The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological ...process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.
Downstream ERK kinase appears to be the Achilles' Heel of the MAPK pathway. Targeting ERK kinase provides potential therapeutic opportunities for a broad spectrum of cancers bearing RAS, RAF and MEK mutations as well as those with acquired resistance to BRAF and MEK inhibitors (RAFi and MEKi). Display omitted
Mesenchymal stem cell (MSC) transplantation alone may be insufficient for treatment of liver fibrosis because of complicated histopathological changes in the liver. Given that miR‐122 plays an ...essential role in liver fibrosis by negatively regulating the proliferation and transactivation of hepatic stellate cells (HSCs), this study investigated whether miR‐122 modification can improve the therapeutic efficacy of adipose tissue‐derived MSCs in treating liver fibrosis. MiR‐122‐modified AMSCs (AMSC‐122) were constructed through lentivirus‐mediated transfer of pre‐miR‐122. MiR‐122‐modified AMSCs expressed high level of miR‐122, while they retained their phenotype and differentiation potential as naïve AMSCs. AMSC‐122 more effectively suppressed the proliferation of and collagen maturation in HSCs than scramble miRNA‐modified AMSCs. In addition, AMSC‐derived exosomes mediated the miR‐122 communication between AMSCs and HSCs, further affecting the expression levels of miR‐122 target genes, such as insulin‐like growth factor receptor 1 (IGF1R), Cyclin G(1) (CCNG1) and prolyl‐4‐hydroxylase α1 (P4HA1), which are involved in proliferation of and collagen maturation in HSCs. Moreover, miR‐122 modification enhanced the therapeutic efficacy of AMSCs in the treatment of carbon tetrachloride (CCl4)‐induced liver fibrosis by suppressing the activation of HSCs and alleviating collagen deposition. Results demonstrate that miR‐122 modification improves the therapeutic efficacy of AMSCs through exosome‐mediated miR‐122 communication; thus, miR‐122 modification is a new potential strategy for treatment of liver fibrosis.
Previous meta-analyses on associations between air pollution (AP) and type 2 diabetes mellitus (T2DM) were mainly focused on studies conducted in high-income countries. Evidence should be updated by ...including more recent studies, especially those conducted in low- and middle-income countries. We therefore conducted a systematic review and meta-analysis of epidemiological studies to conclude an updated pooled effect estimates between long-term AP exposure and the prevalence and incidence of T2DM. We searched PubMed, Embase, and Web of Science to identify studies regarding associations of AP with T2DM prevalence and incidence prior to January 2019. A random-effects model was employed to analyze the overall effects. A total of 30 articles were finally included in this meta-analysis. The pooled results showed that higher levels of AP exposure were significantly associated with higher prevalence of T2DM (per 10 μg/m3 increase in concentrations of particles with aerodynamic diameter < 2.5 μm (PM2.5): odds ratio (OR) = 1.09, 95% confidence interval (95%CI): 1.05, 1.13; particles with aerodynamic diameter < 10 μm (PM10): OR = 1.12, 95%CI: 1.06, 1.19; nitrogen dioxide (NO2): OR = 1.05, 95%CI:1.03, 1.08). Besides, higher level of PM2.5 exposure was associated with higher T2DM incidence (per 10 μg/m3 increase in concentration of PM2.5: hazard ratio (HR) = 1.10, 95%CI:1.04, 1.16), while the associations between PM10, NO2 and T2DM incidence were not statistically significant. The associations between AP exposure and T2DM prevalence showed no significant difference between high-income countries and low- and middle-incomes countries. However, different associations were identified between PM2.5 exposure and T2DM prevalence in different geographic areas. No significant differences were found in associations of AP and T2DM prevalence/incidence between females and males, except for the effect of NO2 on T2DM incidence. Overall, AP exposure was positively associated with T2DM. There still remains a need for evidence from low- and middle-income countries on the relationships between AP and T2DM.
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•Long-term exposure to air pollution was associated with an increased risk of T2DM.•Different associations between females and males were not identified.•Epidemiologic studies on exposure-response relationship should be encouraged.
Long-term exposure to air pollution was positively associated with T2DM.
