The central nervous system (CNS) is an active participant in the innate immune response to infection and injury. In these studies, we show embryonic cortical neurons express a functional, ...deoxyribonucleic acid (DNA)-responsive, absent in melanoma 2 (AIM2) inflammasome that activates caspase-1. Neurons undergo pyroptosis, a proinflammatory cell death mechanism characterized by the following: (a) oligomerization of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC); (b) caspase-1 dependency; (c) formation of discrete pores in the plasma membrane; and (d) release of the inflammatory cytokine interleukin-1β (IL-1β). Probenecid and Brilliant Blue FCF, inhibitors of the pannexin1 channel, prevent AIM2 inflammasome-mediated cell death, identifying pannexin1 as a cell death effector during pyroptosis and probenecid as a novel pyroptosis inhibitor. Furthermore, we show activation of the AIM2 inflammasome in neurons by cerebrospinal fluid (CSF) from traumatic brain injury (TBI) patients and oligomerization of ASC. These findings suggest neuronal pyroptosis is an important cell death mechanism during CNS infection and injury that may be attenuated by probenecid.
Persistent androgen receptor (AR) transcriptional activity underlies resistance to AR-targeted therapy and progression to lethal castration-resistant prostate cancer (CRPC). Recent success in ...retargeting persistent AR activity with next generation androgen/AR axis inhibitors such as enzalutamide (MDV3100) has validated AR as a master regulator during all stages of disease progression. However, resistance to next generation AR inhibitors limits therapeutic efficacy for many patients. One emerging mechanism of CRPC progression is AR gene rearrangement, promoting synthesis of constitutively active truncated AR splice variants (AR-V) that lack the AR ligand-binding domain. In this study, we show that cells with AR gene rearrangements expressing both full-length and AR-Vs are androgen independent and enzalutamide resistant. However, selective knock-down of AR-V expression inhibited androgen-independent growth and restored responsiveness to androgens and antiandrogens. In heterogeneous cell populations, AR gene rearrangements marked individual AR-V-dependent cells that were resistant to enzalutamide. Gene expression profiling following knock-down of full-length AR or AR-Vs showed that AR-Vs drive resistance to AR-targeted therapy by functioning as constitutive and independent effectors of the androgen/AR transcriptional program. Further, mitotic genes deemed previously to be unique AR-V targets were found to be biphasic targets associated with a proliferative level of signaling output from either AR-Vs or androgen-stimulated AR. Overall, these studies highlight AR-Vs as key mediators of persistent AR signaling and resistance to the current arsenal of conventional and next generation AR-directed therapies, advancing the concept of AR-Vs as therapeutic targets in advanced disease.
Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) ...in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The use of the Gibbs sampler with fully conditionally specified models, where the distribution of each variable given the other variables is the starting point, has become a popular method to create ...imputations in incomplete multivariate data. The theoretical weakness of this approach is that the specified conditional densities can be incompatible, and therefore the stationary distribution to which the Gibbs sampler attempts to converge may not exist. This study investigates practical consequences of this problem by means of simulation. Missing data are created under four different missing data mechanisms. Attention is given to the statistical behavior under compatible and incompatible models. The results indicate that multiple imputation produces essentially unbiased estimates with appropriate coverage in the simple cases investigated, even for the incompatible models. Of particular interest is that these results were produced using only five Gibbs iterations starting from a simple draw from observed marginal distributions. It thus appears that, despite the theoretical weaknesses, the actual performance of conditional model specification for multivariate imputation can be quite good, and therefore deserves further study.
Parallel connections can be found in many battery applications. Therefore, it is of high interest to understand how the current distributes within parallel battery cells. However, the number of ...publications on this topic is comparably low. Furthermore, the measurement set-ups are often not clearly defined in existing publications and it is likely that additional impedances distorted the measured current distributions.
In this work, the principles of current distributions within parallel-connected battery cells are investigated theoretically, with an equivalent electric circuit model, and by measurements. A measurement set-up is developed that does not significantly influence the measurements, as proven by impedance spectroscopy.
On this basis, two parameter scenarios are analyzed: the ΔR scenario stands for battery cells with differing impedances but similar capacities and the ΔC scenario for differing capacities and similar impedances. Out of 172 brand-new lithium-ion battery cells, pairs are built to practically represent the ΔR and ΔC scenarios.
If a charging pulse is applied to the ΔR scenario, currents initially divide according to the current divider but equalize in constant current phases. The current divider has no effect on ΔC pairs but, as a rule of thumb for long-term loads, currents divide according to the battery cell capacities.
•Current distribution is investigated theoretically, by measurement, and simulation.•A sophisticated set-up is developed in order not to distort the measurements.•Scenarios with differing impedances and capacities of battery cells are analyzed.•For each scenario a rule of thumb is derived and discussed.
