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Chronic kidney disease (CKD) is thus deemed to a global health problem. Renal fibrosis, characterized by accumulation of extracellular matrix (ECM) components in the kidney, is considered a common pathway leading to CKD. Regulator of calcineurin1 (RCAN1), identified as a competitive endogenous inhibitor of the phosphatase calcineurin, participates in ECM deposition in various organs. However, the role of RCAN1 in renal fibrosis remains unclear. Here, unilateral ureteral obstruction (UUO), a well-known model to induce renal fibrosis in vivo, was performed on mice for a week. To overexpress RCAN1.4 in vivo, recombinant adeno-associated virus 9-packed RCAN1.4 over-expression plasm was employed in mice kidney. Lentivirus-packed RCAN1.4 over-expression plasm was employed to transfer into HK-2 and NRK-49F cells in vitro. The results indicated that RCAN1.4 expression was impaired both in UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibrosis in vitro. However, knocking in of RCAN1.4 suppressed the production of extracellular matrix (ECM) both in vivo and in vitro. Furthermore, in vitro, the apoptosis-related proteins, including the ratio of Bax/Bcl-2 and cleaved-caspase3, were elevated in cells transfected with RCAN1.4 overexpression plasmid. In addition, we found that RCAN1.4 could rugulated NFAT2 nuclear distribution by inhibiting calcineurin pathway. So overexpression of RCAN1.4 could reverse renal fibrosis, attenuate ECM related protein accumulation, promote apoptosis of myofibroblast via inhibiting Calcineurin/NFAT2 signaling pathway. Taken together, our study demonstrated that targeting RCAN1.4 may be therapeutic efficacy in renal fibrosis.

Xudong Qian,1 Qianqian Xu,1 Guoyun Li,2 Yi Bu,1 Fan Sun,1 Jian Zhang1 1Department of Neurology, Affiliated Hospital of Chengde Medical University, Chengde, 067000, Hebei, People’s Republic of China; 2Department of Respiratory, Affiliated Hospital of Chengde Medical University, Chengde, 067000, Hebei, People’s Republic of ChinaCorrespondence: Jian ZhangDepartment of Neurology, Affiliated Hospital of Chengde Medical University, No. 36, Nanyingzi Street, Chengde, 067000, Hebei, People’s Republic of ChinaTel/Fax +86 0314-2279965Email Zhangjian8141@163.comBackground: Vascular dementia (VD) is a brain disease featured by cognitive impairment and cerebrovascular pathologies. Idebenone can treat neurodegenerative diseases. This study evaluated the mechanism of Idebenone in VD.Methods: The VD rat model was established by permanent occlusion of bilateral common carotid arteries, followed by intragastrical administration of Idebenone. The learning and spatial memory abilities, and the levels of MDA, SOD, IL-6 and TNF-α were measured. Histological staining was adopted to observe the damage of neurons in the hippocampal cortex and to quantitatively analyze the neuronal damage in CA1 area of hippocampus. Microarray analysis was performed to find out the effect of Idebenone treatment on microRNA (miR) expression in hippocampus of rats. The potential target genes of miR and the pathways regulated by target genes were searched by bioinformatics analysis, and verified by experiments. The mechanism of action behind Idebenone in VD rats was proved by rescue experiment.Results: Idebenone treatment improved the learning and spatial memory abilities of VD rats, inhibited neuroinflammation and oxidative stress, and prevented neuronal apoptosis. Idebenone treatment elevated miR-216a expression in hippocampus of rats, but the therapeutic effect of Idebenone was averted by lentivirus inhibition of miR-216a. miR-216a targeted RSK2. Overexpression of RSK2 annulled the therapeutic effect of Idebenone on VD rats by activating the IκBα/NF-κB axis.Conclusion: Idebenone inhibits the activation of RSK2/IκBα/NF-κB axis by increasing miR-216a, thus alleviating oxidative stress and neuroinflammation in VD rats.Keywords: vascular dementia, idebenone, microRNA-216a, RSK2, IκBα/NFκB, oxidative stress

In order to guarantee the system reliability and enhance post-fault maintenance efficiency of inverters, this paper presents an current observer-based online open-switch fault diagnosis method for the voltage-source inverters (VSI). Analyzing the state space model of VSI when fault occurs, a state observer of the system is built to estimate phase currents. Once the open-switch fault occurs, the current residual vector between the estimated currents on observer and the measured currents, and fault diagnosis is realized by exploiting the featured amplitude and phase of the current residual vector. In order to realize on-line diagnosis with high reliability and speed, the average value of current residuals in a fundamental period is obtained and Clark transformation is performed so as to acquire vector angle. In addition, the sum of absolute values of measured currents is normalized to serve as the sign of fault occurrence. The simulation and experimental results show the effectiveness of proposed method.

