Targeting Oncogenic BRAF: Past, Present, and Future.

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a "precision medicine" paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies

The low frequency oscillation in the flow over a NACA0012 airfoil with an iced leading edge

The unusually low frequency oscillation in the wake of an airfoil is explored experimentally as well as computationally for a NACA0012 airfoil with a glaze ice accretion at the leading edge. Experimentally, flow oscillations were observed at low frequencies that correspond to a Strouhal number of about 0.02. This occurred in the angle of attack range of 8 to 9 deg, near the onset of static stall for this airfoil. With a Navier-Stokes computation, limit-cycle oscillations in the flow and in the aerodynamic forces were also observed at low Strouhal numbers. However, the occurrence of the oscillation is found to depend on the turbulence model in use as well as the Reynolds number

Monkey tests for random number generators

AbstractThis article describes some very simple, as well as some quite sophisticated, tests that shed light on the suitability of certain random number generators

Effect of Microjet Injection on Supersonic Jet Noise

The effect of microjet (jet) injection on the noise from supersonic jets is investigated. Three convergent-divergent (C-D) nozzles and one convergent nozzle, all having the same exit diameters, are used in the study. The jets are injected perpendicular to the primary jet close to the nozzle lip from six equally-spaced ports having a jet-to-primary-jet diameter ratio of 0.0054. Effects in the over-expanded, fully expanded as well as underexpanded flow regimes are explored. Relative to the effect on subsonic jets, larger reductions in the overall sound pressure level (OASPL) are achieved in most supersonic conditions. The largest reductions are typically associated with suppression of screech and transonic tones. For a shock-free, fully expanded case, the OASPL reductions achieved are comparable to that in the subsonic case; the same correlation, found for subsonic jet noise reduction at shallow observation angle, applies

Maximum weight lifting prediction considering dynamic joint strength

Thesis (M.S.) University of Alaska Fairbanks, 2018This thesis describes an efficient optimization method for predicting the maximum lifting weight considering dynamic joint strength in symmetric box lifting using a skeletal model. Dynamic joint strength is modeled as a three-dimensional function of joint angle and joint angular velocity based on experimentally obtained joint strength data. The function is further formulated as the joint torque limit constraint in an inverse dynamics optimization formulation to predict the lifting motion. In the proposed optimization formulation, external load is treated as design variables along with joint angle profiles, which are represented by control points of B-spline curves. By using this new formulation, dynamic lifting motion and strategy can be predicted for a symmetric maximum weight box lifting task with given initial and final box locations. Results show that incorporating dynamic strength is critical in predicting the lifting motion in extreme lifting conditions. The prediction outputs in joint space are incorporated in OpenSim software to find out muscles force and activity during the movement. Electromyography data are collected for a regular weight lifting to validate the integration process between the predictive model (joint model) and OpenSim model (muscle model). The proposed algorithm and analysis method based on motion prediction and OpenSim can be further developed as a useful ergonomic tool to protect workers from injury in manual material handling.Chapter 1 Introduction -- 1.1 Motivation and Objectives -- 1.2 Background -- 1.2.1 Lifting Simulation -- 1.2.2 Muscle modelling -- 1.3 Overview of thesis and specific contribution. Chapter 2 Human Modelling, Kinematics, and Dynamics. Chapter 3 Optimization Formulation -- 3.1 Basic optimization formulation -- 3.2 New optimization formulation -- 3.2.1 External force as design variable -- 3.2.2 Time grid points as design variables -- 3.2.3 Dynamic joint strength. Chapter 4 Maximum Weight Prediction. Chapter 5 OpenSim Simulation for Maximum Weight Lifting -- 5.1 OpenSim -- 5.2 OpenSim simulation and processing -- 5.3 Data processing -- 5.4 Post processing and analysis -- 5.5 Results and comparison. Chapter 6 Validation of Electromyography -- 6.1 Electromyography -- 6.2 Experimental setup -- 6.3 Procedure -- 6.4 Data acquisition -- 6.5 Results and conclusion. Chapter 7 Conclusion and Future Work -- 7.1 Conclusion -- 7.2 Future Work -- Reference -- Appendix

