Optimizing ABA-based chemically induced proximity for enhanced intracellular transcriptional activation and modification response to ABA.

Abscisic acid (ABA)-based chemically induced proximity (CIP) is primarily mediated by the interaction of the ABA receptor pyrabactin resistance 1-like 1 (PYL1) and the 2C-type protein phosphatase ABI1, which confers ABA-induced proximity to their fusion proteins, and offers precise temporal control of a wide array of biological processes. However, broad application of ABA-based CIP has been limited by ABA response intensity. In this study, we demonstrated that ABA-induced interaction between another ABA receptor pyrabactin resistance 1 (PYR1) and ABI1 exhibited higher ABA response intensity than that between PYL1 and ABI1 in HEK293T cells. We engineered PYR1-ABI1 and PYL1-ABI1 into ABA-induced transcriptional activation tools in mammalian cells by integration with CRISPR/dCas9 and found that the tool based on PYR1-ABI1 demonstrated better ABA response intensity than that based on PYL1-ABI1 for both exogenous and endogenous genes in mammalian cells. We further achieved ABA-induced RNA m6A modification installation and erasure by combining ABA-induced PYR1-ABI1 interaction with CRISPR/dCas13, successfully inhibiting tumor cell proliferation. We subsequently improved the interaction of PYR1-ABI1 through phage-assisted continuous evolution (PACE), successfully generating a PYR1 mutant (PYR1m) whose interaction with ABI1 exhibited a higher ABA response intensity than that of the wild-type. In addition, we tested the transcriptional activation tool based on PYRm-ABI1 and found that it also showed a higher ABA response intensity than that of the wild type. These results demonstrate that we have developed a novel ABA-based CIP and further improved upon it using PACE, providing a new approach for the modification of other CIP systems.

[Influence of wind, cold and dampness on clinical manifestation of knee osteoarthritis patients based on the stratifications of traditional Chinese medicine constitution].

OBJECTIVE: To explore influence of external factors of wind, cold and dampness on clinical symptoms in knee osteoarthritis (KOA) patients with different constitutions of traditional Chinese medicine. METHODS: A cross-sectional stratified study was performed to select 108 patients with GradeⅡKOA in Kellgren & Lawrence (K-L) classification, including 22 males and 86 females, aged from 47 to 75 years old with an average of (60.7±6.0) years old;body mass index(BMI) ranged from 17.87 to 31.22 kg·m-2 with an average of (23.80±2.86) kg·m-2. According to Classification and Judgment of TCM Physique (ZYYXH/T157-2009), the types of TCM physique were determined and divided into 4 layers according to the deficiency and actual physique. Among them, there were 24 patients without biased physique, 12 males and 12 females, aged from 51 to 73 years old with an average of(62.8±6.0) years old, BMI ranged from 17.87 to 31.14 kg·m-2 with an average of (24.32±3.25) kg·m-2;there were 46 patients with virtual bias constitution, including 7 males and 39 females, aged from 47 to 70 years old with an average of (60.0±5.8) years old, BMI ranged from 19.38 to 31.22 kg·m-2 with an average of(23.42±2.97) kg·m-2;There were 26 patients with solid bias constitution, including 2 males and 24 females, aged from 48 to 75 years old with an average of (60.4±5.8) years old, BMI ranged from 21.16 to 30.76 kg·m-2 with an average of (24.15±2.33) kg·m-2;there were 9 patients with special constitution, 1 male and 8 female, aged from 53 to 75 years old with an average of (59.8±7.5) years old, BMI ranged from 19.26 to 26.67 kg·m-2 with an average of (23.79±2.49) kg·m-2. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to evaluate severity of clinical symptoms. The wind-cold-dampness external factor score was calculated through the questionnaire of wind-cold-dampness syndrome scale to evaluate degree of influence of wind-cold-dampness external factor. Pearson correlation analysis and partial correlation analysis were used to calculate the correlation coefficient between severity of external factors affecting wind, cold and dampness and severity of clinical symptoms in patients with different TCM constitution stratification. RESULTS: There was no statistical significance between total score of wind-cold-dampness and WOMAC score in patients with no biased constitution and special condition. Total wind-cold-dampness score of patients with virtual biased constitution was positively correlated with WOMAC stiffness score (r=0.327, P=0.032), and total wind-cold-dampness score of patients with solid biased constitution was positively correlated with WOMAC pain score (r=0.561, P=0.005) and WOMAC overall score (r=0.446, P=0.033). After further adjusting for the interaction of external factors of wind-cold-dampness, there was no statistical significance between wind-cold-dampness scores and WOMAC scores in patients with solid biased constitution. The score of dampness and pathogenic factors was positively correlated with WOMAC stiffness score (r=0.414, P=0.007). CONCLUSION: The external factors of wind-cold dampness have different effects on the clinical symptoms of KOA patients with different TCM constitutions. Compared with other constitutions, the rigid symptoms of patients with asthenic biased constitutions are more susceptible to dampness pathogenic factors.

