The polymer-to-ceramic transformation kinetics of two widely employed ceramic precursors, 1,3,5,7-tetramethyl-1,3,5,7-tetravinylcyclotetrasiloxane (TTCS) and polyureamethylvinylsilazane (CERASET), ...have been investigated using coupled thermogravimetry and mass spectrometry (TG-MS), Raman, XRD and FTIR. The thermally induced decomposition of the pre-ceramic polymer is the critical step in the synthesis of polymer derived ceramics (PDCs) and accurate kinetic modeling is key to attaining a complete understanding of the underlying process and to attempt any behavior predictions. However, obtaining a precise kinetic description of processes of such complexity, consisting of several largely overlapping physico-chemical processes comprising the cleavage of the starting polymeric network and the release of organic moieties, is extremely difficult. Here, by using the evolved gases detected by MS as a guide it has been possible to determine the number of steps that compose the overall process, which was subsequently resolved using a semiempirical deconvolution method based on the Frasier-Suzuki function. Such a function is more appropriate that the more usual Gaussian or Lorentzian functions since it takes into account the intrinsic asymmetry of kinetic curves. Then, the kinetic parameters of each constituent step were independently determined using both model-free and model-fitting procedures, and it was found that the processes obey mostly diffusion models which can be attributed to the diffusion of the released gases through the solid matrix. The validity of the obtained kinetic parameters was tested not only by the successful reconstruction of the original experimental curves, but also by predicting the kinetic curves of the overall processes yielded by different thermal schedules and by a mixed TTCS-CERASET precursor.
The six possible equiatomic five-transition metal High Entropy Carbides (HECs) of the IVB (Ti, Zr, Hf) and VB (V, Nb, Ta) groups of the periodic table, i.e., TiZrHfVNbC5, TiZrHfVTaC5, TiZrHfNbTaC5, ...TiZrVNbTaC5, TiHfVNbTaC5 and ZrHfVNbTaC5, were successfully obtained via a powder metallurgy route at room temperature, specifically, by one-step diffusion mechanosynthesis starting from the elemental constituents (using graphite as the carbon source). Three of those HECs, TiZrHfVTaC5, TiZrVNbTaC5 and ZrHfVNbTaC5, were developed for the first time. Their development was possible without any subsequent thermal treatment, in contrast to the usual way (reactive sintering at 1800–2200 °C), and in a powder form, make them potential advanced raw ceramics for hard, refractory and oxidation resistance coatings or matrix phase composites.
Escherichia coli is an important experimental, medical and industrial cell factory for recombinant protein production. The inducible lac promoter is one of the most commonly used promoters for ...heterologous protein expression in E. coli. Isopropyl-β-D-thiogalactoside (IPTG) is currently the most efficient molecular inducer for regulating this promoter's transcriptional activity. However, limitations have been observed in large-scale and microplate production, including toxicity, cost and culture monitoring. Here, we report the novel SILEX (Self-InducibLe Expression) system, which is a convenient, cost-effective alternative that does not require cell density monitoring or IPTG induction. We demonstrate the broad utility of the presented self-inducible method for a panel of diverse proteins produced in large amounts. The SILEX system is compatible with all classical culture media and growth temperatures and allows protein expression modulation. Importantly, the SILEX system is proven to be efficient for protein expression screening on a microplate scale.
Titanosauria was the most diverse and successful lineage of sauropod dinosaurs. This clade had its major radiation during the middle Early Cretaceous and survived up to the end of that period. Among ...sauropods, this lineage has the most disparate values of body mass, including the smallest and largest sauropods known. Although recent findings have improved our knowledge on giant titanosaur anatomy, there are still many unknown aspects about their evolution, especially for the most gigantic forms and the evolution of body mass in this clade. Here we describe a new giant titanosaur, which represents the largest species described so far and one of the most complete titanosaurs. Its inclusion in an extended phylogenetic analysis and the optimization of body mass reveals the presence of an endemic clade of giant titanosaurs inhabited Patagonia between the Albian and the Santonian. This clade includes most of the giant species of titanosaurs and represents the major increase in body mass in the history of Titanosauria.
