Oncogenic Signalling in t(12;21) Acute Lymphoblastic Leukaemia

The t(12;21)(p13;q22) translocation is present in up to 25% of children with pre-B cell Acute Lymphoblastic Leukaemia (ALL). This translocation involves two transcription factors, TEL (ETV6) and AML (RUNX1), both of which have crucial roles in regulating haematopoiesis. Clinically, TEL-AML1 positive patients have good prognoses. However, late relapses, additional genetic lesions affecting prognosis, and long-term side-effects of chemotherapy remain a cause for concern. In light of recent studies showing genetic and functional heterogeneities in cells responsible for cancer clone maintenance and propagation, targeting common deregulated pathways may be critical for the success of novel therapies. Using Affymetrix GeneChip global gene expression analysis our laboratory previously identified three genes: Tbx2, E2f5 and Lif-R, specifically expressed in TEL-AML1 transduced mouse foetal liver haematopoietic progenitor cells (HPC) cells compared with control cells. Over-expression of these genes was confirmed by real-time qPCR and the specificity of target gene expression was evaluated in human TEL-AML1 positive and negative leukaemia cells. Pathway analysis of TEL-AML1 transcriptional target genes also demonstrated deregulated expression of genes associated with STAT3 signalling, known to be one of the most important pathways required for proliferation and maintenance of multipotency in cancer stem cells. In this study we demonstrate the importance of STAT3 activity in a mouse model of TEL-AML1 overexpression, in human TEL-AML1 positive leukaemia cells and primary human leukaemic samples. Our data indicate a central role for TEL-AML1 in maintaining activated STAT3. This is mediated by transcriptional induction of the Guanine nucleotide exchange factor, ARHGEF4, leading to RAC1 activation and consequent stimulation of STAT3. The latter is necessary for survival, proliferation and self-renewal of TEL-AML1 positive leukaemia through transcriptional induction of MYC expression. In conclusion, we show a novel signalling pathway important for maintenance of t(12;21) leukaemia that constitutes a promising novel therapeutic target for the treatment of this disease

Synthetic aperture radar and optical remote sensing image fusion for flood monitoring in the Vietnam lower Mekong basin: a prototype application for the Vietnam Open Data Cube

Flood monitoring systems are crucial for flood management and consequence mitigation in flood prone regions. Different remote sensing techniques are increasingly used for this purpose. However, the different approaches suffer various limitations, including cloud and weather effects (optical data), and low spatial resolution and poor colour presentation (synthetic aperture radar data). This study fuses two data types (Landsat and Sentinel-1) to overcome these limitations and produce better quality images for a prototype flood application in the Vietnam Open Data Cube (VODC). Visual and quantitative evaluation of fused image quality revealed improvement in the images compared with the original scenes. Ground-truth data was used to develop the study flood extraction algorithm and we found a good agreement between our results and SERVIR Mekong (a joint initiative by the US agency for International Development (USAID), National Aeronautics and Space Administration (NASA), Myanmar, Thailand, Cambodia, Laos and Vietnam) maps. While the algorithm is run on a personal computer (PC), it has a clear potential to be developed for application on a big data system

Efficient Photon Upconversion Enabled by Strong Coupling Between Organic Molecules and Quantum Dots

Hybrid structures formed between organic molecules and inorganic quantum dots can accomplish unique photophysical transformations by taking advantage of their disparate properties. The electronic coupling between these materials is typically weak, leading photoexcited charge carriers to spatially localize to a dot or a molecule at its surface. However, we show that by converting a chemical linker that covalently binds anthracene molecules to silicon quantum dots from a carbon-carbon single bond to a double bond, we access a strong-coupling regime where excited carriers spatially delocalize across both anthracene and silicon. By pushing the system to delocalize, we design a photon upconversion system with a higher efficiency (17.2%) and lower threshold intensity (0.5 W/cm^2) than that of a corresponding weakly-coupled system. Our results show that strong coupling between molecules and nanostructures achieved through targeted linking chemistry provides a new route for tailoring properties in materials for light-driven applications.Comment: 33 pages (20 in main text, 13 in supporting information), 12 figures (5 in main text, 7 in supporting information

Novel role for polycystin-1 in modulating cell proliferation through calcium oscillations in kidney cells