Short-term legacy effects of long-term nitrogen and water addition on soil chemical properties and micro-bial characteristics in a temperate grassland.

Nitrogen deposition and summer precipitation in eastern Inner Mongolia are predicted to increase in recent decades. However, such increases in nitrogen inputs and precipitation may not be continuous under the future new patterns of global change, with the direction and magnitude of which may change or weaken. The legacy effects of nitrogen and water addition after cessation on ecosystems are still unclear. Based on a 13-year nitrogen and water addition experiment in temperate grassland of northern China, we examined the short-term (2 years) legacy effects of historical nitrogen and water addition on soil physicochemical properties and microbial properties after the cessation of nitrogen and water addition in the 14th year. The results showed that the positive effects of historical nitrogen addition on most of soil nutrient variables diminished after two years of cessation, including ammonium nitrogen, nitrate nitrogen, dissolved organic carbon and nitrogen, and Olsen-P concentrations. In contrast, there were legacy effects on soil microbial characteristics. For example, the historical nitrogen input of 15 g N·m-2·a-1 reduced microbial biomass carbon, respiration, and alkaline phosphomonoesterase activity by 73.3%, 81.9%, and 70.3% respectively. It implied that microbial parameters restored slowly in comparison with soil nutrients, showing a hysteresis effect. Results of Pearson's correlation and redundancy analysis showed that the legacy effects of historical nitrogen addition on microbial parameters could be attributed to the negative effects of nitrogen addition on soil pH. Historical water addition showed significant legacy effects on soil pH, ammonium nitrogen, dissolved organic carbon and nitrogen, respiration, and soil enzyme activities, which significantly interacted with historical nitrogen addition. These results are of great significance to predict the changes in grassland ecosystem functions and services under the local environmental improvement conditions, and to reveal the restoration mechanism of degraded grassland.

Study of the Microstructure of Coal at Different Temperatures and Quantitative Fractal Characterization.

In order to understand the influence of underground coal fires on coal fractures and pores, mercury intrusion porosimetry (MIP) and scanning electron microscopy (SEM) are combined to study the development of coal pore and fracture under high-temperature treatment and calculate the fractal dimension to analyze the relationship between the development of coal pore and fracture and the fractal dimension. The results show that the volume of pores and fractures of the coal sample (C200) treated at 200 °C (0.1715 mL/g) is greater than that of the coal sample (C400) treated at 400 °C (0.1209 mL/g), and both are greater than the original coal sample (RC) (0.1135 mL/g). The volume increase is mainly due to mesopores and macropores, and the proportions of mesopores and macropores in C200 were 70.15 and 59.97% in C400. The MIP fractal dimension shows a decreasing trend with the increase of temperature, and the connectivity of coal samples improved with the increase of temperature. The changes in volume and three-dimensional fractal dimension of C200 and C400 showed the opposite trend and are related to the different stress of coal matrix at different temperatures. The experimental SEM images confirm that the connectivity of coal fractures and pores improves with the increase of temperature. Based on the SEM experiment, the larger the fractal dimension, the more complex the surface is. The SEM surface fractal dimensions indicate that the surface fractal dimension of C200 is the smallest and that of C400 is the largest, which is consistent with the observations made by SEM. The combination of the two fractal dimensions is used to characterize the self-similarity of coal using the fractal dimension difference. When the temperature increased to 200 °C, the unordered expansion of the coal sample resulted in the largest fractal dimension difference and the lowest self-similarity. When heated to 400 °C, the fractal dimension difference of the coal sample is the smallest, and the microstructure of coal shows a regular groove-like development.

The protein phosphatase PC1 dephosphorylates and deactivates CatC to negatively regulate H2O2 homeostasis and salt tolerance in rice.

