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To estimate the variations in clinical target volumes (CTVs) and organs at risk delineation within the quality assurance (QA) program of the POTENTIAL trial, which is a multicenter, randomized phase 3 trial evaluating postmastectomy radiation therapy (RT), with or without internal mammary nodal irradiation, for patients with high-risk breast cancer.The simulating computed tomography scan data set of a benchmark case was sent to the participating centers, and the delineation of CTVs and organs at risk was required to be completed by the investigators following protocol guidelines. All submitted contours were reviewed and compared with the reference contours created by the QA team, using quantitative geometric analysis regarding volume and the Jaccard Index (JCI), Dice similarity coefficient, Geographic Miss Index, Discordance Index, and mean distance to agreement. In addition to the whole-volume analysis of all structures, the combination contour of the supraclavicular fossa and level III and II axilla (CTVsc + axIII + axII) was further analyzed on a slice-by-slice basis.The contours from 26 centers were reviewed and variations were observed between submission and reference. The variations of the CTV of the chest wall, contralateral breast, and heart were small, for which the mean JCI values were 0.62, 0.68, and 0.87, respectively. However, the mean JCI values of the CTV of the internal mammary nodal region, ipsilateral brachial plexus, left anterior descending coronary artery, and right coronary artery were 0.38, 0.21, 0.29, and 0.18, respectively, suggesting marked variations. In addition, marked under- and overoutlining variations were identified on 4 slices of CTVsc + axIII + axII on slice-by-slice analysis.There were residual contouring variations despite a detailed protocol being provided, confirming the importance of pretrial QA in RT and highlighting the need for education and consideration of a real-time central review of the target delineation before the trial participants begin RT.

piRNAs are important in protecting germline integrity. 3’-terminal 2’-O-methylation is essential for piRNA maturation and to protect it from degradation. HENMT1 carries out the 2’-O-methylation, which is of key importance for piRNA stability and functionality. However, neither the structure nor the catalytic mechanism of HENMT1 have been studied. We have constructed a catalytic-competent HENMT1 complex using computational approaches, in which Mg2+is primarily coordinated by four evolutionary conserved residues, and is further auxiliary coordinated by the 3’-O and 2’-O on the 3’-terminal nucleotide of the piRNA. Our study suggests that metal has limited effects on substrate and cofactor binding but is essential for catalysis. The reaction consists of deprotonation of the 2’-OH to 2’-O and methyl transfer from SAM to the 2’-O. The methyl transfer is spontaneous and fast. Our in-depth analysis suggests that the 2’-OH may be deprotonated before entering the active site or it may be partially deprotonated at the active site by His800 and Asp859, which are in a special alignment that facilitates the proton transfer out of the active site. Furthermore, we have developed a detailed potential reaction scenario and our study indicates that HEN1 is Mg2+utilizing but is not a Mg2+dependent enzyme.

The PRDM family of methyltransferases has been implicated in cellular proliferation and differentiation and is deregulated in human diseases, most notably in cancer. PRDMs are related to the SET domain family of methyltransferases; however, from the 19 PRDMs only a few PRDMs with defined enzymatic activities are known. PRDM15 is an uncharacterized transcriptional regulator, with significant structural disorder and lack of defined small-molecule binding pockets. Many aspects of PRDM15 are yet unknown, including its structure, substrates, reaction mechanism, and its methylation profile. Here, we employ a series of computational approaches for an exploratory investigation of its potential substrates and reaction mechanism. Using the knowledge of PRDM9 and current knowledge of PRDM15 as basis, we tried to identify genuine substrates of PRDM15. We start from histone-based peptides and learn that the native substrates of PRDM15 may be non-histone proteins. In the future, a combination of sequence-based approaches and signature motif analysis may provide new leads. In summary, our results provide new information about the uncharacterized methyltransferase, PRDM15.