Objectives: Polycystin-1 (PC1), a signalling receptor regulating Ca2+-permeable cation channels, is mutated in autosomal dominant polycystic kidney disease, which is typically characterized by increased cell proliferation. However, the precise mechanisms by which PC1 functions on Ca2+ homeostasis, signalling and cell proliferation remain unclear. Here, we investigated the possible role of PC1 as a modulator of non-capacitative Ca2+ entry (NCCE) and Ca2+ oscillations, with downstream effects on cell proliferation. Results and discussion: By employing RNA interference, we show that depletion of endogenous PC1 in HEK293 cells leads to an increase in serum-induced Ca2+ oscillations, triggering nuclear factor of activated T cell activation and leading to cell cycle progression. Consistently, Ca2+ oscillations and cell proliferation are increased in PC1-mutated kidney cystic cell lines, but both abnormal features are reduced in cells that exogenously express PC1. Notably, blockers of the NCCE pathway, but not of the CCE, blunt abnormal oscillation and cell proliferation. Our study therefore provides the first demonstration that PC1 modulates Ca2+ oscillations and a molecular mechanism to explain the association between abnormal Ca2+ homeostasis and cell proliferation in autosomal dominant polycystic kidney disease

Energy band diagram of device-grade silicon nanocrystals

This work was supported by the EPSRC (EP/K022237/1) and the Leverhulme International Network (IN-2012-136). SA would like to acknowledge the support of the Ulster University Vice-Chancellor's Research Studentship and CR that of the NI-DEL studentship.Device grade silicon nanocrystals (NCs) are synthesized using an atmospheric-pressure plasma technique. The Si NCs have a small and well defined size of about 2.3 nm. The synthesis system allows for the direct creation of thin films, enabling a range of measurements to be performed and easy implementation of this material in different devices. The chemical stability of the Si NCs is evaluated, showing relatively long-term durability thanks to hydrogen surface terminations. Optical and electrical characterization techniques, including Kelvin probe, ultraviolet photoemission spectroscopy and Mott-Schottky analysis, are employed to determine the energy band diagram of the Si NCs.Publisher PDFPeer reviewe

Diagnostic and prognostic microRNAs in the serum of breast cancer patients measured by droplet digital PCR

Background: Breast cancer circulating biomarkers include carcinoembryonic antigen and carbohydrate antigen 15-3, which are used for patient follow-up. Since sensitivity and specificity are low, novel and more useful biomarkers are needed. The presence of stable circulating microRNAs (miRNAs) in serum or plasma suggested a promising role for these tiny RNAs as cancer biomarkers. To acquire an absolute concentration of circulating miRNAs and reduce the impact of preanalytical and analytical variables, we used the droplet digital PCR (ddPCR) technique. Results: We investigated a panel of five miRNAs in the sera of two independent cohorts of breast cancer patients and disease-free controls. The study showed that miR-148b-3p and miR-652-3p levels were significantly lower in the serum of breast cancer patients than that in controls in both cohorts. For these two miRNAs, the stratification of breast cancer patients versus controls was confirmed by receiver operating characteristic curve analyses. In addition, we showed that higher levels of serum miR-10b-5p were associated with clinicobiological markers of poor prognosis. Conclusions: The study revealed the usefulness of the ddPCR approach for the quantification of circulating miRNAs. The use of the ddPCR quantitative approach revealed very good agreement between two independent cohorts in terms of comparable absolute miRNA concentrations and consistent trends of dysregulation in breast cancer patients versus controls. Overall, this study supports the use of the quantitative ddPCR approach for monitoring the absolute levels of diagnostic and prognostic tumor-specific circulating miRNAs

Ionic liquids as a neat lubricant applied to steel-steel contacts

This paper studies the use of 3 ionic liquids ([(NEMM)MOE][FAP], [BMP][FAP] and [BMP][NTf2]) as neat lubricant within steel-steel contact conditions. Tribological tests (at 40 and 100 C) were conducted in a HFRR tribometer and hence a complementary study was developed using a MTM tribometer. The wear surface on the discs was measured after the HFRR tests by confocal microscopy and also analyzed by SEM and XPS. The [BMP][NTf2] showed the lowest friction coefficient in the MTM and HFRR tests at 40 C but at 100 C its tribological behavior worsened due to its lowest viscosity. Similar results were found for wear behavior. Both antifriction and antiwear results were related to the tribofilms formation from the ECR and XPS measurements. © 2013 Elsevier Ltd