Complex solitary waves composed of intersecting vortex lines are predicted in a channeled superfluid. Their shapes in a cylindrical trap include a cross, spoke wheels, and Greek Φ, and trace the ...nodal lines of unstable vibration modes of a planar dark soliton in analogy to Chladni's figures of membrane vibrations. The stationary solitary waves extend a family of solutions that include the previously known solitonic vortex and vortex rings. Their bifurcation points from the dark soliton indicating the onset of new unstable modes of the snaking instability are predicted from scale separation for Bose-Einstein condensates (BECs) and superfluid Fermi gases across the BEC-BCS crossover, and confirmed by full numerical calculations. Chladni solitons could be observed in ultracold gas experiments by seeded decay of dark solitons.
A measurement of the ratio of the branching fractions of the B(+) → K(+)μ(+)μ(-) and B(+) → K(+)e(+)e(-) decays is presented using proton-proton collision data, corresponding to an integrated ...luminosity of 3.0 fb(-1), recorded with the LHCb experiment at center-of-mass energies of 7 and 8 TeV. The value of the ratio of branching fractions for the dilepton invariant mass squared range 1 < q(2) < 6 GeV(2)/c(4) is measured to be 0.745(-0.074)(+0.090)(stat) ± 0.036(syst). This value is the most precise measurement of the ratio of branching fractions to date and is compatible with the standard model prediction within 2.6 standard deviations.
Advanced gravitational wave interferometers, currently under realization, will soon permit the detection of gravitational waves from astronomical sources. To open the era of precision gravitational ...wave astronomy, a further substantial improvement in sensitivity is required. The future space-based Laser Interferometer Space Antenna and the third-generation ground-based observatory Einstein Telescope (ET) promise to achieve the required sensitivity improvements in frequency ranges. The vastly improved sensitivity of the third generation of gravitational wave observatories could permit detailed measurements of the sources' physical parameters and could complement, in a multi-messenger approach, the observation of signals emitted by cosmological sources obtained through other kinds of telescopes. This paper describes the progress of the ET project which is currently in its design study phase.
•We retrieved 44 publications and 199 observations comparing continuous cereal with grain legume-cereal rotation in SSA.•Cereal after legume yielded on average 0.49t grain ha−1 or 41% more than ...continuous cereal.•Sustained residual benefits of legumes with large N applications indicate the importance of non-N effects.•Relevant non-N effects include improved P availability, changes in SOM, and in pest, disease and striga pressure.
We conducted a systematic review of literature on the residual effects of grain legumes in cereal-based systems of sub-Saharan Africa (SSA) to quantify the magnitude and variability of rotational effects, to explore the importance of environmental and management factors in determining variability and to evaluate the evidence of the different mechanisms that explain rotational effects. We retrieved 44 unique publications providing 199 observations comparing continuous cereal performance with that of a grain legume-cereal rotation. The overall mean yield increase of 0.49t grainha−1, equal to an increase of 41% of the continuous cereal yield, is highly significant, but the variability in residual effects is large. Effects were more pronounced in southern Africa, the highlands of East Africa and the Guinea savannah, and less in the humid forest/derived savannah of West Africa and the Sudano-Sahelian zone. Maize showed stronger yield responses after a legume than millet and sorghum. Agro-ecological zone and cereal type were however confounded. All grain legume types significantly improved cereal yields, with stronger residual effects observed after soybean and groundnut than after cowpea. Fertiliser N application to cereals reduces the residual effects of legumes, but the response at 60–120kgNha−1 still equalled 0.32tha−1 or 59% of the response when no N is applied. The sustained benefits with large N applications indicate the importance of non-N effects. While mechanisms for improved soil P availability after grain legumes have been studied in some detail, it remains uncertain how important these are in farmers’ fields. Grain legumes are unlikely to have a major influence on the availability of nutrients other than N and P, or on soil pH. Beneficial impacts of grain legumes on soil organic matter content can occur if legumes contribute to a greater overall cropping productivity, but studies generally report no such impacts. Evidence of impacts of grain legumes on weeds is limited to striga. Studies on the impacts on nematode pressure in cereals are inconclusive, probably because legumes act as a host for some of the key nematode genera that harm maize. The impact on the pressure of other pests and diseases in cereals is probably important, but evidence on this from SSA is lacking. Future research on N2-fixation by grain legumes and residual N benefits should focus on explaining the wide variability observed among sites. There is a clear need for more detailed mechanistic studies to assess the occurrence and relevance of non-N effects of grain legumes, particularly in relation to common pests and diseases in cereals.
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