Catalase (CAT) is often phosphorylated and activated by protein kinases to maintain hydrogen peroxide (H2O2) homeostasis and protect cells against stresses, but whether and how CAT is switched off by protein phosphatases remains inconclusive. Here, we identified a manganese (Mn2+)-dependent protein phosphatase, which we named PHOSPHATASE OF CATALASE 1 (PC1), from rice (Oryza sativa L.) that negatively regulates salt and oxidative stress tolerance. PC1 specifically dephosphorylates CatC at Ser-9 to inhibit its tetramerization and thus activity in the peroxisome. PC1 overexpressing lines exhibited hypersensitivity to salt and oxidative stresses with a lower phospho-serine level of CATs. Phosphatase activity and seminal root growth assays indicated that PC1 promotes growth and plays a vital role during the transition from salt stress to normal growth conditions. Our findings demonstrate that PC1 acts as a molecular switch to dephosphorylate and deactivate CatC and negatively regulate H2O2 homeostasis and salt tolerance in rice. Moreover, knockout of PC1 not only improved H2O2-scavenging capacity and salt tolerance but also limited rice grain yield loss under salt stress conditions. Together, these results shed light on the mechanisms that switch off CAT and provide a strategy for breeding highly salt-tolerant rice.

N-linoleyltyrosine resisted the growth of non-small cell lung cancer cells via the regulation of CB1 and CB2 involvement of PI3K and ERK pathways.

Background: N-linoleyltyrosine (NITyr), one of the anandamide analogs, exerts activity via the endocannabinoid receptors (CB1 and CB2), which showed anti-tumor effects in various tumors. Therefore, we speculated that NITyr might show anti-non-small cell lung cancer (NSCLC) effects via the CB1 or CB2 receptor. The purpose of the investigation was to reveal the anti-tumor ability of NITyr on A549 cells and its mechanisms. Methods: The viability of A549 cells was measured by MTT assay, and the cell cycle and apoptosis were both examined by flow cytometry; in addition, cell migration was tested by wound healing assay. Apoptosis-related markers were measured by immunofluorescence. The downstream signaling pathways (PI3K, ERK, and JNK) of CB1 or CB2 were examined through Western blotting. The expressions of CB1 and CB2 were detected by immunofluorescence. Finally, the AutoDock software was used to validate the binding affinity between the targets, such as CB1 and CB2, with NITyr. Results: We found that NITyr inhibited cell viability, hindered the cell cycle, resulted in apoptosis, and inhibited migration. The CB1 inhibitor, AM251, and the CB2 inhibitor, AM630, weakened the aforementioned phenomenon. The immunofluorescence assay suggested that NITyr upregulated the expression of CB1 and CB2. Western blot analysis indicated that NITyr upregulated the expression of p-ERK, downregulated the expression of p-PI3K, and did not affect p-JNK expression. In conclusion, NITyr showed a role in inhibiting NSCLC through the activation of CB1 and CB2 receptors involved in PI3K and ERK pathways.

Unconventional Bilateral Compressive Strained Ni-Ir Interface Synergistically Accelerates Alkaline Hydrogen Oxidation.

The alkaline hydrogen oxidation reaction (HOR) involves the coupling of adsorbed hydrogen (Had) and hydroxyl (OHad) species and is thus orders of magnitude slower than that in acid media. According to the Sabatier principle, developing electrocatalysts with appropriate binding energy for both intermediates is vital to accelerating the HOR though it is still challenging. Herein, we propose an unconventional bilateral compressive strained Ni-Ir interface (Ni-Ir(BCS)) as efficient synergistic HOR sites. Density functional theory (DFT) simulations reveal that the bilateral compressive strain effect leads to the appropriate adsorption for both Had and OHad, enabling their coupling thermodynamically spontaneous and kinetically preferential. Such Ni-Ir(BCS) is experimentally achieved by embedding sub-nanometer Ir clusters in graphene-loaded high-density Ni nanocrystals (Ni-Ir(BCS)/G). As predicted, it exhibits a HOR mass activity of 7.95 and 2.88 times those of commercial Ir/C and Pt/C together with much enhanced CO tolerance, respectively, ranking among the most active state-of-the-art HOR catalysts. These results provide new insights into the rational design of advanced electrocatalysts involving coordinated adsorption and activation of multiple reactants.

[Clinical and radiologic comparison between oblique lateral interbody fusion and minimally invasive transforaminal lumbar interbody fusion for degenerative lumbar spondylolisthesis].

