Background
Triple‐negative breast cancer (TNBC) is prone to metastasis and has a poor prognosis, with lower survival rates than other breast cancer subtypes. MicroRNAs have recently emerged as ...powerful regulators of cancer processes and become a promising target in cancer therapy.
Methods
Expression of miR‐128 was examined in invasive ductal breast cancer, and its relationship with clinicopathological features analysed. A series of in vitro and in vivo experiments were performed to investigate the function and mechanism of miR‐128 in the development of invasive ductal breast cancer.
Results
A cohort of 110 women with TNBC and 117 with non‐TNBC were included in the study. In multivariable Cox regression analysis, overall and disease‐free survival were significantly associated with lymph node metastasis, histological grade and molecular subtype. Subgroup analysis showed that low expression of miR‐128 correlated with shorter overall and disease‐free survival in TNBC (P < 0·001), and shorter overall but not disease‐free survival in non‐TNBC. In addition, miR‐128 was able to inhibit glucose metabolism, mitochondrial respiration and proliferation of TNBC cells. These effects were consistent with miR‐128 targeting inhibition of the insulin receptor and insulin receptor substrate 1.
Conclusion
MiR‐128 might be a prognostic marker and possible molecular target for therapy in patients with TNBC.
New molecular target?
The dipyridyl herbicide paraquat induces oxidative stress in cells and is implicated in adult neurodegenerative diseases. However, less is known about paraquat toxicity in early stages of vertebrate ...development. To address this gap, zebrafish (Danio rerio) embryos were exposed to 1, 10 and 100 μM paraquat for 96 h. Paraquat did not induce significant mortality nor deformity in embryos and larvae, but it did accelerate time to hatch. To evaluate whether mitochondrial respiration was related to earlier hatch times, oxygen consumption rate was measured in whole embryos. Maximal respiration of embryos exposed to 100 μM paraquat for 24 h was reduced by more than 70%, suggesting that paraquat negatively impacts mitochondrial bioenergetics in early development. Based upon this evidence for mitochondrial dysfunction, transcriptional responses of oxidative stress- and apoptosis-related genes were measured. Fish exposed to 1 μM paraquat showed higher expression levels of superoxide dismutase 2, heat shock protein 70, Bcl-2-associated X protein, and B-cell CLL/lymphoma 2a compared to control fish. No differences among groups were detected in larvae exposed to 10 and 100 μM paraquat, suggesting a non-monotonic response. We also measured endpoints related to larval behavior and dopaminergic signaling as paraquat is associated with degeneration of dopamine neurons. Locomotor activity was stimulated with 100 μM paraquat and dopamine transporter and dopamine receptor 3 mRNA levels were increased in larvae exposed to 1 μM paraquat, interpreted to be a compensatory response at lower concentrations. This study improves mechanistic understanding into the toxic actions of paraquat on early developmental stages.
•Paraquat is an aquatic contaminant with multiple modes of action.•Exposure to 1, 10, 100 μM paraquat induced premature hatching in zebrafish.•Paraquat at 100 μM increased activity of zebrafish larvae.•Maximal respiration of 24 hpf larvae was affected by 100 μM paraquat.•Genes related to oxidative stress and dopamine signaling were altered by paraquat.
Red-skin root of Asian ginseng (Panax ginseng) significantly reduces the quality and limits the production of ginseng in China. The disease has long been thought to be a noninfectious physiological ...disease, except one report that proved it was an infectious disease. However, the causal agents have not been successfully determined. In the present study, we were to reveal the pathogens that cause red-skin disease.
Ginseng roots with red-skin root symptoms were collected from commercial fields in Northeast China. Fungi were isolated from the lesion and identified based on morphological characters along with multilocus sequence analyses on internal transcription spacer, β-tubulin (tub2), histone H3 (his3), and translation elongation factor 1α (tef-1α). Pathogens were confirmed by inoculating the isolates in ginseng roots.
A total of 230 isolates were obtained from 209 disease samples. These isolates were classified into 12 species, including Dactylonectria sp., D. hordeicola, Fusariumacuminatum, F. avenaceum, F. solani, F. torulosum, Ilyonectria mors-panacis, I. robusta, Rhexocercosporidium panacis, and three novel species I. changbaiensis, I. communis, and I. qitaiheensis. Among them, I. communis, I. robusta, and F. solani had the highest isolation frequencies, being 36.1%, 20.9%, and 23.9%, respectively. All these species isolated were pathogenic to ginseng roots and caused red-skin root disease under appropriate condition.
Fungal complex is the causal agent of red-skin root in P. ginseng.