Excessive fat accumulation in the liver has become a major health threat worldwide. Unresolved fat deposition in the liver can go undetected until it develops into fatty liver disease, followed by steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Lipid deposition in the liver is governed by complex communication, primarily between metabolic organs. This can be mediated by hormones, organokines, and also, as has been more recently discovered, metabolites. Although how metabolites from peripheral organs affect the liver is well documented, the effect of metabolic players released from the liver during the development of fatty liver disease or associated comorbidities needs further attention. Here we focus on interorgan crosstalk based on metabolites released from the liver and how these molecules act as signaling molecules in peripheral tissues. Due to the liver’s specific role, we are covering lipid and bile mechanism-derived metabolites. We also discuss the high sucrose intake associated with uric acid release from the liver. Excessive fat deposition in the liver during fatty liver disease development reflects disrupted metabolic processes. As a response, the liver secretes a variety of signaling molecules as well as metabolites which act as a footprint of the metabolic disruption. In the coming years, the reciprocal exchange of metabolites between the liver and other metabolic organs will gain further importance and will help to better understand the development of fatty liver disease and associated diseases.

Protein-protein coupling reactions under physiological conditions that do not impact the three-dimensional structures of the proteins are in high demand. Owing to the combination of phenylsulfonyl and aldehyde groups in 5-fluoro-4-(phenylsulfonyl)picolinaldehyde (FPPA), the fluorine substituent shows high reactivity toward free thiols. In FPPA, the fluorine is more reactive than phenylsulfonyl for free thiols. Thus the first quantitative nucleophilic substitution can be followed by selective substitution of phenylsulfonyl by an additional thiol or cyclization of aldehyde with a 1,2-aminothiol molecule. The FPPA mediated protein-protein coupling proceeds efficiently under mild conditions, resulting in stable protein conjugates. This coupling method has negligible 3D structural perturbations on the target proteins, and it produces overall intact, nearly traceless, and native structural folds of proteins. It is highly suitable for reconstruction of proteins that are difficult to make and segmental isotopic labeling of multidomain proteins.

In this paper, the polyvinylpyrrolidone (PVP) as a stabilizer, a novel composite material Cu2O-g–C3N4–PVP-GF is formed by co-deposition of cuprous oxide (Cu2O) and graphene-like graphite carbon nitride (g-C3N4) on graphite felt (GF). Moreover, via different means, analysis results clarify the potential application of this material in the field of photoelectrochemistry. Herein, apparent physicochemical properties of materials were characterized by means of Field Emission Scanning Electron Microscope (FESEM), High Resolution Transmission Electron Microscope (HRTEM), X-ray Diffractometer (XRD), Raman and X-ray Photoelectron Spectroscopy (XPS), while photoelectric properties of ones were further analyzed through UV–visible Diffuse Reflectance Spectroscopy (UV–Vis-DRS), Photoluminescence (PL), Ultraviolet Photoelectron Spectroscopy (UPS), EIS and other means. Subsequently, the research focused on continuous-in-situ photoelectrochemical synthesis of hydrogen peroxide in seawater environment by laboratory scale electrochemical system. It is worth mentioning that the optimal composite material produced has the stable hydrogen peroxide content of up to about 84 mg/L and about 99% current efficiency under the illumination of white LEDs, which is of great significance in engineering applications.

In this study, we explored a novel approach to enhancing the production and bioactivities of Ganoderma exopolysaccharides. The homologous phosphomannomutase gene (PMM1) was cloned and overexpressed in Ganoderma for the first time. As a result, the maximum production of exopolysaccharides by the PMM1 transformant was 1.53 g/L, which was 1.41-fold higher than of a wild-type (WT) strain in a 5-L bioreactor. The transcription levels of PMM1 and PMM2 increased 40.5- and 2.4-fold, respectively, whereas the value of the GDP-D-mannose pyrophosphorylase gene did not change significantly in this transgenic strain. Furthermore, the major exopolysaccharide fractions from PMM1 transformants contained higher amounts of mannose (56.5 % and 21.1 %) than those from a WT strain (26.7 % and 9.3 %). Moreover, the major fractions from PMM1 transformants exhibited stronger regulation effects on macrophage. In conclusion, this study is helpful for the efficient production and application of Ganoderma exopolysaccharides and facilitates an understanding of polysaccharide biosynthesis regulation.

