The RAS-RAF-MEK1/2-ERK1/2 pathway is a key signal transduction pathway in the cells. Critically, it remains constitutively active in approximately 30% of human cancers, having key roles in cancer ...development, maintenance and progression, while being responsible for poorer prognosis and drug resistance. Consequently, the inhibition of this pathway has been the subject of intense research for >25 years. The advent of better patient screening techniques has increasingly shown that upstream regulators like RAS and RAF remain persistently mutated in many cancer types. These gain-of-function mutations, such as KRAS-4B(G12V/G13D/Q61K), NRAS(Q61L/Q61R) or BRAF(V600E), lead to tremendous increase in their activities, resulting in constitutively active extracellular signal-regulated kinase 1/2 (ERK1/2). They were not efficiently targeted by the first-generation inhibitors such as Lonafarnib or Sorafenib, which were essentially broad spectrum inhibitors targeting pan-RAS and pan-RAF, respectively. This triggered the development of the second-generation inhibitors selective against the mutated proteins. Second generation inhibitors such as Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar) targeting BRAF(V600E), Trametinib (Mekinist) targeting MEK1/2 and the first generation pan-RAF inhibitor Sorafenib (Nexavar) have already been approved for treating renal, hepatocellular, thyroid cancers and BRAF(V600E/K) harboring metastatic melanoma. Others against RAF and MEK1/2 are presently undergoing clinical trials. Their success would depend on the better understanding of the acquired resistance mechanisms to these drugs in the cancer cells and the identification of predictive biomarkers for the proper administration of suitable inhibitor(s).
An understanding of the high-temperature copper oxide (cuprate) superconductors has eluded the physics community for over thirty years and represents one of the greatest unsolved problems in ...condensed matter physics. Particularly enigmatic is the normal state from which superconductivity emerges, so much so that this phase has been dubbed a "strange metal." In this article, we review recent research into this strange metallic state as realized in the electron-doped cuprates with a focus on their transport properties. The electron-doped compounds differ in several ways from their more thoroughly studied hole-doped counterparts, and understanding these asymmetries of the phase diagram may prove crucial to developing a final theory of the cuprates. Most of the experimental results discussed in this review have yet to be explained and remain an outstanding challenge for theory.
The development and characterization of an organic thin-film diode based on herbal dyes has been presented. The electronic parameters of the diode are retrieved using a thermionic emission approach ...from the I-V characteristics. Furthermore, the computed values of ideality factor (n), barrier height (ϕ) and series resistance (Rs) of Al/Beetroot/Cu using the Cheung and Cheung functions are 4.5, 0.73 eV and 1.10 KΩ, respectively. The values of Rs in these two different approaches are very similar, but a discrepancy in values of n confirms the existence of high Rs and high interface state density. The band gap of betanin and temperature dependence of n, ϕ, and Rs confirm the semiconducting behaviour of beet root. We observed a linear relationship between ϕ and 1/n for Al/Beetroot/Cu, confirming that the device is a Schottky diode. The fact that quantum tunneling plays a significant role in the charge conduction procedure with thermionic emission is confirmed by the parabolic conductance of Al/Beetroot/Cu. We have identified that Schottky emission dominates Poole-Frenkle emission for the Al/Beetroot/Cu diode based on both theoretical and experimental values of β. The G(V) vs V plot was used to explain the existence of the reported dye's trapping effect. We also calculated the device's trap energy (Ec), which is substantially lower than previously reported organic diodes. The theoretically estimated value of the insulating temperature for Al/Beetroot/Cu is 133 K. When we utilise beetroot dye instead of indigo dye, the value of n and Rs decreases from 11.65 to 4.5 and 430 KΩ to 1.1 KΩ, respectively, according to the comparison analysis. The trap energy drops from 0.0732 to 0.021 eV once more.
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•The electronic parameters of the diode are retrieved using thermionic emission approach from the I-V characteristics and using Cheung and Cheung function.•Semiconducting behaviour of beet root is confirmed by the band gap and temperature dependence of Rs.•We observed a linear relationship between ϕ and 1/n, for Al/Beet/Cu confirming that the device is a Schottky diode.•The fact that quantum tunneling plays a significant role in the current conduction process with thermionic emission is confirmed by the Parabolic conductance of Al/Beet/Cu.•When we utilise beetroot dye instead of indigo dye, the value of n and Rs decreases from 11.65 to 4.5 and 430 KΩ to 1.1 KΩ, respectively. The trap energy drops from 0.0732 to 0.021 eV once more.