Demands are growing rapidly in the operational prediction and applications communities for forecasts that fill the gap between medium-range weather and long-range or seasonal forecasts. Based on the ...potential for improved forecast skill at the subseasonal to seasonal time range, the Subseasonal to Seasonal (S2S) Prediction research project has been established by the World Weather Research Programme/World Climate Research Programme. A main deliverable of this project is the establishment of an extensive database containing subseasonal (up to 60 days) forecasts, 3 weeks behind real time, and reforecasts from 11 operational centers, modeled in part on the The Observing System Research and Predictability Experiment (THORPEX) Interactive Grand Global Ensemble (TIGGE) database for medium-range forecasts (up to 15 days).
The S2S database, available to the research community since May 2015, represents an important tool to advance our understanding of the subseasonal to seasonal time range that has been considered for a long time as a “desert of predictability.” In particular, this database will help identify common successes and shortcomings in the model simulation and prediction of sources of subseasonal to seasonal predictability. For instance, a preliminary study suggests that the S2S models significantly underestimate the amplitude of the Madden–Julian oscillation (MJO) teleconnections over the Euro-Atlantic sector. The S2S database also represents an important tool for case studies of extreme events. For instance, a multimodel combination of S2S models displays higher probability of a landfall over the islands of Vanuatu 2–3 weeks before Tropical Cyclone Pam devastated the islands in March 2015.
Whilst limited information on nitrogen and sulfur isotopic composition in wet deposition in cities is available, very few data on the sources of sulfur and nitrogen in both light rainfalls (<5
mm in ...precipitation and <4
h in duration) and heavy rainfalls (>100
mm in precipitation and <24
h in duration, caused by typhoon from the Pacific Ocean) have been accumulated. For both species a significant difference in mean sulfur and nitrogen isotopic composition was reported in this study between samples collected from light rainfalls (−4.9±2.8‰ for sulfate and +2.0±4.4‰ for nitrate) and heavy rainfalls (+4.6±5.0‰ for sulfate and +4.1±4.0‰ for nitrate), supporting that sulfur and nitrogen in the two types of rainfalls are of different sources. For sulfate, the negative
δ
34S values in light rainfalls are associated with local sources (coal combustion and biogenic sulfur) while sulfur in heavy rainfalls, with positive
δ
34S values, is of maritime origin. For nitrate, there is no definite information on the sources of nitrogen in light rainfalls because of a wide range of
δ
15N values (−3.8‰ to +10.7‰), but the higher
δ
15N values (>+6.0‰) are probably ascribed to dry deposition or coal-fired power plants; the mean
δ
15N value of +4.1‰ in heavy rainfalls may also be a reflection of maritime origin. Measurements of
δ
15N values for ammonium in light rainfalls show that
δ
15N values are closely related with ammonium concentrations (
R
2=0.92). The lower values in the range of
δ
15N values (−1.7‰ to −22.0‰) for ammonium are due to less incorporation of
15N by cloud water, which probably has a
δ
15N value of about −22.0‰. But the higher concentrations (averaging 1.25
mg
l
−1) and lower
δ
15N values (averaging −12.2±6.7‰) indicated that ammonium steps from excretory wastes are extensively applied in agriculture and NH
3 released from soils.
ABSTRACT
The study of blazar jet has been performed for several decades via VLBI technique, while its generation and propagation stay unclear. In the present work, we compiled a sample of 407 VLBI ...detected Fermi blazars (VFBs) and studied the correlations between apparent velocity (${\rm log}\, \beta _{\rm app}$) and jet/accretion disc properties. We found a positive correlation between γ-ray luminosity (${\rm log}\, L_{\rm \gamma }$) and ${\rm log}\, \beta _{\rm app}$; the correlation suggests that the apparent motion of jet knot is related to the jet power. The correlations between ${\rm log}\, \beta ^{\rm max}_{\rm app}$ and the jet radiation power (${\rm log}\, L_{\rm rad}$), and between ${\rm log}\, \beta ^{\rm max}_{\rm app}$ and the jet extended region luminosity at 5 GHz (${\rm log}\, L_{\rm 5GHz}^{\rm ext}$), which is an indicator of jet kinetic power, reveal that the knots apparent motion is correlated with both jet radiation power and the kinetic power. But this indication is not held for flat-spectrum radio quasar (FSRQs) in terms of the correlation ${\rm log}\, L_{\rm 5GHz}^{\rm ext}\, versus \, {\rm log}\, \beta ^{\rm max}_{\rm app}$. Besides, ${\rm log}\, \beta ^{\rm max}_{\rm app}$ has a moderate correlation with accretion disc luminosity (${\rm log}\, L_{\rm Disk}$) and the normalized accretion disc luminosity ${\rm log}\, (L_{\rm Disk}/L_{\rm Edd})$, which may suggest both the power of accretion disc and the accretion rate are critical to generate knots and to accelerate them. In addition, we found the VFBs have larger average values of γ-ray luminosity (${\rm log}\, L_{\rm \gamma }$), γ-ray photon index (αph), and variability index (${\rm log}\, VI$) than the rest of Fermi blazars. Through Gaussian mixture models method, we generated a criteria, ${\rm log}\, L_{\rm \gamma } \gt 45.40$, αph > 2.24, and ${\rm log}\, VI \gt 1.71$ to find VFB candidates, selected 228 VFB candidates from the rest of Fermi blazar.