As a result of molecular phylogenetic analyses and morphological studies, two new species of the genus Pseudosperma, namely P. fulvidiscum and P. singulare were discovered in Wuzhishan Nature Reserve of Hainan Province of China. The two new species are distinct from other known Pseudosperma species in the phylogenetic polygram inferred from a combined nuclear ribosomal internal transcribed spacer region (ITS), the nuclear ribosomal large subunit (nrLSU), and the nuclear second-largest subunit of RNA polymerase II (RPB2) sequence data. Muscarine contents of the two new species were detected using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach. In addition, a new combination was proposed based on phylogenetic evidences.

This is supplementary material to the data in the manuscript, including 3 tables and a figure.

Aspirin as a chemopreventive agent is able to restrict the tumor growth. Phosphoglycerate mutase 1 (PGAM1) is a key enzyme of glycolysis, playing an important role in the development of cancer. However, the underlying mechanism by which aspirin inhibits the proliferation of cancer cells is poorly understood. This study aims to identify the effects of aspirin on modulating PGAM1 enzymatic activities in liver cancer. Here, we found that aspirin attenuated the PGAM1 succinylation to suppress the PGAM1 enzymatic activities and glycolysis in hepatoma cells. Mechanically, aspirin remarkably reduced the global succinylation levels of hepatoma cells, including the PGAM1 succinylation, which led to the block of conversion from 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG) in cells. Interestingly, RNA-seq analysis identified that aspirin could significantly decrease the levels of histone acetyltransferase 1 (HAT1), a writer of PGAM1 succinylation, in liver cancer. As a target of aspirin, NF-κB p65 could effectively up-regulate the expression of HAT1 in the system, resulting in the increase of PGAM1 enzymatic activities. Moreover, we observed that the PGAM1-K99R mutant failed to rescue the aspirin-induced inhibition of PGAM1 activities, glycolysis, and proliferation of hepatoma cells relative to PGAM1-WT. Functionally, aspirin down-regulated HAT1 and decreased the PGAM1 succinylation levels in the tumor tissues from mice treated with aspirin in vivo. Thus, we conclude that aspirin modulates PGAM1K99 succinylation to restrict the PGAM1 activities and glycolysis through NF-κB p65/HAT1/PGAM1 signaling in liver cancer. Our finding provides new insights into the mechanism by which aspirin inhibits glycolysis in hepatocellular carcinoma.

Nuclear receptors (NRs) are key regulators of energy homeostasis, body development, and sexual reproduction. Xenobiotics binding to NRs may disrupt natural hormonal systems and induce undesired adverse effects in the body. However, many chemicals of concerns have limited or no experimental data on their potential or lack-of-potential endocrine-disrupting effects. Here, we propose a virtual screening method based on molecular docking for predicting potential endocrine-disrupting chemicals (EDCs) that bind to NRs. For 12 NRs, we systematically analyzed how multiple crystal structures can be used to distinguish actives and inactives found in previous high-throughput experiments. Our method is based on (i) consensus docking scores from multiple structures at a single functional state (agonist-bound or antagonist-bound), (ii) multiple functional states (agonist-bound and antagonist-bound), and (iii) multiple pockets (orthosteric site and alternative sites) of these NRs. We found that the consensus enrichment from multiple structures is better than or comparable to the best enrichment from a single structure. The discriminating power of this consensus strategy was further enhanced by a chemical similarity-weighted scoring scheme, yielding better or comparable enrichment for all studied NRs. Applying this optimized method, we screened 252 fatty acids against peroxisome proliferator-activated receptor gamma (PPARγ) and successfully identified 3 previously unknown fatty acids with Kd = 100–250 μM including two furan fatty acids: furannonanoic acid (FNA) and furanundecanoic acid (FUA), and one cyclopropane fatty acid: phytomonic acid (PTA). These results suggested that the proposed method can be used to rapidly screen and prioritize potential EDCs for further experimental evaluations. Electronic supplementary material The online version of this article (10.1007/s00204-020-02897-x) contains supplementary material, which is available to authorized users.

