A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers.

mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA- HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy

Parrot beak‐inspired metamaterials with friction and interlocking mechanisms 3D/4D printed in micro and macro scales for supreme energy absorption/dissipation

Energy absorption and dissipation features of mechanical metamaterials have widespread applications in everyday life, ranging from absorbing shock impacts to mechanical vibrations. This article proposes novel bioinspired friction-based mechanical metamaterials with a zero Poisson's ratio behavior inspired from parrot's beaks and manufactured additively. The mechanical performances of the corresponding metamaterials are studied at both macro and micro scales by experiments and finite element analysis (FEA). An excellent agreement is observed between the FEA and both microscopic and macroscopic scale experiments, showing the accuracy of the developed digital tool. Performances are compared to traditional triangular lattice metamaterials. Both experimental tests and FEA results demonstrate the following advantages: 1) absorbing and dissipating energy per unit of mass (SEA) at large compressive strains without global buckling; 2) bistable deformation patterns including friction-based and interlocking mechanisms; 3) reversible deformation patterns after unloading; 4) shape recovery behavior after a heating–cooling process; and 5) the higher elastic modulus of micro metamaterials compared with their macro counterparts. This is the first demonstration of a bioinspired friction-based design of 3D-printed mechanical metamaterials that feature absorbing/dissipating energy, stability, and reversibility properties to cater to a wide range of sustainable meta-cylinders in micro and macro scales

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Desing and Validation of a Light Inference System to Support Embedded Context Reasoning

Embedded context management in resource-constrained devices (e.g. mobile phones, autonomous sensors or smart objects) imposes special requirements in terms of lightness for data modelling and reasoning. In this paper, we explore the state-of-the-art on data representation and reasoning tools for embedded mobile reasoning and propose a light inference system (LIS) aiming at simplifying embedded inference processes offering a set of functionalities to avoid redundancy in context management operations. The system is part of a service-oriented mobile software framework, conceived to facilitate the creation of context-aware applications—it decouples sensor data acquisition and context processing from the application logic. LIS, composed of several modules, encapsulates existing lightweight tools for ontology data management and rule-based reasoning, and it is ready to run on Java-enabled handheld devices. Data management and reasoning processes are designed to handle a general ontology that enables communication among framework components. Both the applications running on top of the framework and the framework components themselves can configure the rule and query sets in order to retrieve the information they need from LIS. In order to test LIS features in a real application scenario, an ‘Activity Monitor’ has been designed and implemented: a personal health-persuasive application that provides feedback on the user’s lifestyle, combining data from physical and virtual sensors. In this case of use, LIS is used to timely evaluate the user’s activity level, to decide on the convenience of triggering notifications and to determine the best interface or channel to deliver these context-aware alerts.

Cohort Randomised Controlled Trial of a Multifaceted Podiatry Intervention for the Prevention of Falls in Older People (The REFORM Trial)

BACKGROUND: Falls are a major cause of morbidity among older people. A multifaceted podiatry intervention may reduce the risk of falling. This study evaluated such an intervention. DESIGN: Pragmatic cohort randomised controlled trial in England and Ireland. 1010 participants were randomised (493 to the Intervention group and 517 to Usual Care) to either: a podiatry intervention, including foot and ankle exercises, foot orthoses and, if required, new footwear, and a falls prevention leaflet or usual podiatry treatment plus a falls prevention leaflet. The primary outcome was the incidence rate of self-reported falls per participant in the 12 months following randomisation. Secondary outcomes included: proportion of fallers and those reporting multiple falls, time to first fall, fear of falling, Frenchay Activities Index, Geriatric Depression Scale, foot pain, health related quality of life, and cost-effectiveness. RESULTS: In the primary analysis were 484 (98.2%) intervention and 507 (98.1%) control participants. There was a small, non statistically significant reduction in the incidence rate of falls in the intervention group (adjusted incidence rate ratio 0.88, 95% CI 0.73 to 1.05, p = 0.16). The proportion of participants experiencing a fall was lower (49.7 vs 54.9%, adjusted odds ratio 0.78, 95% CI 0.60 to 1.00, p = 0.05) as was the proportion experiencing two or more falls (27.6% vs 34.6%, adjusted odds ratio 0.69, 95% CI 0.52 to 0.90, p = 0.01). There was an increase (p = 0.02) in foot pain for the intervention group. There were no statistically significant differences in other outcomes. The intervention was more costly but marginally more beneficial in terms of health-related quality of life (mean quality adjusted life year (QALY) difference 0.0129, 95% CI -0.0050 to 0.0314) and had a 65% probability of being cost-effective at a threshold of £30,000 per QALY gained. CONCLUSION: There was a small reduction in falls. The intervention may be cost-effective. TRIAL REGISTRATION: ISRCTN ISRCTN68240461