OBJECTIVE: To compare the short-term clinical efficacy and radiologic differences between oblique lateral interbody fusion(OLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) for degenerative lumbar spondylolisthesis. METHODS: A retrospective analysis was performed on 58 patients with lumbar spondylolisthesis treated with OLIF or MIS-TLIF from April 2019 to October 2020. Among them, 28 patients were treated with OLIF (OLIF group), including 15 males and 13 females aged 47 to 84 years old with an average age of (63.00±9.38) years. The other 30 patients were treated with MIS-TLIF(MIS-TLIF group), including 17 males and 13 females aged 43 to 78 years old with an average age of (61.13±11.10) years. General conditions, including operation time, intraoperative blood loss, postoperative drainage, complications, lying in bed, and hospitalization time were recorded in both groups. Radiological characteristics, including intervertebral disc height (DH), intervertebral foramen height (FH), and lumbar lordosis angle (LLA), were compared between two groups. The visual analogue scale (VAS) and Oswestry disability index (ODI) were used to evaluate the clinical effect. RESULTS: The operation time, intraoperative blood loss, postoperative drainage, lying in bed, and hospitalization time in OLIF group were significantly less than those in the MIS-TLIF group (P<0.05). The intervertebral disc height and intervertebral foramen height were significantly improved in both groups after the operation (P<0.05). The lumbar lordosis angle in OLIF group was significantly improved compared to before the operation(P<0.05), but there was no significant difference in the MIS-TLIF group before and after operation(P>0.05). Postoperative intervertebral disc height, intervertebral foramen height, and lumbar lordosis were better in the OLIF group than in the MIS-TLIF group (P<0.05). The VAS and ODI of the OLIF group were lower than those of the MIS-TLIF group within 1 week and 1 month after the operation (P<0.05), and there were no significant differences in VAS and ODI at 3 and 6 months after the operation between the two groups(P>0.05). In the OLIF group, 1 case had paresthesia of the left lower extremity with flexion-hip weakness and 1 case had a collapse of the endplate after the operation;in the MIS-TLIF group, 2 cases had radiation pain of lower extremities after decompression. CONCLUSION: Compared with MIS-TLIF, OLIF results in less operative trauma, faster recovery, and better imaging performance after lumbar spine surgery.

Interfacial assembly of binary atomic metal-Nx sites for high-performance energy devices.

Anion-exchange membrane fuel cells and Zn-air batteries based on non-Pt group metal catalysts typically suffer from sluggish cathodic oxygen reduction. Designing advanced catalyst architectures to improve the catalyst's oxygen reduction activity and boosting the accessible site density by increasing metal loading and site utilization are potential ways to achieve high device performances. Herein, we report an interfacial assembly strategy to achieve binary single-atomic Fe/Co-Nx with high mass loadings through constructing a nanocage structure and concentrating high-density accessible binary single-atomic Fe/Co-Nx sites in a porous shell. The prepared FeCo-NCH features metal loading with a single-atomic distribution as high as 7.9 wt% and an accessible site density of around 7.6 × 1019 sites g-1, surpassing most reported M-Nx catalysts. In anion exchange membrane fuel cells and zinc-air batteries, the FeCo-NCH material delivers peak power densities of 569.0 or 414.5 mW cm-2, 3.4 or 2.8 times higher than control devices assembled with FeCo-NC. These results suggest that the present strategy for promoting catalytic site utilization offers new possibilities for exploring efficient low-cost electrocatalysts to boost the performance of various energy devices.

Influence of wind, cold and dampness on clinical manifestation of knee osteoarthritis patients based on the stratifications of traditional Chinese medicine constitution / 中国骨伤

OBJECTIVE@#To explore influence of external factors of wind, cold and dampness on clinical symptoms in knee osteoarthritis (KOA) patients with different constitutions of traditional Chinese medicine.@*METHODS@#A cross-sectional stratified study was performed to select 108 patients with GradeⅡKOA in Kellgren & Lawrence (K-L) classification, including 22 males and 86 females, aged from 47 to 75 years old with an average of (60.7±6.0) years old;body mass index(BMI) ranged from 17.87 to 31.22 kg·m-2 with an average of (23.80±2.86) kg·m-2. According to Classification and Judgment of TCM Physique (ZYYXH/T157-2009), the types of TCM physique were determined and divided into 4 layers according to the deficiency and actual physique. Among them, there were 24 patients without biased physique, 12 males and 12 females, aged from 51 to 73 years old with an average of(62.8±6.0) years old, BMI ranged from 17.87 to 31.14 kg·m-2 with an average of (24.32±3.25) kg·m-2;there were 46 patients with virtual bias constitution, including 7 males and 39 females, aged from 47 to 70 years old with an average of (60.0±5.8) years old, BMI ranged from 19.38 to 31.22 kg·m-2 with an average of(23.42±2.97) kg·m-2;There were 26 patients with solid bias constitution, including 2 males and 24 females, aged from 48 to 75 years old with an average of (60.4±5.8) years old, BMI ranged from 21.16 to 30.76 kg·m-2 with an average of (24.15±2.33) kg·m-2;there were 9 patients with special constitution, 1 male and 8 female, aged from 53 to 75 years old with an average of (59.8±7.5) years old, BMI ranged from 19.26 to 26.67 kg·m-2 with an average of (23.79±2.49) kg·m-2. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to evaluate severity of clinical symptoms. The wind-cold-dampness external factor score was calculated through the questionnaire of wind-cold-dampness syndrome scale to evaluate degree of influence of wind-cold-dampness external factor. Pearson correlation analysis and partial correlation analysis were used to calculate the correlation coefficient between severity of external factors affecting wind, cold and dampness and severity of clinical symptoms in patients with different TCM constitution stratification.@*RESULTS@#There was no statistical significance between total score of wind-cold-dampness and WOMAC score in patients with no biased constitution and special condition. Total wind-cold-dampness score of patients with virtual biased constitution was positively correlated with WOMAC stiffness score (r=0.327, P=0.032), and total wind-cold-dampness score of patients with solid biased constitution was positively correlated with WOMAC pain score (r=0.561, P=0.005) and WOMAC overall score (r=0.446, P=0.033). After further adjusting for the interaction of external factors of wind-cold-dampness, there was no statistical significance between wind-cold-dampness scores and WOMAC scores in patients with solid biased constitution. The score of dampness and pathogenic factors was positively correlated with WOMAC stiffness score (r=0.414, P=0.007).@*CONCLUSION@#The external factors of wind-cold dampness have different effects on the clinical symptoms of KOA patients with different TCM constitutions. Compared with other constitutions, the rigid symptoms of patients with asthenic biased constitutions are more susceptible to dampness pathogenic factors.