Diabetic patients are more susceptible to renal ischemia/reperfusion (I/R) injury (RI/RI) and have a poor prognosis, but the underlying mechanism remains unclear. The present study aimed to examine whether diabetes could worsen acute kidney injury induced by I/R in rats and clarify its mechanism. Control and streptozotocin-induced diabetic rats were subjected to 45 min renal pedicle occlusion followed by 24 h reperfusion. Tert-butylhydroquinone (TBHQ, 16.7 mg/kg) was administrated intraperitoneally 3 times at intervals of 8 h before ischemia. Serum and kidneys were harvested after reperfusion to evaluate renal function and histological injury. Enzyme-linked immunosorbent assays were used to test pro-inflammatory cytokines. Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assays were used to detect apoptotic cells, and western blotting was performed to determine the expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3, as well as oxidative stress and inflammation-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB). Compared with control animals, diabetic rats undergoing I/R exhibited more severe tubular damage and renal dysfunction. Diabetes exacerbated oxidative stress, the inflammatory response, and apoptosis after renal I/R by enhancing TLR4/NF-κB signaling and blocking the Nrf2/HO-1 pathway. RI/RI in diabetic rats was attenuated by pretreatment with TBHQ (a Nrf2 agonist), which exerted anti-inflammatory and anti-apoptotic properties by inhibiting NF-κB signaling. These findings indicate that hyperglycemia exacerbates RI/RI by intensifying oxidative stress, inflammation, and apoptosis. Antioxidant pretreatment may alleviate RI/RI in diabetic patients.

Xiaohui Huang,1,* Ze Yu,2,* Shuhong Bu,1 Zhiyan Lin,1 Xin Hao,3 Wenjun He,2 Peng Yu,2 Zeyuan Wang,2 Fei Gao,2 Jian Zhang,1 Jihui Chen1 1Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Beijing Medicinovo Technology Co. Ltd., Beijing, People’s Republic of China; 3Dalian Medicinovo Technology Co. Ltd., Dalian, Liaoning Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jihui Chen; Jian ZhangDepartment of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of ChinaTel +86-2125077155; +86-2125077150Email chenjihui@xinhuamed.com.cn; zhangjian@xinhuamed.com.cnPurpose: This study aimed to establish an optimal model to predict vancomycin trough concentrations by using machine learning.Patients and Methods: We enrolled 407 pediatric patients (age < 18 years) who received vancomycin intravenously and underwent therapeutic drug monitoring from June 2013 to April 2020 at Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine. The median (interquartile range) age and weight of the patients were 2 (0.63– 5) years and 12 (7.8– 19) kg. Vancomycin trough concentrations were considered as the target variable, and eight different algorithms were used for predictive performance comparison. The whole dataset (407 cases) was divided into training group and testing group at the ratio of 80%: 20%, which were 325 and 82 cases, respectively.Results: Ultimately, five algorithms (XGBoost, GBRT, Bagging, ExtraTree and decision tree) with high R 2 (0.657, 0.514, 0.468, 0.425 and 0.450, respectively) were selected and further ensembled to establish the final model and achieve an optimal result. For missing data, through filling the missing values and model ensemble, we obtained R 2=0.614, MAE=3.32, MSE=24.39, RMSE=4.94 and a prediction accuracy of 51.22% (predicted trough concentration within ± 30% of the actual trough concentration). In comparison with the pharmacokinetic models (R 2=0.3), the machine learning model works better in model fitting and has better prediction accuracy.Conclusion: Therefore, the ensemble model is useful for the vancomycin concentration prediction, especially in the population of children with great individual variation. As machine learning methods evolve, the clinical value of the ensemble model will be demonstrated in the clinical practice.Keywords: machine learning, XGBoost, prediction, vancomycin, trough concentration, pediatric patients