FAP- Anion Ionic Liquids Used in the Lubrication of a Steel–Steel Contact

This study compares the tribological behavior of two ionic liquids ([BMP][FAP] and [(NEMM)MOE][FAP]) used as oil additive for the lubrication of a steel–steel contact. Friction and wear experiments were performed using a HFRR test machine. Friction coefficient and electrical contact resistance were measured during the tests, and the wear surface was analyzed by confocal microscopy and XPS. The tribological results showed that both ionic liquids used as additive decrease friction and wear but the [BMP][FAP] had a better performance than the [(NEMM)MOE][FAP] due to its higher reactivity with the steel

Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape

Hotspot mutations in the PEST-domain of NOTCH1 and NOTCH2 are recurrently identified in B cell malignancies. To address how NOTCH-mutations contribute to a dismal prognosis, we have generated isogenic primary human tumor cells from patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), differing only in their expression of the intracellular domain (ICD) of NOTCH1 or NOTCH2. Our data demonstrate that both NOTCH-paralogs facilitate immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-? signaling. In addition, NOTCH-activation causes silencing of the entire HLA-class II locus via epigenetic regulation of the transcriptional co-activator CIITA. Notably, while NOTCH1 and NOTCH2 govern similar transcriptional programs, disease-specific differences in their expression levels can favor paralog-specific selection. Importantly, NOTCH-ICD also strongly down-regulates the expression of CD19, possibly limiting the effectiveness of immune-therapies. These NOTCH-mediated immune escape mechanisms are associated with the expansion of exhausted CD8+ T cells in vivo.© 2022. The Author(s)

Multimorphic Materials: Spatially Tailoring Mechanical Properties via Selective Initiation of Interpenetrating Polymer Networks

Access to multimaterial polymers with spatially localized properties and robust interfaces is anticipated to enable new capabilities in soft robotics, such as smooth actuation for advanced medical and manufacturing technologies. Here, orthogonal initiation is used to create interpenetrating polymer networks (IPNs) with spatial control over morphology and mechanical properties. Base catalyzes the formation of a stiff and strong polyurethane, while blue LEDs initiate the formation of a soft and elastic polyacrylate. IPN morphology is controlled by when the LED is turned „on‟, with large phase separation occurring for short time delays (~1-2 minutes) and a mixed morphology for longer time delays (>5 minutes), which was supported by dynamic mechanical analysis, small angle X-ray scattering, and atomic force microscopy. Through tailoring morphology, tensile moduli and fracture toughness can be tuned across ~1-2 orders of magnitude. Moreover, a simple spring model is used to explain the observed mechanical behavior. Photopatterning produces “multimorphic” materials, where morphology is spatially localized with fine precision (<100 µm), while maintaining a uniform chemical composition throughout to mitigate interfacial failure. The fabrication of hinges represents a possible use-case for multimorphic materials in soft robotics.This work was primarily supported by the National Science Foundation under Grant No. DMR- 2045336 (M.J.A., C. B., and Z.A.P., synthesis and mechanical characterization). Partial support was provided from the U.S. Department of Energy, Office of Science, Basic Energy Sciences under Award #DE-SC0022050 (N.P. and X. G., morphology characterization related to scattering and AFM-IR) and through the Center for Materials for Water and Energy Systems (M-WET), an Energy Frontier Research Center under Award #DE-SC0019272 (M.J.A. and B.D.F., nanoindentation characterization), the National Science Foundation under Grant No. CMMI-2038512 (L.M.C., AFM fast force distance mapping characterization), NSF Graduate Research Fellowship under Grant No. DGE-1610403 (M.J.A.), and the Robert A. Welch Foundation under Grant No. F-2007 (Z.A.P., partial materials and supplies support). The authors acknowledge the use of shared research facilities supported in part by the Texas Materials Institute and the Center for Dynamics and Control of Materials (NSF MRSEC) under Grant No. DMR-1720595.Center for Dynamics and Control of Material