Clinical and radiologic comparison between oblique lateral interbody fusion and minimally invasive transforaminal lumbar interbody fusion for degenerative lumbar spondylolisthesis / 中国骨伤

OBJECTIVE@#To compare the short-term clinical efficacy and radiologic differences between oblique lateral interbody fusion(OLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) for degenerative lumbar spondylolisthesis.@*METHODS@#A retrospective analysis was performed on 58 patients with lumbar spondylolisthesis treated with OLIF or MIS-TLIF from April 2019 to October 2020. Among them, 28 patients were treated with OLIF (OLIF group), including 15 males and 13 females aged 47 to 84 years old with an average age of (63.00±9.38) years. The other 30 patients were treated with MIS-TLIF(MIS-TLIF group), including 17 males and 13 females aged 43 to 78 years old with an average age of (61.13±11.10) years. General conditions, including operation time, intraoperative blood loss, postoperative drainage, complications, lying in bed, and hospitalization time were recorded in both groups. Radiological characteristics, including intervertebral disc height (DH), intervertebral foramen height (FH), and lumbar lordosis angle (LLA), were compared between two groups. The visual analogue scale (VAS) and Oswestry disability index (ODI) were used to evaluate the clinical effect.@*RESULTS@#The operation time, intraoperative blood loss, postoperative drainage, lying in bed, and hospitalization time in OLIF group were significantly less than those in the MIS-TLIF group (P<0.05). The intervertebral disc height and intervertebral foramen height were significantly improved in both groups after the operation (P<0.05). The lumbar lordosis angle in OLIF group was significantly improved compared to before the operation(P<0.05), but there was no significant difference in the MIS-TLIF group before and after operation(P>0.05). Postoperative intervertebral disc height, intervertebral foramen height, and lumbar lordosis were better in the OLIF group than in the MIS-TLIF group (P<0.05). The VAS and ODI of the OLIF group were lower than those of the MIS-TLIF group within 1 week and 1 month after the operation (P<0.05), and there were no significant differences in VAS and ODI at 3 and 6 months after the operation between the two groups(P>0.05). In the OLIF group, 1 case had paresthesia of the left lower extremity with flexion-hip weakness and 1 case had a collapse of the endplate after the operation;in the MIS-TLIF group, 2 cases had radiation pain of lower extremities after decompression.@*CONCLUSION@#Compared with MIS-TLIF, OLIF results in less operative trauma, faster recovery, and better imaging performance after lumbar spine surgery.

Synthesis and Antibacterial Activity Evaluation of Biphenyl and Dibenzofuran Derivatives as Potential Antimicrobial Agents against Antibiotic-Resistant Bacteria.

