The objective of this study was to evaluate the interfacial fracture toughness (IFT) of composite cement with dispersed filler (DF) versus polymer-infiltrated ceramic network (PICN) computer-aided ...design and computer-aided manufacturing (CAD-CAM) composite blocks after 2 different surface pretreatments using the notchless triangular prism (NTP) test. Two DFs (Cerasmart CRT and Lava Ultimate LVA), 2 PICNs (Enamic ENA and experimental PICN EXP), and e.max CAD lithium disilicate glass-ceramic (EMX, control) prism samples were bonded to their counterparts with Variolink Esthetic DC composite cement after either hydrofluoric acid etching (HF) or gritblasting (GR). Both procedures were followed by silanization. All samples (n = 30 per group) were thermocycled (10,000 cycles) and tested for their IFT in a water bath at 36°C. Moreover, representative samples from each group were subjected to a developed interfacial area ratio (Sdr) measurement by profilometry and scanning electron microscopy (SEM) characterization. EXP-HF gave the highest IFT (1.85 ± 0.39 MPa·m1/2), followed by EMX-HF and ENA-HF, while CRT-HF gave the lowest (0.15 ± 0.22 MPa·m1/2). PICNs gave significantly better results with HF, and DF showed better results with GR. A 2-way analysis of variance indicated that there were significantly higher IFT and Sdr for PICNs than for DF. A positive correlation (r² = 0.872) was found between IFT and Sdr. SEM characterization showed the specific microstructure of the surface of etched PICNs, indicating the presence of a retentive polymer-based honeycomb structure. Etching of the typical double-network microstructure of PICNs causes an important increase in the Sdr and IFT, while DF should be gritblasted. DF exhibited significantly lower Sdr and IFT values than PICNs. The present results show the important influence of the material class and surface texture, and consequently the micromechanical bond, on the adhesive interface performance of CAD-CAM composites.
Electrical resistivity tomography (ERT) can be used to constrain seawater intrusion models because of its high sensitivity to total dissolved solid contents (TDS) in groundwater and its relatively ...high lateral coverage. However, the spatial variability of resolution in electrical imaging may prevent the correct recovery of the desired hydrochemical properties such as salt mass fraction. This paper presents a sequential approach to evaluate the feasibility of identifying hydraulic conductivity and dispersivity in density‐dependent flow and transport models from surface ERT‐derived mass fraction. In the course of this study, geophysical inversion was performed by using a smoothness constraint Tikhonov approach, whereas the hydrological inversion was performed using a gradient‐based Levenberg‐Marquardt algorithm. Two synthetic benchmarks were tested. They represent a pumping experiment in a homogeneous and heterogeneous coastal aquifer, respectively. These simulations demonstrated that only the lower salt mass fraction of the seawater‐freshwater transition zone can be recovered for different times. This ability has here been quantified in terms of cumulative sensitivity and our study has further demonstrated that the mismatch between the targeted and the recovered salt mass fraction occurs from a certain threshold. We were additionally able to explore the capability of sensitivity‐filtered ERT images using ground surface data only to recover (in both synthetic cases) the hydraulic conductivity while the dispersivity is more difficult to estimate. We attribute the latter mainly to the lack of ERT‐derived data at depth (where resolution is poorer) as well as to the smoothing effect of the ERT inversion.
Key Points
Inversion of nonlinear groundwater model
To perform quantitative hydrogeophysics
To develop a methodology to characterize seawater intrusion
Visualization system designers must decide whether and how to aggregate data by default. Aggregating distributional information in a single summary mark like a mean or sum simplifies interpretation, ...but may lead untrained users to overlook distributional features. We ask, How are the conclusions drawn by untrained visualization users affected by aggregation strategy? We present two controlled experiments comparing generalizations of a population that untrained users made from visualizations that summarized either a 1000 record or 50 record sample with either single mean summary mark, a disaggregated view with one mark per observation or a view overlaying a mean summary mark atop a disaggregated view. While we observe no reliable effect of aggregation strategy on generalization accuracy at either sample size, users of purely disaggregated views were slightly less confident in their generalizations on average than users whose views show a single mean summary mark, and less likely to engage in dichotomous thinking about effects as either present or absent. Comparing results from 1000 record to 50 record data set, we see a considerably larger decrease in the number of generalizations produced and reported confidence in generalizations among viewers who saw disaggregated data relative to those who saw only mean summary marks.
Visualization system designers must decide whether and how to aggregate data by default. Aggregating distributional information in a single summary mark like a mean or sum simplifies interpretation, but may lead untrained users to overlook distributional features. We ask, How are the conclusions drawn by untrained visualization users affected by aggregation strategy? We present two controlled experiments comparing generalizations of a population that untrained users made from visualizations that summarized either a 1000 record or 50 record sample with either single mean summary mark, a disaggregated view with one mark per observation or a view overlaying a mean summary mark atop a disaggregated view. While we observe no reliable effect of aggregation strategy on generalization accuracy at either sample size, users of purely disaggregated views were slightly less confident in their generalizations on average than users whose views show a single mean summary mark, and less likely to engage in dichotomous thinking about effects as either present or absent. Comparing results from 1000 record to 50 record data set, we see a considerably larger decrease in the number of generalizations produced and reported confidence in generalizations among viewers who saw disaggregated data relative to those who saw only mean summary marks.