Reconceptualising Personas Across Cultures: Archetypes, Stereotypes & Collective Personas in Pastoral Namibia

The paucity of projects where persona is the research foci and a lack of consensus on this artefact keep many reticent about its purpose and value. Besides crafting personas is expected to differ across cultures, which contrasts the advancements in Western theory with studies and progress in other sites. We postulate User-Created Personas reveal specific characteristics of situated contexts by allowing laypeople to design persona artefacts in their own terms. Hence analysing four persona sessions with an ethnic group in pastoral Namibia –ovaHerero– brought up a set of fundamental questions around the persona artefact regarding stereotypes, archetypes, and collective persona representations: (1) to what extent user depictions are stereotypical or archetypal? If stereotypes prime (2) to what degree are current personas a useful method to represent end-users in technology design? And, (3) how can we ultimately read accounts not conforming to mainstream individual persona descriptions but to collectives

Interface modification of clay and graphene platelets reinforced epoxy nanocomposites: a comparative study

The interface between the matrix phase and dispersed phase of a composite plays a critical role in influencing its properties. However, the intricate mecha-nisms of interface are not fully understood, and polymer nanocomposites are no exception. This study compares the fabrication, morphology, and mechanical and thermal properties of epoxy nanocomposites tuned by clay layers (denoted as m-clay) and graphene platelets (denoted as m-GP). It was found that a chemical modification, layer expansion and dispersion of filler within the epoxy matrix resulted in an improved interface between the filler mate-rial and epoxy matrix. This was confirmed by Fourier transform infrared spectroscopy and transmission electron microscope. The enhanced interface led to improved mechanical properties (i.e. stiffness modulus, fracture toughness) and higher glass transition temperatures (Tg) compared with neat epoxy. At 4 wt% m-GP, the critical strain energy release rate G1c of neat epoxy improved by 240 % from 179.1 to 608.6 J/m2 and Tg increased from 93.7 to 106.4 �C. In contrast to m-clay, which at 4 wt%, only improved the G1c by 45 % and Tg by 7.1 %. The higher level of improvement offered by m-GP is attributed to the strong interaction of graphene sheets with epoxy because the covalent bonds between the carbon atoms of graphene sheets are much stronger than silicon-based clay

The effect of distance on observed mortality, childhood pneumonia and vaccine efficacy in rural Gambia.

We investigated whether straight-line distance from residential compounds to healthcare facilities influenced mortality, the incidence of pneumonia and vaccine efficacy against pneumonia in rural Gambia. Clinical surveillance for pneumonia was conducted on 6938 children living in the catchment areas of the two largest healthcare facilities. Deaths were monitored by three-monthly home visits. Children living >5 km from the two largest healthcare facilities had a 2·78 [95% confidence interval (CI) 1·74-4·43] times higher risk of all-cause mortality compared to children living within 2 km of these facilities. The observed rate of clinical and radiological pneumonia was lower in children living >5 km from these facilities compared to those living within 2 km [rate ratios 0·65 (95% CI 0·57-0·73) and 0·74 (95% CI 0·55-0·98), respectively]. There was no association between distance and estimated pneumococcal vaccine efficacy. Geographical access to healthcare services is an important determinant of survival and pneumonia in children in rural Gambia

Cyclic Testing of Aggregates for Pavement Design

Two most commonly encountered aggregates that are used as subbases/bases of roadways in Oklahoma were selected and tested under cyclic loading to evaluate their Resilient Modulus (RM). Following the repeated triaxial RM testing, the specimens were subjected to the triaxial compression tests from which the parameters of cohesion (C), and friction angle (Φ) were obtained. A good statistical correlation was established between RM and C and Φ. The repeated triaxial RM testing procedure serves as a “conditioning” prior to the static triaxial compression and it simulates the loads imposed by the moving vehicle. The effects of conditioning on C and Φ were investigated. The strength increase through conditioning was found to vary from 18 to 85 percent, depending confining pressure and aggregate type. Also, it was found that C increases and ø decreased because of conditioning