The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, a series of biphenyl and dibenzofuran derivatives were designed and synthesized by Suzuki-coupling and demethylation reactions in moderate to excellent yields (51-94% yield). Eleven compounds exhibited potent antibacterial activities against the prevalent antibiotic-resistant Gram-positive and Gram-negative pathogens, among which compounds 4'-(trifluoromethyl)-[1,1'-biphenyl]-3,4,5-triol (6i) and 5-(9H-carbazol-2-yl) benzene-1,2,3-triol (6m) showed the most potent inhibitory activities against methicillin-resistant Staphylococcus aureus and multidrug-resistant Enterococcus faecalis with MIC (minimum inhibitory concentration) values as low as 3.13 and 6.25 µg/mL, respectively. Compounds 3',5'-dimethyl-[1,1'-biphenyl]-3,4,4',5-tetraol (6e), 4'-fluoro-[1,1'-biphenyl]-3,4,5-triol (6g), and 4'-(trifluoromethyl)-[1,1'-biphenyl]-3,4,5-triol (6i) showed comparable inhibitory activities with ciprofloxacin to Gram-negative bacterium carbapenems-resistant Acinetobacter baumannii. Study of the structure-activity relationship indicated that a strong electron-withdrawing group on the A ring and hydroxyl groups on the B ring of biphenyls were beneficial to their antibacterial activities, and for benzo-heterocycles, N-heterocycle exhibited optimal antibacterial activity. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria.

N-linoleyltyrosine protects neurons against Aß1-40-induced cell toxicity via autophagy involving the CB2/AMPK/mTOR/ULK1 pathway.

Beta-amyloid protein (Aß) is one of the most important pathogenic factors of Alzheimer's disease (AD). N-linoleyltyrosine (NITyr) was synthesized in our laboratory and exerted neuroprotective effects in APP/PS1 transgenic mice in previous reports. In this study, the neuroprotective effects and mechanisms of NITyr were evaluated in Aß1-40-treated primary cortical neurons for the first time in vitro. NITyr treatment attenuated cytotoxicity induced by Aß1-40, and the best effect of NITyr was observed at 1 µmol/L. NITyr treatment increased the BDNF protein expression and the ratio of p-CREB/CREB, but weakened the Caspase-3 protein expression. Meanwhile, NITyr enhanced the expressions of autophagy-related proteins (LC3-II, Beclin-1, ATG5 and ATG13). The autophagy inhibitor 3-methyladenine (3MA) reversed the effects of NITyr on cell viability and the protein expressions of neuron-related proteins, including BDNF, p-CREB and Caspase-3. The CB2 receptor antagonist AM630 weakened the neuroprotective effects of NITyr and the autophagy-related protein expression (LC3-II, Beclin-1, ATG5 and ATG13). Moreover, NITyr significantly increased the expressions of p-AMPK, p-mTOR and p-ULK1, but not p-p38. AM630 ablated the above phenomenon. Therefore, NITyr protected the neurons against Aß1-40-induced cytotoxicity by inducing autophagy, which involved the CB2/AMPK/mTOR/ULK1 pathway.

LncRNA CASC9 activated by STAT3 promotes the invasion of breast cancer and the formation of lymphatic vessels by enhancing H3K27ac-activated SOX4.

Numerous long noncoding RNAs (lncRNAs) are abnormally expressed in breast cancer (BC), but the underlying mechanisms remain large unknown. Here, we aimed to investigate the functions and mechanisms of lncRNA cancer susceptibility candidate 9 (CASC9) in BC. Western blotting and quantitative real-time PCR (qRT-PCR) were performed to assess gene and protein expression, respectively. The proliferative and metastatic abilities of BC cells were tested by cell counting kit-8 and transwell assays, respectively. The formation of lymphatic vessels was detected by tube formation assay. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were performed to verify molecular interactions. CASC9 was found to be highly expressed in BC tissues and cell lines, and ectopic overexpression was positively associated with tumor volume, TNM stage, and lymph node metastasis. In addition, CASC9 silencing significantly inhibited the proliferation and invasion of BC cells, as well as BC-associated invasion and formation of lymphatic vessels of human dermal lymphatic endothelial cells. Mechanical studies demonstrated that CASC9 could be transcriptionally activated by STAT3 and elevate SOX4 expression by enhancing the acetylation of its promoter region. Our results illustrated that STAT3-activated CASC9 served as a tumor-promoting gene involved in promoting BC invasion and BC-associated formation of lymphatic vessels by upregulating SOX4 through altering H3K27ac level. This finding elucidated a new underlying network of CASC9 in the metastasis of BC.

Electrocatalytic Hydrogen Oxidation in Alkaline Media: From Mechanistic Insights to Catalyst Design.