First released in 2009, MetaboAnalyst (www.metaboanalyst.ca) was a relatively simple web server designed to facilitate metabolomic data processing and statistical analysis. With continuing advances ...in metabolomics along with constant user feedback, it became clear that a substantial upgrade to the original server was necessary. MetaboAnalyst 2.0, which is the successor to MetaboAnalyst, represents just such an upgrade. MetaboAnalyst 2.0 now contains dozens of new features and functions including new procedures for data filtering, data editing and data normalization. It also supports multi-group data analysis, two-factor analysis as well as time-series data analysis. These new functions have also been supplemented with: (i) a quality-control module that allows users to evaluate their data quality before conducting any analysis, (ii) a functional enrichment analysis module that allows users to identify biologically meaningful patterns using metabolite set enrichment analysis and (iii) a metabolic pathway analysis module that allows users to perform pathway analysis and visualization for 15 different model organisms. In developing MetaboAnalyst 2.0 we have also substantially improved its graphical presentation tools. All images are now generated using anti-aliasing and are available over a range of resolutions, sizes and formats (PNG, TIFF, PDF, PostScript, or SVG). To improve its performance, MetaboAnalyst 2.0 is now hosted on a much more powerful server with substantially modified code to take advantage the server's multi-core CPUs for computationally intensive tasks. MetaboAnalyst 2.0 also maintains a collection of 50 or more FAQs and more than a dozen tutorials compiled from user queries and requests. A downloadable version of MetaboAnalyst 2.0, along detailed instructions for local installation is now available as well.
The effect of tensile straining on the precipitation and dislocation behavior of the over-aged 7075 aluminum alloy at T7352 temper have been investigated. Microstructures depict dissolution of the ...precipitates at low tensile straining but reprecipitation occurs at a higher amount of strain. Such precipitation improves the resistance against stress-corrosion cracking as well as other mechanical properties. Detailed characterization displayed the formation of dislocation loops, forest dislocation along with tangled dislocations at a low amount of straining corresponding to a true strain of ~0.02. In contrast, low-density, high-density Taylor lattices, and dislocation cell structures were seen at higher true straining of 0.06, and 0.1 respectively. Dissolution, reprecipitation of second phases, changes in orientation, and development of dislocation structures are contributing to the two-slope deformation behavior of AA7075T7352 alloy.
According to conventional wisdom, the extraordinary properties of the cuprate high-temperature superconductors arise from doping a strongly correlated antiferromagnetic insulator. The highly ...overdoped cuprates-whose doping lies beyond the dome of superconductivity-are considered to be conventional Fermi liquid metals. We report the emergence of itinerant ferromagnetic order below 4 kelvin for doping beyond the superconducting dome in thin films of electron-doped La
Ce
CuO
(LCCO). The existence of this ferromagnetic order is evidenced by negative, anisotropic, and hysteretic magnetoresistance, hysteretic magnetization, and the polar Kerr effect, all of which are standard signatures of itinerant ferromagnetism in metals. This surprising result suggests that the overdoped cuprates are strongly influenced by electron correlations.
Bovine respiratory disease (BRD) is one of the leading causes of morbidity and mortality in dairy calves. Identification of reliable biomarkers of naturally occurring BRD is essential for ensuring ...early diagnosis and treatment of calves and monitoring treatment efficacy. This need is punctuated, especially in mild to moderate cases that would greatly help to decrease recurrence and the overall prevalence of BRD. The present study was conducted to investigate the changes in serum concentrations of haptoglobin (Hpt) and serum amyloid A (SAA) and association between oxidative stress and acute phase proteins (APPs) in BRD. Hpt and SAA levels significantly increased (P < .01) in BRD stressed calves as compared to healthy subjects. There was a significant decrease (P < .01) in serum albumin (Alb) concentration of infected calves as compared to controls. The oxidative stress markers revealed a significant (P < .01) increase in lipid peroxidation (LPO) and a concurrent decrease in activities of superoxide dismutase (SOD), reduced glutathione (R-GSH) and catalase (CAT) in BRD. A significant correlation among APPs, extent of oxidative stress and clinical score (CS) of calves was depicted. A stepwise decrease in Hpt and SAA and increase in Alb was observed in infected calves post-treatment. These results suggest implication of oxidative stress in enhancing APPs and monitoring of APPs as a potential complement to clinical assessment of treatment in calves with naturally occurring BRD. Hpt may be useful as the most sensitive biomarker in BRD. However, the combined use of Hpt and oxidative stress biomarkers would greatly improve the diagnostic accuracy.
•Acute phase reaction may be employed for early diagnosis and treatment monitoring of bovine respiratory disease (BRD).•Haptoglobin, serum amyloid A (SAA) and oxidative stress parameters are potential biomarkers to distinguish healthy and BRD-stressed calves.•Haptoglobin is the most sensitive diagnostic biomarker of naturally occurring BRD in calves.