The S-adenosyl-L-methionine (SAM)-dependent methyltransferases attach a methyl group to the deprotonated methyl lysine (Kme0) using SAM as a donor. An intriguing, yet unanswered, question is how the deprotonation of the methyl lysine takes place which results in a lone pair of electrons at the Nϵ atom of the methyl lysine for the following methyl transfer. PRDM9, one of the few methyltransferases with well-defined enzyme activity in vitro and in vivo, is a good representative of the PR/SET domain methyltransferase family to study the deprotonation and subsequently the methyl transfer. The reaction consists of two progressing steps: (i) the absolutely required substrate methyl lysine deprotonation and (ii) the transfer of the methyl group to the deprontonated methyl lysine. We use empirical valence bond (EVB) simulations to evaluate Y357 at the active site as potential general base for the deprotonation of the methyl lysine. Indeed, our study has found that the pKa of Tyr357 is low enough to make it an ideal candidate for proton abstraction from the methyl lysine. The partially deprontonated Tyr357 is able to change its H-bond pattern thus bridging two proton tunneling states (OH- H 0-Tyr357 and Kme0-Nϵ H O-Tyr357) and providing a cascading proton transfer from Tyr357 to hydroxide, generating deprotonated Tyr357 and then from Kme0 to the deprotonated Tyr357 resulting in deprotonated methyl lysine. This cascading proton transfer shortens the lifespan of the labile intermediates, and affects the conformational changes during the product release important to promote the proton release to the bulk solvent. Our computational efforts have uncovered a new catalytic mechanism to unravel the unanswered question about the deprotonation of the methyl lysine in methyltransferases. (Less)

Objective: To study the lipid soluble constituents of wild Russula in Fangcheng-Henan province. Methods: The lipid soluble chemical constituents of wild Russula in henan province were analyzed by GC-MS. Results: The Fatty acids was the highest content of lipid soluble components in wild Russula, 27 compounds were identified, accounting for 99.44% of the total detected components, the main compounds were (E)- 9-octadecenoic acid (44.93%), linoleic acid (28.18%), Palmitic acid (12.07%) and (E)- 12,15-octadecenoic acid (4.17%). Conclusion: The study provides experimental datas for the further development and utilization of wild Russula.

In this paper, in-situ growth of titanium dioxide nanotubes on titanium mesh and deposition of silver (Ag) and graphene (GO) were combined to construct 3D catalysts. By introducing ultraviolet-A/Light emitting diodes (UVA-LEDs), the GO-Ag-TNTs/UVA-LEDs photocatalytic system was setup for methyl orange (MO) degradation. Herein, Ag and GO were doped by photoreduction deposition and hydrothermal reduction respectively, which the doping amount of Ag and GO was optimized, the optimal silver nitrate precursor concentration was 5 mM, and the optimal concentration of GO was 25 mg added into 90 mL of ethanol and deionized water. Additionally, Field emission scanning electron microscopy (FESEM), Raman, Fourier transform infrared spectroscopy (FTIR), UV–vis diffuse reflectance spectrophotometer (UV–vis-DRS), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and Ultraviolet Photoelectron Spectroscopy (UPS) were utilized to directly and indirectly clarify the structural characteristics of the catalysts before and after loading, while photoelectric properties were checked by Electrochemical Workstation. Results showed that GO-Ag joint-doped TNTs sample exhibited the highest photocurrent response and lowest transfer charge resistance compared to other TNTs samples. As for MO degradation and TOC mineralization, GO-Ag optimally doped-TNTs sample enhanced photocatalytic effects (about 20% and 30% improvement respectively) compared with bare TNTs sample.

To observe the effect of electroacupuncture (EA) on the expression of myocardial protein kinase B (Akt) and mammalian target of rapamycin (mTOR) in acute myocardial ischemia (AMI) rats.Thirty male SD rats were randomly divided into control, model and EA groups (Following ligature of DAB, the ECG-ST level was significantly increased in the model group in comparison with the control group (EA at HT5 and HT7 can improve AMI in AMI rats, which may be related to its effect in facilitating Akt/mTOR signaling.