With the potential to circumvent the need for scarce and cost-prohibitive platinum-based catalysts in proton-exchange membrane fuel cells, anion-exchange membrane fuel cells (AEMFCs) are emerging as alternative technologies with zero carbon emission. Numerous noble metal-free catalysts have been developed with excellent catalytic performance for cathodic oxygen reduction reaction in AEMFCs. However, the anodic catalysts for hydrogen oxidation reaction (HOR) still rely on noble metal materials. Since the kinetics of HOR in alkaline media is 2-3 orders of magnitude lower than that in acidic media, it is a major challenge to either improve the performance of noble metal catalysts or to develop high-performance noble metal-free catalysts. Additionally, the mechanisms of alkaline HOR are not yet clear and still under debate, further hampering the design of electrocatalysts. Against this backdrop, this review starts with the prevailing theories for alkaline HOR on the basis of diverse activity descriptors, i.e., hydrogen binding energy theory and bifunctional theory. The design principles and recent advances of HOR catalysts employing the aforementioned theories are then summarized. Next, the strategies and recent progress in improving the antioxidation capability of HOR catalysts, a thorny issue which has not received sufficient attention, are discussed. Moreover, the significance of correlating computational models with real catalyst structure and the electrode/electrolyte interface is further emphasized. Lastly, the remaining controversies about the alkaline HOR mechanisms as well as the challenges and possible research directions in this field are presented.

Chemokines in colon cancer progression.

Colon cancer is a major human cancer accounting for about a tenth of all cancer cases thus making it among the top three cancers in terms of incidence as well as mortality. Metastasis to distant organs, particularly to liver, is the primary reason for associated mortality. Chemokines, the chemo-attractants for various immune cells, have increasingly been reported to be involved in cancer initiation and progression, including in colon cancer. Here we discuss the available knowledge on the role of several chemokines, such as, CCL2, CCL3, CCL5, CXCL1, CXCL2, CXCL8 in colon cancer progression. CCL20 is one chemokine with emerging evidence for its role in influencing colon cancer tumor microenvironment through the documents effects on fibroblasts, macrophages and immune cells. We focus on CCL20 and its receptor CCR6 as promising factors that affect multiple levels of colon cancer progression. They interact with several cytokines and TLR receptors leading to increased aggressiveness, as supported by multitude of evidence from in vitro, in vivo studies as well as human patient samples. CCL20-CCR6 bring about their biological effects through regulation of several signaling pathways, including, ERK and NF-κB pathways, in addition to the epithelial-mesenchymal transition. Signaling involving CCL20-CCR6 has profound effect on colon cancer hepatic metastasis. Combined with elevated CCL20 levels in colon tumors and metastatic patients, the above information points to a need for further evaluation of chemokines as diagnostic and/or prognostic biomarkers.

Study of the therapeutic effect of raw and processed Vladimiriae Radix on ulcerative colitis based on intestinal flora, metabolomics and tissue distribution analysis.

BACKGROUND: The intestinal flora imbalance and metabolic disorders are closely related to the pathogenesis of ulcerative colitis (UC). As a commonly used herb for the treatment of gastrointestinal diseases, Vladimiriae Radix (VR) has been used for hundreds of years, and its main active ingredients are costunolide (COS) and dehydrocostus lactone (DEH). Clinical usage habits and previous studies have shown that the processed Vladimiriae Radix (pVR) seems to be more suitable for treating bowel disease than the raw Vladimiriae Radix (rVR), but there is still no relevant comparative study. PURPOSE: To investigate the therapeutic effect of rVR and pVR on UC by analyzing the intestinal flora, metabolomics and tissue distribution. METHODS: UC rat models were established to investigate the anti-inflammatory activities of rVR and pVR by enzyme-linked immunosorbent assay (ELISA), and to study their regulation of intestinal flora and metabolism by 16s rRNA gene analysis and Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). Moreover, the distribution of COS and DEH in UC mouse tissues were also observed by High Performance Liquid Chromatography Mass Spectrometry (HPLC-MS). RESULTS: rVR and pVR reduced tissue damage and the levels of TNF-α, IL-6, IL-1ß, IL-10, TGF-ß and MPO, especially pVR. 16s rRNA gene analysis showed that rVR superior in ameliorating species evenness and restoring the abundance of Lachnospiraceae and Ruminococcaceae, while pVR is better at increasing the richness and the abundance of Prevotellaceae. Metabolomics analysis suggested that rVR regulates the ß-alanine, pantothenic acid and coenzyme A biosynthesis, but pVR regulates more abundant metabolic pathways. The tissue distribution data indicated the accumulation of COS and DEH in the gastrointestinal tract. CONCLUSION: rVR and pVR had obvious therapeutic effect on UC. The potential mechanisms might be regulating abnormal metabolism, affecting the diversity and structure of intestinal flora, and accumulation of COS and DEH in colon.

Exosomal miR-21 promotes proliferation, invasion and therapy resistance of colon adenocarcinoma cells through its target PDCD4.