A decade ago, non-radiative wireless power transmission re-emerged as a promising alternative to deliver electrical power to devices where a physical wiring proved impracticable. However, ...conventional "coupling-based" approaches face performance issues when multiple devices are involved, as they are restricted by factors like coupling and external environments. Zenneck waves are excited at interfaces, like surface plasmons and have the potential to deliver electrical power to devices placed on a conducting surface. Here, we demonstrate, efficient and long range delivery of electrical power by exciting non-radiative waves over metal surfaces to multiple loads. Our modeling and simulation using Maxwell's equation with proper boundary conditions shows Zenneck type behavior for the excited waves and are in excellent agreement with experimental results. In conclusion, we physically realize a radically different class of power transfer system, based on a wave, whose existence has been fiercely debated for over a century.
Previous studies have suggested that exposure to air pollution may increase stroke risk, but the results remain inconsistent. Evidence of more recent studies is highly warranted, especially gas air ...pollutants.
We searched PubMed, Embase, and Web of Science to identify studies till February 2020 and conducted a meta-analysis on the association between air pollution (PM
, particulate matter with aerodynamic diameter less than 2.5 μm; PM
, particulate matter with aerodynamic diameter less than 10 μm; NO
, nitrogen dioxide; SO
, sulfur dioxide; CO, carbon monoxide; O
, ozone) and stroke (hospital admission, incidence, and mortality). Fixed- or random-effects model was used to calculate pooled odds ratios (OR)/hazard ratio (HR) and their 95% confidence intervals (CI) for a 10 μg/m
increase in air pollutant concentration.
A total of 68 studies conducted from more than 23 million participants were included in our meta-analysis. Meta-analyses showed significant associations of all six air pollutants and stroke hospital admission (e.g., PM
: OR = 1.008 (95% CI 1.005, 1.011); NO
: OR = 1.023 (95% CI 1.015, 1.030), per 10 μg/m
increases in air pollutant concentration). Exposure to PM
, SO
, and NO
was associated with increased risks of stroke incidence (PM
: HR = 1.048 (95% CI 1.020, 1.076); SO
: HR = 1.002 (95% CI 1.000, 1.003); NO
: HR = 1.002 (95% CI 1.000, 1.003), respectively). However, no significant differences were found in associations of PM
, CO, O
, and stroke incidence. Except for CO and O
, we found that higher level of air pollution (PM
, PM
, SO
, and NO
) exposure was associated with higher stroke mortality (e.g., PM
: OR = 1.006 (95% CI 1.003, 1.010), SO
: OR = 1.006 (95% CI 1.005, 1.008).
Exposure to air pollution was positively associated with an increased risk of stroke hospital admission (PM
, PM
, SO
, NO
, CO, and O
), incidence (PM
, SO
, and NO
), and mortality (PM
, PM
, SO
, and NO
). Our study would provide a more comprehensive evidence of air pollution and stroke, especially SO
and NO
.
Generally, UHS-ECC should consume massive cement, which is negative to its sustainability as cement production leads to 8% of global CO2 emissions. To decrease the cost of production and carbon ...emissions of UHS-ECC, rice husk ash was employed to replace the cement as a supplementary cementitious material in this study. Experiment results illustrate that blending rice husk ash (RHA) would decrease the fluidity of mortar. Furthermore, the green UHS-ECC shows a maximum compressive strength of 130.3 MPa at 28 days when RHA content was 20% of cement. The ultimate tensile strength of UHS-ECCs first increased and then decreased, while both tensile strain and strain energy presented an opposite tendency. At the micro-scale, if RHA content was lower than 20% of cement, incorporating RHA can significantly decreasing fiber bridging complementary energy of UHS-ECC, thus reducing pseudo strain hardening energy (PSHenergy) index, which finely agrees with the degradation of ductility of UHS-ECCs. To guarantee the features of ultra-high strength, acceptable workability, and high tensile ductility, the RHA dosage should not be in excess 20% of cement. These researched results are prospected to the contribution of pozzolanic RHA on the efficient usage of sustainable UHS-ECC.