The TATA-box binding protein (TBP) is the sole transcription factor common in the initiation complexes of the three major eukaryotic RNA Polymerases (Pol I, II and III). Although TBP is central to ...transcription by the three RNA Pols in various species, the emergence of TBP paralogs throughout evolution has expanded the complexity in transcription initiation. Furthermore, recent studies have emerged that questioned the centrality of TBP in mammalian cells, particularly in Pol II transcription, but the role of TBP and its paralogs in Pol I transcription remains to be re-evaluated. In this report, we show that in murine embryonic stem cells TBP localizes onto Pol I promoters, whereas the TBP paralog TRF2 only weakly associates to the Spacer Promoter of rDNA, suggesting that it may not be able to replace TBP for Pol I transcription. Importantly, acute TBP depletion does not fully disrupt Pol I occupancy or activity on ribosomal RNA genes, but TBP binding in mitosis leads to efficient Pol I reactivation following cell division. These findings provide a more nuanced role for TBP in Pol I transcription in murine embryonic stem cells.The TATA-box binding protein (TBP) is the sole transcription factor common in the initiation complexes of the three major eukaryotic RNA Polymerases (Pol I, II and III). Although TBP is central to transcription by the three RNA Pols in various species, the emergence of TBP paralogs throughout evolution has expanded the complexity in transcription initiation. Furthermore, recent studies have emerged that questioned the centrality of TBP in mammalian cells, particularly in Pol II transcription, but the role of TBP and its paralogs in Pol I transcription remains to be re-evaluated. In this report, we show that in murine embryonic stem cells TBP localizes onto Pol I promoters, whereas the TBP paralog TRF2 only weakly associates to the Spacer Promoter of rDNA, suggesting that it may not be able to replace TBP for Pol I transcription. Importantly, acute TBP depletion does not fully disrupt Pol I occupancy or activity on ribosomal RNA genes, but TBP binding in mitosis leads to efficient Pol I reactivation following cell division. These findings provide a more nuanced role for TBP in Pol I transcription in murine embryonic stem cells.
An open-label, multicenter, single-arm phase II trial was conducted to investigate the clinical activity of dacomitinib in recurrent/metastatic squamous-cell carcinoma of the head and neck ...(RM-SCCHN).
Eligible patients were administered dacomitinib at 45 mg orally daily, in 21-day cycles. Primary end point was objective response rate.
Sixty-nine patients were enrolled with a median age of 62 years. Among response-evaluable patients, 8 12.7%, 95% confidence interval (CI) 5.6% to 23.5% achieved a partial response and 36 (57.1%) had stable disease, lasting ≥24 weeks in 9 patients (14.3%). The median progression-free survival (PFS) was 12.1 weeks and the median overall survival (OS) was 34.6 weeks. Most adverse events (AEs) were tolerable. The most common grade 3 or higher treatment-related AEs were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Treatment-related AEs led to at least one dose interruption in 28 (40.6%) patients and dose reductions in 26 (37.7%). Permanent treatment discontinuation occurred in 8 (11.6%) patients due to treatment-related AEs.
Dacomitinib demonstrated clinical activity in RM-SCCHN, and the primary end point of this study was met. The toxicity profile of this agent was generally manageable with dose interruptions and adjustments.
The possibility to accelerate electron beams to ultra-relativistic velocities over short distances by using plasma-based technology holds the potential for a revolution in the field of particle ...accelerators
. The compact nature of plasma-based accelerators would allow the realization of table-top machines capable of driving a free-electron laser (FEL)
, a formidable tool to investigate matter at the sub-atomic level by generating coherent light pulses with sub-ångström wavelengths and sub-femtosecond durations
. So far, however, the high-energy electron beams required to operate FELs had to be obtained through the use of conventional large-size radio-frequency (RF) accelerators, bound to a sizeable footprint as a result of their limited accelerating fields. Here we report the experimental evidence of FEL lasing by a compact (3-cm) particle-beam-driven plasma accelerator. The accelerated beams are completely characterized in the six-dimensional phase space and have high quality, comparable with state-of-the-art accelerators
. This allowed the observation of narrow-band amplified radiation in the infrared range with typical exponential growth of its intensity over six consecutive undulators. This proof-of-principle experiment represents a fundamental milestone in the use of plasma-based accelerators, contributing to the development of next-generation compact facilities for user-oriented applications
.
Despite effective treatment for those living with Human Immunodeficiency Virus (HIV), there are still two million new infections each year. Protein-based HIV entry inhibitors, being highly effective ...and specific, could be used to protect people from initial infection. One of the most promising of these for clinical use is 5P12-RANTES, a variant of the chemokine RANTES/CCL5. The N-terminal amino acid of 5P12-RANTES is glutamine (Gln; called Q0), a residue that is prone to spontaneous cyclization when at the N-terminus of a protein. It is not known how this cyclization affects the potency of the inhibitor or whether cyclization is necessary for the function of the protein, although the N-terminal region of RANTES has been shown to be critical for receptor interactions, with even small changes having a large effect. We have studied the kinetics of cyclization of 5P12-RANTES as well as N-terminal variations of the protein that either produce an identical cyclized terminus (Glu0) or that cannot similarly cyclize (Asn0, Phe0, Ile0, and Leu0). We find that the half life for N-terminal cyclization of Gln is roughly 20 h at pH 7.3 at 37 °C. However, our results show that cyclization is not necessary for the potency of this protein and that several replacement terminal amino acids produce nearly-equally potent HIV inhibitors while remaining CC chemokine receptor 5 (CCR5) antagonists. This work has ramifications for the production of active 5P12-RANTES for use in the clinic, while also opening the possibility of developing other inhibitors by varying the N-terminus of the protein.
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