Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced ...stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC.
The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections.
Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis.
Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.
Long noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma ...(HCC). Here, we show that lnc-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumour size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models. Lnc-EGFR stimulates Treg differentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner. Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression. Lnc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potential therapeutic target for HCC.
A novel heat pipe photovoltaic/thermal (PV/T) system that could simultaneously supply electrical and thermal energy was proposed. Compared with a traditional water-type PV/T system, the heat pipe ...PV/T system can be used in cold regions without becoming frozen. A dynamic model of the heat pipe PV/T system was presented, and a test rig was constructed. Experiments were conducted to validate the results of the simulation. Based on the validated model, the performances of the heat pipe PV/T system were studied under different parametric conditions, such as water flow rates, PV cell covering factor of the collector, tube space of heat pipes, and kinds of solar absorptive coatings of the absorber plate.
► A novel heat pipe photovoltaic/thermal system was designed and constructed. ► Performance of the HP-PV/T system is comparable with the water-type system. ► A dynamic model of the HP-PV/T system was presented.
Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients ...exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3–7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.
Significance Glaucoma is a leading cause of blindness, associated with elevated intraocular pressure (IOP) and progressive loss of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit diffuse loss of visual sensitivity, but the cellular origins of such sensitivity loss is unknown. In this study, we present evidence showing that elevated IOP decreases the efficacy of the rod bipolar cell to the AII amacrine cell synapse, resulting in reduction of RGC sensitivity. These findings, for the first time to our knowledge, identify the synaptic loci mediating visual sensitivity loss in early glaucoma, and can be used to develop new diagnostic tools and treatments for this blinding disease.
Cowpea (
) is widely cultivated across the world. Due to its symbiotic nitrogen fixation capability and many agronomically important traits, such as tolerance to low rainfall and low fertilization ...requirements, as well as its high nutrition and health benefits, cowpea is an important legume crop, especially in many semi-arid countries. However, research in
is dramatically hampered by the lack of mutant resources and efficient tools for gene inactivation in vivo. In this study, we used clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). We applied the CRISPR/Cas9-mediated genome editing technology to efficiently disrupt the representative symbiotic nitrogen fixation (SNF) gene in
. Our customized guide RNAs (gRNAs) targeting symbiosis receptor-like kinase (SYMRK) achieved ~67% mutagenic efficiency in hairy-root-transformed plants, and nodule formation was completely blocked in the mutants with both alleles disrupted. Various types of mutations were observed near the PAM region of the respective gRNA. These results demonstrate the applicability of the CRISPR/Cas9 system in
, and therefore should significantly stimulate functional genomics analyses of many important agronomical traits in this unique crop legume.
Some mammalian rod bipolar cells (RBCs) can receive excitatory chemical synaptic inputs from both rods and cones (DBCR2), but anatomical evidence for mammalian cone‐RBC contacts has been sparse. We ...examined anatomical cone‐RBC contacts using neurobiotin (NB) to visualize individual mouse cones and standard immuno‐markers to identify RBCs, cone pedicles and synapses in mouse and baboon retinas. Peanut agglutinin (PNA) stained the basal membrane of all cone pedicles, and mouse cones were positive for red/green (R/G)‐opsin, whereas baboon cones were positive for calbindin D‐28k. All synapses in the outer plexiform layer were labeled for synaptic vesicle protein 2 (SV2) and PSD (postsynaptic density)‐95, and those that coincided with PNA resided closest to bipolar cell somas. Cone‐RBC synaptic contacts were identified by: (a) RBC dendrites deeply invaginating into the center of cone pedicles (invaginating synapses), (b) RBC dendritic spines intruding into the surface of cone pedicles (superficial synapses), and (c) PKCα immunoreactivity coinciding with synaptic marker SV2, PSD‐95, mGluR6, G protein beta 5 or PNA at cone pedicles. One RBC could form 0‐1 invaginating and 1‐3 superficial contacts with cones. 20.7% and 38.9% of mouse RBCs contacted cones in the peripheral and central retina (p < .05, n = 14 samples), respectively, while 34.4% (peripheral) and 48.5% (central) of cones contacted RBCs (p > .05). In baboon retinas (n = 4 samples), cone‐RBC contacts involved 12.2% of RBCs (n = 416 cells) and 22.5% of cones (n = 225 cells). This suggests that rod and cone signals in the ON pathway are integrated in some RBCs before reaching AII amacrine cells.
Using confocal microscopy combined with cellular and synaptic markers, the authors show that a subset of mouse and primate rod bipolar cells (RBCs) receives synapses from both cone and rod photoreceptors. These synapses allow such a novel subtype of rod bipolar cells to integrate rod and cone signals for better processing of mesopic light signals in the retinal ON pathway.
Idiopathic pulmonary fibrosis (IPF) is a lethal and agnogenic interstitial lung disease, which has limited therapeutic options. Recently, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) ...inflammasome has been demonstrated as an important contributor to various fibrotic diseases following its persistent activation. However, the role of NLRP3 inflammasome in pulmonary fibrogenesis still needs to be further clarified. Here, we found that the activation of the NLRP3 inflammasome was raised in fibrotic lungs. In addition, the NLRP3 inflammasome was found to be activated in alveolar epithelial cells (AECs) in the lung tissue of both IPF patients and pulmonary fibrosis mouse models. Further research revealed that epithelial cells, following activation of the NLRP3 inflammasome, could induce the myofibroblast differentiation of lung-resident mesenchymal stem cells (LR-MSCs). In addition, inhibiting the activation of the NLRP3 inflammasome in epithelial cells promoted the expression of dickkopf-1 (DKK1), a secreted Wnt antagonist. DKK1 was capable of suppressing the profibrogenic differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis. In conclusion, this study not only provides a further in-depth understanding of the pathogenesis of pulmonary fibrosis, but also reveals a potential therapeutic strategy for disorders associated with pulmonary fibrosis.
