to a substrate. Our finding that this theory also applies to cells in suspension provides the foundation for a quantitative high-throughput measurement of cell mechanical properties with microfluidic devices