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to technical limitations, including (a) the location of absolutely required Mg2+ ion, and (b) the substrate-bound form of MTHFD2. Using computational modeling and simulations, we propose that two magnesium ions are present at the active site whereby (i) Arg233, Asp225, and two water molecules coordinate [Formula: see text], while [Formula: see text] together with Arg233 stabilize the inorganic phosphate (Pi); (ii) Asp168 and three water molecules coordinate [Formula: see text], and [Formula: see text] further stabilizes Pi by forming a hydrogen bond with two oxygens of Pi; (iii) Arg201 directly coordinates the Pi; and (iv) through three water-mediated interactions, Asp168 contributes to the positioning and stabilization of [Formula: see text], [Formula: see text] and Pi. Our computational study at the empirical valence bond level allowed us also to elucidate the detailed reaction mechanisms. We found that the dehydrogenase activity features a proton-coupled electron transfer with charge redistribution connected to the reorganization of the surrounding water molecules which further facilitates the subsequent cyclohydrolase activity. The cyclohydrolase activity then drives the hydration of the imidazoline ring and the ring opening in a concerted way. Furthermore, we have uncovered that two key residues, Ser197/Arg233, are important factors in determining the cofactor (NADP+/NAD+) preference of the dehydrogenase activity. Our work sheds new light on the structural and kinetic framework of MTHFD2, which will be helpful to design small molecule inhibitors that can be used for cancer treatment.

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to technical limitations, including (a) the location of absolutely required Mg2+ ion, and (b) the substrate-bound form of MTHFD2. Using homology modeling and simulation studies, we propose that two magnesium ions are present at the active site whereby (i) Arg233, Asp225, and two water molecules coordinate MgA, while MgA together with Arg233 stabilize the inorganic phosphate (Pi); (ii) Asp168 and three water molecules coordinate MgB, and MgB further stabilizes Pi by forming a hydrogen bond with two oxygens of Pi; (iii) Arg201 directly coordinates the Pi; and (iv) through three water-mediated interactions, Asp168 contributes to the positioning and stabilization of MgA, MgB and Pi. Our computational study at the empirical valence bond level allowed us to elucidate the detailed reaction mechanisms. We found that the dehydrogenase activity features a proton-coupled electron transfer with charge redistribution coupled to the reorganization of the surrounding water molecules which further facilitates the subsequent cyclohydrolase activity. The cyclohydrolase activity then drives the hydration of the imidazoline ring and the ring opening in a concerted way. Furthermore, we have uncovered that two key residues Ser197/Arg233 are key factors in determining the cofactor (NADP+/NAD+) preference of the dehydrogenase activity. Our work sheds new light on the structural and kinetic framework of MTHFD2, which will be helpful to design small molecule inhibitors that can be used for cancer therapy.

To observe the effect of long-term inhalation of moxa-smoke on olfactory epithelial cells in rats, in order to explore the safety of moxa-smoke inhalation (MSI).A total of 32 SD rats (half male and half female) were randomly divided into 4 groups: normal, low concentration (LCMSI), medium concentration (MCMSI) and high concentration (HCMSI), with 8 rats in each group. Rats of the LCMSI, MCMSI and HCMSI groups were put into closed boxes which were filled with ignited moxa stick-released smoke at concentrations of (0.11±0.05)mg/mThe latency of BFP was significantly longer in the MCMSI and HCMSI groups than in the normal and LCMSI groups (Long-term inhalation of medium and high concentrations of moxa smoke may cause a reduction of the olfactory sensitivity and an increase of apoptosis of olfactory epithelial cells and proliferation of basal cells.

The protein arginine methyltransferase 5 (PRMT5), which is highly expressed in tumour tissues, plays a crucial role in cancer development. However, the mechanism by which PRMT5 promotes cancer growth is poorly understood. Here, we report that PRMT5 contributes to lipid metabolism reprogramming, tumour growth and metastasis depending on the SIRT7-mediated desuccinylation of PRMT5 K387 in tumours. Mass spectrometric analysis identified PRMT5 lysine 387 as its succinylation site. Moreover, the desuccinylation of PRMT5 K387 enhances the methyltransferase activity of PRMT5. SIRT7 catalyses the desuccinylation of PRMT5 in cells. The SIRT7-mediated dessuccinylation of PRMT5 lysine 387 fails to bind to STUB1, decreasing PRMT5 ubiquitination and increasing the interaction between PRMT5 and Mep50, which promotes the formation of the PRMT5-Mep50 octamer. The PRMT5-Mep50 octamer increases PRMT5 methyltransferase activity, leading to arginine methylation of SREBP1a. The symmetric dimethylation of SREBP1a increases the levels of cholesterol, fatty acid, and triglyceride biogenesis in the cells, escaping degradation through the ubiquitin-proteasome pathway. Functionally, the desuccinylation of PRMT5 K387 promotes lipid metabolism reprogramming, tumour growth and metastasis in vitro and in vivo in tumours.