Vectorial optical fields (VOFs) exhibiting arbitrarily designed wavefronts and polarization distributions are highly desired in photonics. However, current methods to generate them either require ...complicated setups or exhibit limited functionalities, which is unfavorable for integration-optics applications. Here, we propose a generic approach to efficiently generate arbitrary VOFs based on metasurfaces exhibiting full-matrix yet inhomogeneous Jones-matrix distributions. We illustrate our strategy with analytical calculations on a model system and an experimental demonstration of a meta-device that can simultaneously deflect light and manipulate its polarization. Based on these benchmark results, we next experimentally demonstrate the generation of a far-field VOF exhibiting both a vortex wavefront and an inhomogeneous polarization distribution. Finally, we design/fabricate a meta-device and experimentally demonstrate that it can generate a complex near-field VOF-a cylindrically polarized surface plasmon wave possessing orbital angular momentum-with an efficiency of ~34%. Our results establish an efficient and ultracompact platform for generating arbitrary predesigned VOFs in both the near- and far-fields, which may find many applications in optical manipulation and communications.
An increasing number of studies have been conducted to determine a possible linkage between maternal exposure to ambient fine particulate matter and effects on the developing human fetus that can ...lead to adverse birth outcomes, but, the present results are not consistent. A total of 23 studies published before July 2016 were collected and analyzed and the mean value of reported exposure to fine particulate matter (PM2.5) ranged from 1.82 to 22.11 We found a significantly increased risk of preterm birth with interquartile range increase in PM2.5 exposure throughout pregnancy (odds ratio (OR) = 1.03; 95% conditional independence (CI): 1.01–1.05). The pooled OR for the association between PM2.5 exposure, per interquartile range increment, and term low birth weight throughout pregnancy was 1.03 (95% CI: 1.02–1.03). The pooled ORs for the association between PM2.5 exposure per 10 increment, and term low birth weight and preterm birth were 1.05 (95% CI: 0.98–1.12) and 1.02 (95% CI: 0.93–1.12), respectively throughout pregnancy. There is a significant heterogeneity in most meta-analyses, except for pooled OR per interquartile range increase for term low birth weight throughout pregnancy. We here show that maternal exposure to fine particulate air pollution increases the risk of preterm birth and term low birth weight. However, the effect of exposure time needs to be further explored. In the future, prospective cohort studies and personal exposure measurements needs to be more widely utilized to better characterize the relationship between ambient fine particulate exposure and adverse birth outcomes.
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•The results had shorter intervals indicate and smaller heterogeneity by using IQR increment increase as selected standard.•The manuscript included the latest research results and updated the previous systematic review and meta-analysis.
Meta-analysis of preterm birth and term low birth weight of PM2.5
Sunlight drives photosynthesis and associated biological processes, and also influences inorganic processes that shape Earth’s climate and geochemistry. Bacterial solar-to-chemical energy conversion ...on this planet evolved to use an intricate intracellular process of phototrophy. However, a natural nonbiological counterpart to phototrophy has yet to be recognized. In this work, we reveal the inherent “phototrophic-like” behavior of vast expanses of natural rock/soil surfaces from deserts, red soils, and karst environments, all of which can drive photon-to-electron conversions. Using scanning electron microscopy, transmission electron microscopy, micro-Raman spectroscopy, and X-ray absorption spectroscopy, Fe and Mn (oxyhydr)oxide-rich coatings were found in rock varnishes, as were Fe (oxyhydr)oxides on red soil surfaces and minute amounts of Mn oxides on karst rock surfaces. By directly fabricating a photoelectric detection device on the thin section of a rock varnish sample, we have recorded an in situ photocurrent micromapping of the coatings, which behave as highly sensitive and stable photoelectric systems. Additional measurements of red soil and powder separated from the outermost surface of karst rocks yielded photocurrents that are also sensitive to irradiation. The prominent solarresponsive capability of the phototrophic-like rocks/soils is ascribed to the semiconducting Fe- and Mn (oxyhydr)oxide-mineral coatings. The native semiconducting Fe/Mn-rich coatings may play a role similar, in part, to photosynthetic systems and thus provide a distinctive driving force for redox (bio)geochemistry on Earth’s surfaces.
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