•Activation of epithelial cells by NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome promotes pulmonary fibrosis.•NLRP3 inflammasome activation inhibits the expression of dickkopf-1 (DKK1).•Crosstalk between dysregulated epithelial cells and lung-resident mesenchymal stem cells contributes to pulmonary fibrosis.•MCC950 attenuates bleomycin-induced pulmonary fibrosis.
•Comparative study on annual performance of three types of Trombe wall systems.•Optimum blind angles over three seasons and time of day are obtained.•Total electricity saving of Trombe wall with PV ...blind is over 45% higher compared to existing PV Trombe walls.•Carbon emissions reduction of Trombe wall with PV blind are about 1.5 times that of existing PV Trombe walls.
Building-integrated photovoltaic (BIPV) Trombe wall system can provide heating/cooling and generate electricity simultaneously. Precedent studies on the BIPV Trombe wall system were focused on two major types, one with PV cells attached to glass (BIPVGTW) and the other with that attached to mass wall (BIPVMTW), characterized by low thermal (BIPVGTW) and electric efficiency (BIPVMTW). This study presents a PV blind-integrated Trombe wall system (BIPVBTW). Adopting developed models on the BIPVBTW, the optimum PV blind slat angles over three seasons (summer, winter and mid-term seasons) and time of day (9:00–17:00) are investigated. Comparative assessment of the three BIPV Trombe wall systems are conducted all year round under Hefei weather conditions, in terms of thermal and electrical performance. The results have illustrated that annual electricity output of BIPVBTW system is similar to that of BIPVGTW system, which is 1.2 times that of the BIPVMTW system. The BIPVGTW system is superior to the BIPVBTW/BIPVMTW systems in cooling load reduction, while using PVBTW/PVMTW heating load is decreased significantly compared to using the PVGTW. Combining electricity generation and cooling/heating load reduction, the total electricity saving of BIPVBTW system is over 45% higher compared to BIPVGTW/BIPVMTW systems. CO2 emissions reduction of the BIPVBTW system are about 1.5 times that of BIPVGTW/BIPVMTW systems.
By analyzing light-evoked spike responses, cation currents (ΔIC) and chloride currents (ΔICl) of over 100 morphologically-identified retinal ganglion cells (GCs) in dark-adapted mouse retina, we ...found there are at least 14 functionally- and morphologically-distinct types of RGCs. These cells can be divided into 5 groups based on their patterns of spike response to whole field light steps (SRWFLS), a GC identification scheme commonly used in studies with extracellular recording techniques. We also found that all GCs in the mouse retina express strychnine-sensitive glycine receptors, and receive light-elicited chloride current (ΔICl) accompanied by a conductance increase from narrow-field, glycinergic amacrine cells. As the dark membrane potential of RGC are near the chloride-equilibrium potential, mouse GCs’ spike responses are mediated primarily by bipolar cells inputs, and modulated by “shunting inhibition” from narrow-field amacrine cells. Analysis of strychnine actions on light-evoked cation current ΔIC (bipolar cell inputs) in GCs suggests that narrow-field amacrine cells modulate GCs by sending ON-OFF crossover feedback signals to presynaptic bipolar cell axon terminals via sign-inverting glycinergic synapses, and the feedback signals are synergistic to the bipolar cell light responses. Therefore narrow-field amacrine cells enhance light-evoked bipolar cell inputs to GCs by presynaptic “synergistic addition”, besides the abovementioned postsynaptic “shunting inhibition” in GCs.
Compared with wet anaerobic digestion, solid-state fermentation possesses many merits such as low water consumption, high biogas yield and low processing cost. In this work, co-producing biogas and ...humic acid (HA) by two-step solid-state fermentation was innovatively investigated using rice straw and pig manure as materials. The result indicates that C/N ratio, straw particle size, and total solid content (TS%) caused significant effects on the solid-state fermentation process. At the first step for anaerobic biogas fermentation, the optimal fermentation conditions included C/N ratio of 27.5, straw particle size of 0.85 mm and TS% of 25%. The maximal biogas productivity and methane content were up to 0.43 m3/(m3·d) and 64.88%, respectively. This means that biogas production was significantly improved by adjusting C/N ratio during the co-fermentation of rice straw and pig manure. Following, the digested residue was aerobically composted for HA biosynthesis to improve the fertilizer efficiency of the fermented substrate. The optimal aeration rate of 0.75 L/min was obtained, and the volatile solid (VS) degradation rate, HA content, and the germination index (GI) value were up to 19.16%, 100.89 mg/g, and 103.07%, respectively, which indicates that HA biosynthesis and compost maturity were significantly enhanced. Therefore, the co-production of biogas and HA using rice straw and pig manure as fermentation materials was achieved by adopting the two-step solid-state fermentation, and the bioconversion efficiencies of livestock manure and straw were significantly improved.
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•Two-step fermentation method for biogas and humic acid production was adopted.•Co-fermentation of rice straw and pig manure provided a suitable C/N for microbes.•Biogas production was enhanced by optimizing C/N ratio, particle size and TS%.•HA content and maturity were increased through aerobic compost at the second step.
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