To investigate the relationship between the levels of ferritin, C-reactive protein (CRP), lactate dehydrogenase (LDH) and interleukin-6 (IL-6) in peripheral serum and cytokine release syndrome (CRS) in patients with relapse and/or refractory multiple myeloma (R/R MM) after receiving chimeric antigen receptor T cells (CAR-T) immunotherapy.Twenty-eight patients with R/R MM were treated with 1×10Among the 28 patients, 27 cases (96.4%) developed CRS, 24 cases (85.7%) in 1-2 grade CRS and 3 cases (10.7%) in 3-5 grade. The severity grade of CRS of 27 patients was positively correlated with the peak values of ferritin, CRP, LDH, and IL-6 in peripheral blood (rAfter receiving CAR-T cellular immunotherapy, the incidence of CRS in patients with R/R MM is higher, but most of them are in grade 1 or 2. The severity of CRS is positively correlated with the levels of ferritin, CRP, LDH and IL-6 in peripheral blood.多发性骨髓瘤患者CAR-T治疗后细胞因子释放综合征的相关预警指标分析.探讨复发难治性（R/R）多发性骨髓瘤（MM）患者接受嵌合抗原受体T细胞（CAR-T）免疫治疗后，患者外周血铁蛋白、C反应蛋白（CRP）、乳酸脱氢酶（LDH）、白细胞介素6（IL-6）水平与细胞因子释放综合征（CRS）的相关性。.入组28例R/R MM患者在氟达拉滨和环磷酰胺为基础的预处理化疗后，接受各1×1028例患者中，27例（96.4％）发生CRS，1-2级CRS为24例（85.7％），3-5级为3例（10.7％）。27例患者CRS严重程度分级与其外周血铁蛋白、CRP、LDH及IL-6峰值呈正相关关系（rR/R MM患者接受CAR-T细胞治疗后，CRS发生率较高，但大部分是1级或2级。患者的CRS严重程度与外周血铁蛋白、CRP、LDH及IL-6水平呈正相关。.

Lignin is one of the world’s most abundant organic polymers, and 2-pyrone-4,6-dicarboxylate lactonase (LigI) catalyzes the hydrolysis of 2-pyrone-4,6-dicarboxylate (PDC) in the degradation of lignin. The pH has profound effects on enzyme catalysis and therefore we studied this in the context of LigI. We found that changes of the pH mostly affects surface residues, while the residues at the active site are more subject to changes of the surrounding microenvironment. In accordance with this, a high pH facilitates the deprotonation of the substrate. Detailed free energy calculations by the empirical valence bond (EVB) approach revealed that the overall hydrolysis reaction is more likely when the three active site histidines (His31, His33 and His180) are protonated at the ɛ site, however, protonation at the δ site may be favored during specific steps of reaction. Our studies have uncovered the determinant role of the protonation state of the active site residues His31, His33 and His180 in the hydrolysis of PDC.