A
bstract
Optimisation problems are ubiquitous in particle and astrophysics, and involve locating the optimum of a complicated function of many parameters that may be computationally expensive to ...evaluate. We describe a number of global optimisation algorithms that are not yet widely used in particle astrophysics, benchmark them against random sampling and existing techniques, and perform a detailed comparison of their performance on a range of test functions. These include four analytic test functions of varying dimensionality, and a realistic example derived from a recent global fit of weak-scale supersymmetry. Although the best algorithm to use depends on the function being investigated, we are able to present general conclusions about the relative merits of random sampling, Differential Evolution, Particle Swarm Optimisation, the Covariance Matrix Adaptation Evolution Strategy, Bayesian Optimisation, Grey Wolf Optimisation, and the PyGMO Artificial Bee Colony, Gaussian Particle Filter and Adaptive Memory Programming for Global Optimisation algorithms.
Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated ...whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and
alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC.
We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features.
Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months;
= 0.04), while
alterations (29%) were associated with significantly lower ORR (6% vs. 48%;
= 0.01), shorter PFS (2.3 vs. 6.1 months;
= 0.01), and shorter OS (9.7 vs. 20.5 months;
= 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (
= 90) and non-ICI regimens (
= 169).
Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and
alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets.
Stress or heat shock proteins (HSPs) are the most conserved proteins present in both prokaryotes and eukaryotes. Their expression is induced in response to a wide variety of physiological and ...environmental insults. These proteins play an essential role as molecular chaperones by assisting the correct folding of nascent and sress‐accumulated misfolded proteins, and preventing their aggregation. HSPs have a dual function depending on their intracellular or extracellular location. Intracellular HSPs have a protective function. They allow the cells to survive lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. Several HSPs have also been demonstrated to directly interact with various components of the tightly regulated programmed cell death machinery, upstream and downstream of the mitochondrial events. On the other hand, extracellular located or membrane‐bound HSPs mediate immunological functions. They can elicit an immune response modulated either by the adaptive or innate immune system. This review will focus on HSP27, HSP70, and HSP90. We will discuss the dual role of these HSPs, protective vs. immunogenic properties, making a special emphasis in their utility as targets in cancer therapy.
The baroclinic response to barotropic tidal forcing in the Camarinal Sill area, within the Strait of Gibraltar, is investigated with a three‐dimensional, fully nonlinear, nonhydrostatic numerical ...model. The aim of numerical efforts was the assessment of three‐dimensional effects, which are potentially significant in the area because of rather irregular bottom topography, variable background stratification, and complex structure of barotropic tides. Model results reveal a complex baroclinic response under relatively moderate flood tidal currents, which includes the formation of internal hydraulic jumps upstream of the sill, internal cross waves close to the channel walls, and a plunging pycnocline at the lee side of the sill crest. These structures exhibit significant cross‐channel spatial dependence and may appear to be aligned together across the channel. This fact makes their identification difficult from the surface pattern captured by remote sensing images. Under strong barotropic forcing (spring tides) the upstream hydraulic jumps are shifted to the lee side of Camarinal Sill, where a single internal hydraulic jump is formed. Significant first‐ and second‐mode hydraulic jumps are also generated near smaller secondary sills in Tangier basin, thus extending the occurrence of intense water mixing and energy dissipation to other zones of the strait.
Key Points
Three‐dimensional baroclinic response to tidal forcing in the Camarinal Sill
Different baroclinic response under moderate to strong tidal forcing
Generation of multiple internal hydraulic jumps in secondary sills
Time series collected in the Camarinal and Espartel sills, the two main sills of the Strait of Gibraltar, have been analyzed to assess the first transformation of the Mediterranean outflow. In ...Espartel, west of Camarinal sill, the outflow has been estimated from a 6 year long time series of acoustic Doppler current profiler observations. The near bottom water flowing out at Espartel is around 0.1 units saltier and 0.1°C warmer than at Camarinal, which is explained by entrainment and mixing of Atlantic water by the outflow inside the basin bounded by both sills. The constancy of heat and salinity transport implies an Atlantic water entrainment of 0.03 Sv, which is about 4% of the outflow observed at Espartel (0.77 Sv) and a flow of 0.74 Sv at Camarinal (96% of the flow at Espartel). It is also shown that the high energy dissipation rate associated with internal tides is enough to sustain the entrainment and a thorough mixing of the entrained water.
Key Points
Entrainment and mixing in Tangier basin
Increase of volume transport in the Mediterranean outflow
Availability of turbulent kinetic energy to achieve the mixing
Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K ...inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer.
This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies.
Fifty patients were enrolled. Median number of cycles was 2 (range 1-10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval CI 1.6-2.3). Median OS was 11.2 months (95% CI 6.2-25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease.
Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer.
NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.
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