Belle II Technical Design Report

The Belle detector at the KEKB electron-positron collider has collected almost 1 billion Y(4S) events in its decade of operation. Super-KEKB, an upgrade of KEKB is under construction, to increase the luminosity by two orders of magnitude during a three-year shutdown, with an ultimate goal of 8E35 /cm^2 /s luminosity. To exploit the increased luminosity, an upgrade of the Belle detector has been proposed. A new international collaboration Belle-II, is being formed. The Technical Design Report presents physics motivation, basic methods of the accelerator upgrade, as well as key improvements of the detector.Comment: Edited by: Z. Dole\v{z}al and S. Un

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom

Uncovering the potentialities of protic ionic liquids based on alkanolammonium and carboxylate ions and their aqueous solutions as non-derivatizing solvents of Kraft lignin

The present study scrutinized in depth the ability of alkanolammonium-based Protic Ionic Liquids (PILs) with carboxylate anions to dissolve Kraft lignin at 323.15 K. A focus was put on understanding the role of both PIL ions and water on the dissolution process. The results demonstrated that the anion plays a more important role in lignin dissolution than the cation. Furthermore, lignin dissolution was favored by increasing the alkyl chain of the carboxylate anion, while a smaller cation with lower number of hydroxyalkyl groups performed better. Among the studied solvents, the 2-hydroxyethylammonium hexanoate (HEAH) displayed the highest lignin solubility (37 wt%). In general, the addition of water had a negative influence on lignin solubility with the tested PILs. A sharp decrease in lignin solubility curves of 2-hydroxyethylammonium formate (HEAF) and acetate (HEAA) was observed, while a more softly effect was observed for 2-hydroxyethylammonium propionate (HEAP) and HEAH with the addition of water. However, a distinct behavior was observed for 2-hydroxyethylammonium octanoate (HEAO) that acted as hydrotrope enhancing lignin solubility in aqueous solutions to a maximum value at 40 wt% water content. Furthermore, by increasing the temperature, the lignin solubility was favored due to endothermic behavior of lignin dissolution process. The dissolution of Kraft lignin was also performed at 393.15 K to unravel any lignin modification unleashed by PILs. GPC, FTIR-ATR and 2D NMR were employed for lignin characterization and the changes observed between native lignin and recovered lignin samples were negligible demonstrating the non-derivatizing char- acter of the PILs. Moreover, the recycle of 2-hydroxyethylammonium propionate (HEAP) was successfully de- monstrated for at least 3 cycles. In this way, PILs are herein revealed as promising solvents to apply in lignin valorization towards more efficient and eco-friendly processes.Suzano Papel & Celulosepublishe

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Systems biology approaches applied to regenerative medicine

Systems biology is the creation of theoretical and mathematical models for the study of biological systems, as an engine for hypothesis generation and to provide context to experimental data. It is underpinned by the collection and analysis of complex datasets from different biological systems, including global gene, RNA, protein and metabolite profiles. Regenerative medicine seeks to replace or repair tissues with compromised function (for example, through injury, deficiency or pathology), in order to improve their functionality. In this paper, we will address the application of systems biology approaches to the study of regenerative medicine, with a particular focus on approaches to study modifications to the genome, transcripts and small RNAs, proteins and metabolites