The tumour suppressor p53 is the most frequently mutated gene in human cancer, with more than half of all human tumours carrying mutations in this particular gene. Intense efforts to develop drugs ...that could activate or restore the p53 pathway have now reached clinical trials. The first clinical results with inhibitors of MDM2, a negative regulator of p53, have shown efficacy but hint at on-target toxicities. Here, we describe the current state of the development of p53 pathway modulators and new pathway targets that have emerged. The challenge of targeting protein-protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery.
The opto-thermal properties of Au- and Ag-coated core–shell hybrid nanoparticles (NPs) have been thoroughly investigated by using the PyMieLab V1.0 simulation tool based on electrodynamics modelling. ...We, specifically, investigated the plasmonic resonance tunability and spatial temperature profiles of Au- and Ag-coated composed hybrid core–shell nanospheres as optimized combinations of alloy core (viz. Au
0.25
Ag
0.75
, Au
0.25
Cu
0.75
, Au
0.75
Al
0.25
, Ag
0.75
Cu
0.25
and Ag
0.75
Al
0.25
) immersed in the local water (
n
= 1.33) media. In the present core–shell nanostructure configuration, the alloy core radius (
r
) has been changed from 5 to 50 nm (with 5-nm step-size) and shell thickness,
t
=
5
,
and
10
nm
is kept the same with varying core radii. The localized surface plasmon resonance (LSPR) of Au- and Ag-coated optimized alloys composed of hybrid core–shell nanospheres is tuned between 238–545 nm and 347–531 nm, respectively, and lies under the ultraviolet–visible segment of the electromagnetic band. The temperature recorded at the surface of core–shell NPs (i.e. alloy core@gold/silver shell) lies between the range of 0.20 and 2.38 °C (for Au-coated alloys) and 0.64–2.44 °C (for Ag-coated alloy) with different core/shell size ratios. The present results are of paramount importance for using these alloy core–plasmonic shell NPs in several types of thermoplasmonic applications.
Graphical Abstract
Aims
This study was conducted to investigate indigenous seed endophyte effects on browntop millet seedling development. We report that seed‐inhabiting bacterial endophytes are responsible for ...promoting seedling development, including stimulation of root hair formation, increasing root and shoot length growth and increasing photosynthetic pigment content of seedlings. Bacterial endophytes also improved resistance of seedlings to disease.
Methods and Results
A total of four endophytic bacteria were isolated from surface‐sterilized seeds and identified by 16S rDNA sequencing as Curtobacterium sp. (M1), Microbacterium sp. (M2), Methylobacterium sp. (M3) and Bacillus amyloliquefaciens (M4). Removal of bacteria with streptomycin treatment from the seeds compromised seedling growth and development. When endophytes were reinoculated onto seeds, seedlings recovered normal development. Strains M3 and M4 were found to be most potent in promoting growth of seedlings. Bacteria were found to produce auxin, solubilize phosphate and inhibit fungal pathogens. Significant protection of seedlings from Fusarium infection was found using strain M4 in microcosm assays. The antifungal lipopeptide genes for surfactin and iturin were detected in M4; culture extracts of M4 showed a positive drop collapse result for surfactins.
Conclusions
This study demonstrates that browntop millet seeds vector indigenous endophytes that are responsible for modulation of seedling development and protection of seedlings from fungal disease.
Significance and Impact of the Study
This study is significant and original in that it is the first report of seed‐inhabiting endophytes of browntop millet that influence seedling development and function in defence against soilborne pathogens. This study suggests that conservation and management of seed‐vectored endophytes may be important in development of more sustainable agricultural practices.
In comparison to single Noble metal nanoparticles (NPs), bimetallic nanoparticles allow fine-tuning of the optical and photothermal properties. Considering the fact that both Au and Ag plasmonic NPs ...exhibit strong and enhanced optical absorption in the visible spectrum, the composition of these two materials is notably intriguing. Therefore, the combination of these two metals as an alloy of Au
x
–Ag
(1−x)
will provide better control of optical and thermoplasmonic properties by changing the size and composition. The proposed computer simulation work examines the thermal effects of Au–Ag alloy nanospheres under surface plasmon resonance (SPR) due to the coherent oscillation of conduction electrons within the NPs. It is demonstrated that the SPR of Au
x
–Ag
(1−x)
alloy nanospheres could be easily altered by varying the radius and also the composition of alloys (in water ambience). The rise of steady-state temperature is calculated by the integration of Ag into spherical Au NPs, as demonstrated by photothermal heat transfer research. Absorption of light by metallic alloy nanospheres was studied by changing the composition of such alloy spheres with a possibility to alter the SPR absorption range, which is tuned from 392 to 580 nm. This investigation of the optical and photothermal properties of bimetallic Au–Ag alloy nanospheres offers a thorough scientific understanding towards the synthesis of new custom plasmonic nanostructured materials.
Graphical abstract
Schematic of the photo-thermal conversion process in spherical NPs along with its temperature profile.
Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height ...within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.
In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio OR 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.
In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.
The performance of Stirling engines meets the demands of the efficient use of energy and environmental security and therefore they are the subject of much current interest. Hence, the development and ...investigation of Stirling engine have come to the attention of many scientific institutes and commercial companies. The Stirling engine is both practically and theoretically a significant device, its practical virtue is simple, reliable and safe which was recognized for a full century following its invention by Robert Stirling in 1816. The engine operates on a closed thermodynamic cycle, which is reversible. Today Stirling cycle-based systems are in commercial use as a heat pump, cryogenic refrigeration and air liquefaction. As a prime mover, Stirling cycles remain the subject of research and development efforts. The objective of this paper is to provide fundamental information and present a detailed review of the past efforts taken for the development of the Stirling cycle engine and techniques used for engine analysis. A number of attempts have been made by researches to build and improve the performance of Stirling engines. It is seen that for successful operation of engine system with good efficiency a careful design of heat exchangers, proper selection of drive mechanism and engine configuration is essential. The study indicates that a Stirling cycle engine working with relatively low temperature with air of helium as working fluid is potentially attractive engines of the future, especially solar-powered low-temperature differential Stirling engines with vertical, double acting, and gamma configuration.
The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus ...letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.
A total of 668 postmenopausal women with HR+, HER2– recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point.
At the time of the second interim analysis, the median duration of follow-up was 26.4months. Median PFS was 25.3months 95% confidence interval (CI) 23.0–30.3 for ribociclib plus letrozole and 16.0months (95% CI 13.4–18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457–0.704; log-rank P=9.63×10−8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517–1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.
The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.
NCT01958021
This article introduces the novel notion of dimension preserving approximation for continuous functions defined on 0, 1 and initiates the study of it. Restrictions and extensions of continuous ...functions in regards to fractal dimensions are also investigated.
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