Exosomes contain cell-specific collections of bioactive materials including proteins, lipids, and RNAs that are transported to recipient cells to exert their impacts. MicroRNAs (miRNAs) can function as tumor suppressor or oncogenic genes and miR-21 is one of the most frequently up-regulated miRNAs in solid tumors including colon cancer. The aim of this study was to investigate the role of miR-21, secreted from exosomes, in proliferation and invasion of colon cancer, along with the mechanistic details. We used a variety of biochemical techniques including ultracentrifugation-based exosome purification, electron transmission microscopy, western blot and RT-qPCR to detect the expression levels of miR-21 in exosomes purified from culture media of human colonic adenocarcinoma cell lines. We then performed functional and mechanistic studies using three colon cancer cell lines HT29, T84 and LS174 as well as the normal colon epithelial cells CRL1831. miR-21 target PDCD4 was investigated for its role in mediating miR-21 effects. Expression of miR-21 was significantly up-regulated in exosomes of colon cancer cells, compared to the normal human colon epithelial cells. Treatment of colon cancer cells with isolated exosomes or miR-21 led to an increased expression of genes involved in cell proliferation, invasion and extracellular matrix formation. miR-21 targets PDCD4, TPM1 and PTEN were down-regulated by exosomes and silencing of PDCD4 mimicked miR-21 functional effects, even the induced resistance against 5-FU. Our study suggests that targeted inhibition of exosomes, particularly those carrying miR-21, may represent a novel approach for treatment of colorectal cancer.

High expression of PSF1 promotes drug resistance and cell cycle transit in leukemia cells.

Escape of cancer cells from chemotherapy is a problem in the management of cancer patients. Research on chemotherapy resistance has mainly focused on the heterogeneity of cancer cells, multiple gene mutations, and quiescence of malignant cancer cells. However, some studies have indicated that interactions between cancer cells and vascular cells promote resistance to chemotherapy. Here, we established mouse leukemia models using the cell lines THP-1 or MEG-1. These were derived from acute and chronic myeloid leukemias, respectively, and highly expressed DNA replication factor PSF1, a member of the GINS complex. We found that, after anti-cancer drug administration, surviving GFP-positive leukemia cells in the bone marrow were located adjacent to blood vessels, as previously reported in a subcutaneous solid tumor transplantation model. Treating THP-1 and MEG-1 cells with anti-cancer drugs in vitro revealed that those most strongly expressing PSF1 were most chemoresistant, suggesting that PSF1 induces not only cell cycle progression but also facilitates cell survival. Indeed, when PSF1 expression was suppressed by shRNA, the growth rate was reduced and cell death was enhanced in both cell lines. Furthermore, PSF1 knockdown in leukemia cells led to a change in their location at a distance from the blood vessels in a bone marrow transplantation model. These findings potentially reflect a mechanism of escape of leukemic cells from chemotherapy and suggest that PSF1 may be a possible therapeutic target to enhance the effect of chemotherapy.

ZnCdO2 monolayer - A complex 2D structure of ZnO and CdO monolayers for photocatalytic water splitting driven by visible-light.

ZnO monolayer possesses band structure matching the conditions of water splitting for hydrogen generation but cannot well response to the visible light, while CdO one, contrariwise, have obvious optical absorption in the visible light range but no satisfactory band edges for the water splitting to produce hydrogen. Here, we predict a two-dimensional ZnCdO2 structure comprising of ZnO and CdO ones to achieve their strengths. The band structures, optical properties, carrier mobility, and the strain engineering for ZnCdO2, ZnO and CdO monolayers are investigated by using the first-principles hybridization functional calculations. The results demonstrate that the two-dimensional ZnCdO2 structure is a promising candidate for water splitting to produce hydrogen. All the structures show a direct band energy gap and the character remains unchanged under the considered biaxial strains. All the conduction band minimums are suitable for water splitting reaction even under the -4% to +4% strain. Moreover, the valence band maximum of ZnCdO2 monolayer matches the conditions of the water-splitting reaction under the -2% to +4% strain. Interestingly, the unsatisfactory valence band maximum of CdO monolayer can be overcome by strain larger than +2%. As expected, the enhanced optical absorption in the visible light range is observed for the ZnCdO2 monolayer. Additionally, the mobilities of the hole and the electron are significantly different for the three monolayers, implying that the low recombination ratio of the photogenerated carrier pairs is available, which is also beneficial for the photocatalytic performance. Therefore, ZnCdO2 monolayer and CdO monolayer (with tensile strain larger than 2%) is a promising candidate for the water splitting to produce hydrogen under the irradiation of the solar light.