The Scaps-1d simulator was used to simulate a lead-free perovskite CH
3
NH
3
SnI
3
based solar cell devices fabricated from different hole transport materials (HTM). This research looks at two ...organic and two inorganic HTM layers. The cell structure used in this study is FTO/TiO
2
/CH
3
NH
3
SnI
3
/HTM (variable)/Au(variable). Spiro-OMeTAD, PEDOT:PSS, CuO and Cu
2
O are the HTM materials used. The results show that utilizing CuO as an HTM produces better outcomes than other HTMs, with an efficiency of 28.45%. The thickness, acceptor concentration (N
A
), and defect density (N
t
) of the perovskite layer on optoelectronic properties of the solar cell are focus of simulation studies. According to this study, an perovskite layer thickness of 1000 nm is suitable for a decent photovoltaic cell. Furthermore, by adjusting the HTM thickness and the defect density of HTM and absorber layer, promising findings of J
sc
of 34.38 mAcm
−2
, V
oc
of 1.011 V, FF of 80.85% and PCE of 28.10% were obtained for Spiro-OMeTAD based PSC. Finally, in order to improve the device's performance, an anode material with high work function is required. Our findings reveal that using a thin absorber layer results in low photo generated charge carriers due to less absorption, but high carrier extraction. Although more carriers are created in the cell due to increased absorption, decreased collection efficiency is related to recombination, which decreases V
oc
for thick perovskite layers. Device efficiency is improved by increasing the doping density up to 10
18
cm
−3
in the perovskite layer due to built-in electric field across the solar cell. Again a very thin or thick HTL is not ideal for high PCE. For low recombination and a high fill factor, an HTM (Spiro-OMeTAD) of 1–100 nm is necessary. The great power conversion efficiency of organic HTM based lead-free PSC brings up the new possibilities for obtaining renewable energy.
In this report, we have used cylindrical and spherical zinc oxide (ZnO) nanoparticles to fabricate FTO/ZnO/Al and herbal dye-based FTO/Beet + ZnO/Al Schottky diodes. Electrical parameters of the ...reported organic Schottky diode have been measured in different methods to analyse the effect of ZnO nano morphology on the device performance. These approaches were found to be remarkably consistent with one another. The calculated values of the FTO/Beetroot/Al series resistance (
R
s
), barrier height (
n
), trap energy (
E
c
), and ideality factor (
n
) are 1.77, 0.65 eV, 0.052 eV, and 589, respectively. These values change to 1.7, 0.62 eV, 0.048 eV, and 61, respectively, after the inclusion of cylindrical ZnO with beetroot dye. The values of
n
and
R
s
drop from 1.7 to 1.4 and 61 to 52 correspondingly when spherical ZnO nanoparticles are used in place of cylindrical ZnO. Again, reduction of trap energy of the reported organic Schottky diode is much higher in presence of Spherical ZnO than cylindrical ZnO. Series resistance (
R
s
), trap energy (
E
t
), and barrier height (ϕ) have all decreased, respectively, by 91%, 11.5%, and 8%. Using spherical ZnO instead of cylindrical ZnO results in a 17% greater reduction in
R
s
. The disclosed devices' mobility and current conductivity are enhanced by this lowering. In this article, the used ZnO nanoparticles are not spherically perfect; if they were, this increase would be more apparent.
Metabolic and neuroactive metabolite production represents one of the mechanisms through which the gut microbiota can impact health. One such metabolite, gamma-aminobutyric acid (GABA), can modulate ...glucose homeostasis and alter behavioural patterns in the host. We previously demonstrated that oral administration of GABA-producing Lactobacillus brevis DPC6108 has the potential to increase levels of circulating insulin in healthy rats. Therefore, the objective of this study was to assess the efficacy of endogenous microbial GABA production in improving metabolic and behavioural outcomes in a mouse model of metabolic dysfunction. Diet-induced obese and metabolically dysfunctional mice received one of two GABA-producing strains, L. brevis DPC6108 or L. brevis DSM32386, daily for 12 weeks. After 8 and 10 weeks of intervention, the behavioural and metabolic profiles of the mice were respectively assessed. Intervention with both L. brevis strains attenuated several abnormalities associated with metabolic dysfunction, causing a reduction in the accumulation of mesenteric adipose tissue, increased insulin secretion following glucose challenge, improved plasma cholesterol clearance and reduced despair-like behaviour and basal corticosterone production during the forced swim test. Taken together, this exploratory dataset indicates that intervention with GABA-producing lactobacilli has the potential to improve metabolic and depressive- like behavioural abnormalities associated with metabolic syndrome in mice.
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