To observe the effect of long-term moxa smoke exposure of different concentrations on olfactory function in rats, and provide experimental basis of safety study of moxa smoke produced by moxibustion.Forty SD rats were randomly divided into a normal control group, a low-concentration moxa smoke group, a moderate-concentration moxa smoke group and a high-concentration moxa smoke group, 10 rats in each one. The rats in the moxa smoke groups were put into three plexiglass moxibustion boxes with different moxa smoke concentrations, 4 hours per times, twice a day for 90 days. The general state of rats was evaluated before and during the experiment. After the intervention, the olfactory function was evaluated by two-bottle experiment (TBE); the morphology of nasal mucosa was observed by HE staining; the apoptosis of olfactory epithelial cells in nasal mucosa was detected by TUNEL method; the serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected by ELISA method.In the late stage of moxa smoke exposure (45-90 days into intervention), the behavioral activity of rats in the moderate-concentration moxa smoke group and the high-concentration moxa smoke group was weaker than that in the normal control group, and their response to stimulation was strong, and their mental state was worse. After intervention, the drinking rate of vinegar-water mixture in the moderate-concentration moxa smoke group and the high-concentration moxa smoke group was higher than that in the normal control group and the low-concentration moxa smoke group (The long-term exposure to low, moderate and high concentrations of moxa smoke could cause pathological changes in nasal mucosa and increase the serum levels of IL-1, IL-6 and TNF-α; the moderate and high concentrations of moxa smoke exposure could cause a series of damage to olfactory function and reduce olfactory sensitivity in rats.

The mechanisms determining the development and individual variability of brain torque (BT) remain unclear. Here, all relevant components of BT were analyzed using neuroimaging data of up to 24,112 individuals from 6 cohorts. Our large-scale data confirmed the population-level predominance of the typical anticlockwise torque and suggested a “first attenuating, then enlarging” dynamic across the lifespan primarily for frontal, occipital and perisylvian BT features. Sex/handedness differences in BT were found and were related to cognitive sex/handedness differences in verbal-numerical reasoning. We observed differential heritability of up to 56% for BT, especially in temporal language areas, and identified numerous genome- and phenome-wide significant associations pointing to neurodevelopment, cognitive functions, lifestyle, neurological and psychiatric disorders, sociodemographic, cardiovascular and anthropometric traits. This study provides a comprehensive description of BT and insights into biological and other factors that may contribute to the development and individual variations of BT.

Glioblastoma is one of the most aggressive primary brain tumors with few treatment strategies. β-Elemene is a sesquiterpene known to have broad spectrum antitumor activity against various cancers. However, the signaling pathways involved in β-elemene induced apoptosis of glioblastoma cells remains poorly understood. In this study, we reported that β-elemene exhibited antiproliferative activity on U87 and SHG-44 cells, and induced cell death through induction of apoptosis. Incubation of these cells with β-elemene led to the activation of caspase-3 and generation of reactive oxygen species (ROS). Western blot assay showed that β-elemene suppressed phosphorylation of STAT3, and subsequently down-regulated the activation of p-JAK2 and p-Src. Moreover, pre-incubation of cells with ROS inhibitor N-acetyl-L-cysteine (NAC) significantly reversed β-elemene-mediated apoptosis effect and down-regulation of JAK2/Src-STAT3 signaling pathway. Overall, our findings implied that generation of ROS and suppression of STAT3 signaling pathway is critical for the apoptotic activity of β-elemene in glioblastoma cells.

Inhibition of Shaker K+ channel activity by external Na+ was previously reported in the melon (Cucumis melo L.) inwardly rectifying K+ channel MIRK and was hypothesized to contribute to salt tolerance. In this study, two inward Shaker K+ channels, CsKAT2 from cucumber (Cucumis sativus) and ClKAT2 from watermelon (Citrullus lanatus), were identified and characterized in Xenopus oocytes. Both channels were inwardly rectifying K+ channels with higher permeability to potassium than other monovalent cations and more active when external pH was acidic. Similarly to MIRK, their activity displayed an inhibition by external Na+, thus suggesting a common feature in Cucurbitaceae (Cucumis spp., Citrullus spp.). CsKAT2 and ClKAT2 are highly expressed in guard cells. After 24 h of plant treatment with 100 mM NaCl, the three KAT2-like genes were significantly downregulated in leaves and guard cells. Reciprocal chimeras were obtained between MIRK and Na+-insensitive AtKAT2 cDNAs. The chimera where the MIRK S5-P-S6 segment was replaced by that from AtKAT2 no longer showed Na+ sensitivity, while the inverse chimera gained Na+ sensitivity. These results provide evidence that the molecular basis of the channel blockage by Na+ is located in the S5-P-S6 region. Comparison of the electrostatic property in the S5-P-S6 region in AtKAT2 and MIRK revealed four key amino acid residues potentially governing Na+ sensitivity.