The dissolved carbon concentration, which is responsible for aquatic ecosystem productivity and water quality, is tightly coupled with hydrological processes. Excess dissolved carbon may exacerbate ...eutrophication and hypoxia in aquatic ecosystems and lead to deterioration of water quality. Storm events dominate the dynamics of dissolved carbon concentrations, and this nonlinear behavior exhibits significant time scale dependence. Here, we identified inter- and intra-event variability in the dissolved carbon concentration–discharge (C–Q) relationship in an agriculture-intensive catchment. The driving factors of C–Q hysteresis patterns for dissolved inorganic carbon (DIC) and organic carbon (DOC) were quantified by redundancy analysis combined with hierarchical partitioning. At the inter-event scale, DIC exhibited mainly clockwise hysteresis, indicating an exhaustible, proximal source (e.g., groundwater). However, DOC hysteresis was generally counter-clockwise, indicating distal and plentiful sources (e.g., soil water) in the agricultural catchment. Hierarchical partitioning showed that total rainfall, peak discharge and flood intensity explained 28.38% of the total variation in C–Q hysteresis for DIC and 39.87% for DOC at the inter-event scale. At the intra-event scale, time series analysis of dissolved carbon concentration and discharge indicated the interconversion of supply limitation to transport limitation, which depends on the activation of the specific DIC or DOC source zones. These findings provide significant insights into understanding the dynamics of dissolved carbon during storm periods and are important for targeted watershed management practices aimed at reducing carbon loading to surface waters.
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Abstract The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic ...pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to 10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2–4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, whereas the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.
Trichloromethane and dichloromethane have toxic effects on the liver, and incidents of toxic liver disease caused by them have been reported from time to time. In November 2021, an occupational ...chemical poisoning incident occurred in a shoe factory in Huidong County, Guangdong Province. After testing the air at the scene and analyzing the clinical data of the poisoning patients, it was preliminarily determined that the poisoning was caused by a mixed gas poisoning incident dominated by trichoromethane. At admission, the liver function of 7 patients was tested for different degrees of impairment (alanine aminotransferase 145-2501 IU/L, aspartate aminotransferase 66-1286 IU/L). The volatile organic components of on-site raw and auxiliary materials were analyzed. The percentages of trichloromethane and dichloromethane detected in 103A powder glue used in the poisoning workshop site accounted for 21.11% and 6.77% respectively.
Our gene expression-profiling analysis aimed to explain the mechanism of breast cancer development by identifying key pathways and constructing networks of related transcription factors (TFs) and ...microRNAs (miRNAs) in breast cancer tissues. Gene expression profiles of normal and breast cancer tissues were downloaded to identify differentially expressed genes (DEGs). Coexpression modules were explored using weighted gene coexpression network analysis (WGCNA). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to discover the enriched functionally associated gene groups and define pathways in breast cancer, respectively. miRNAs-DEGs and TF-DEG regulatory networks were constructed using Cytoscape. CDK6(cyclin-dependent kinase), miR-124, EGF(epidermal growth factor) and NF-κB(nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) expression was also analyzed using real-time quantitative PCR. Totally, 7713 DEGs were identified for WGCNA. The results revealed that 1388 upregulated DEGs were associated with protein transport, protein localization and organic substance transport, whereas 1819 downregulated DEGs were associated with cancer and Wnt signaling pathways. Five miRNAs (miR-760, miR-1276, miR-124, miR-124-3p and miR-506-3p) with a degree of ⩾15 and one important TF (NF-κB) were identified in miRNA and TF regulatory networks. CDK6 mRNA and miR-124 expression was significantly reduced and EGF mRNA expression was clearly enhanced in cancer tissues compared with those in normal breast tissues. The CDK6 gene could be regulated by miR-124, which is involved in Wnt signaling and cancer pathways. NF-κB might initiate the breast cancer pathway by targeting EGF in human breast cancer tissues. This putative information on regulatory networks in breast cancer will be beneficial for future researches on mechanisms underlying its development.
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