Background: Chronic kidney disease (CKD) is thus deemed to a global health problem. Renal fibrosis, characterized by accumulation of extracellular matrix (ECM) components in the kidney, is considered a common pathway leading to CKD. Regulator of calcineurin1 (RCAN1), identified as a competitive endogenous inhibitor of the phosphatase calcineurin, participates in ECM deposition in various organs. However, the role of RCAN1 in renal fibrosis remains unclear. Methods: Unilateral ureteral obstruction (UUO), a well-known model to induce renal fibrosis, was performed on mice for a week. To overexpress RCAN1.4 in vivo, Recombinant adeno-associated virus (rAAV) 9-packed RCAN1.4 over-expression plasm was employed in mice kidney. Lentivirus-packed RCAN1.4 over-expression plasm was employed to transfer into HK-2 and NRK-49F cells in vitro. Hematoxylin and eosin (H & E) were performed to assess histopathological kidney injury, Sirus-red and Masson’s trichrome staining were carried out for observing collagen deposition. Western blotting was also used to determine the expression levels. Results: RCAN1 isoform 4 (RCAN1.4) expression was impaired after suffering UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibrosis in vitro. Furthermore, knocking in of RCAN1.4 in mice kidney, transfected with rAAV9-packed RCAN1.4 over-expression plasm, reduced the expression levels of hallmarks of EMT. In vitro, the apoptosis-related proteins, including the ratio of Bax/Bcl-2 and cleaved-caspase3, were elevated in cells transfected with RCAN1.4 overexpression plasmid. Moreover, over-expression of RCAN1.4 recovered the renal function and attenuated ECM deposition. In addition, RCAN1.4 regulated NFAT2 nuclear distribution by inhibiting calcineurin pathway. Conclusions: The expression of RCAN1.4 was attenuated both in UUO-induced fibrotic kidney of mouse and in TGF-β1-induced fibrotic model in vitro. Moreover, overexpression of RCAN1.4 could reverse renal fibrosis, attenuate ECM related protein accumulation, promote apoptosis of myofibroblast via inhibiting CaN/NFAT2 signaling pathway. Taken together, our study demonstrated that targeting RCAN1.4 may be therapeutic efficacy in renal fibrosis Funding: This study was supported by the National Natural Science Foundation of China (No.82000639) and Innovation Project of Medical School of Wuhan University (TFZZ2018017). Declaration of Interest: The authors declare that they have no conflicts of interest. Ethical Approval: This experiment was authorized by the Ethics Committee of Renmin Hospital of Wuhan University, and the procedures were carried out adhere to the principles of Animal Care of Wuhan University (Wuhan, China).

Renal ischemia-reperfusion injury (I/R) usually occurs in renal transplantation and partial nephrectomy, which could lead to acute kidney injury. However, the effective treatment for renal I/R still remains limited. In the present study, we investigated whether inhibition of chromobox 7 (CBX7) could attenuate renal I/R injury in vivo and in vitro as well as the potential mechanisms. Adult male mice were subjected to right renal ischemia and reperfusion for different periods, both with and without the CBX7 inhibitor UNC3866. In addition, human kidney cells (HK-2) were subjected to a hypoxia/reoxygenation (H/R) process for different periods, both with or without the CBX7 inhibitor or siRNA for CBX7. The results showed that expression of CBX7, glucose regulator protein-78 (GRP78), phosphorylated eukaryotic translation initiation factor-2α (p-eIF2α), and C/EBP homologous protein (CHOP) were increased after extension of I/R and H/R periods. Moreover, overexpression of CBX7 could elevate the expression of CBX7, GRP78, p-eIF2α, and CHOP. However, CBX7 inhibition with either UNC3866 or genetic knockdown led to reduced expression of GRP78, p-eIF2α, and CHOP through nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 activation in I/R and H/R injury. Furthermore, ML385, the Nrf2 inhibitor, could elevate endoplasmic reticulum stress levels, abrogating the protective effects of UNC3866 against renal I/R injury. In conclusion, our results demonstrated that CBX7 inhibition alleviated acute kidney injury by preventing endoplasmic reticulum stress via the Nrf2/HO-1 pathway, indicating that CBX7 inhibitor could be a potential therapeutic target for renal I/R injury.

Water content in jet fuels is detected by thermometric titration (TMT), and the optimal detected system is 2,2-dimethoxypropane as titrant, cyclohexane and isopropanol as titration solvents, and methanesulfonic acid as catalyst in this method. The amounts of oil, concentration and delivery rate of titrant, volumes, and the reliability and accuracy of thermometric titration were emphasized. The results show that the accuracy, validity, and reliability of TMT are excellent by different indicated spiked water contents. The obtained results between TMT and Karl Fischer titration have been proven to be in accord. But, the duration of titration merely spends 3–5 min in the whole process, greatly shortening the detected time. Therefore, rapid and accurate determination of trace water in a jet fuel can be realized by TMT.

Diabetes could aggravate ischemia-reperfusion (I/R) injury, but the underlying mechanism is unclear. In the present study, we aimed to investigate whether diabetes exacerbates renal I/R injury and its possible mechanism. In vitro, HK-2 cells under normal or high glucose conditions were subjected to hypoxia (12 h) followed by reoxygenation (3 h) (H/R). Cell viability, intracellular ATP content, mitochondrial membrane potential, reactive oxygen species production, and apoptosis were measured. In vivo, streptozotocin-induced diabetic and nondiabetic rats were subjected to I/R. Renal pathology, function, and apoptosis were evaluated by hematoxylin and eosin staining, transmission electron microscopy, and Western blot analysis. Compared with the normal glucose + H/R group, mitochondrial function (ATP, mitochondrial membrane potential, and reactive oxygen species) and mitophagy were reduced in the high glucose + H/R group, as was expression of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and Parkin. Also, cells in the high glucose + H/R group exhibited more apoptosis compared with the normal glucose + H/R group, as assessed by flow cytometry, TUNEL staining, and Western blot analysis. Compared with normal rats that underwent I/R, diabetic rats that underwent I/R exhibited more severe tubular damage and renal dysfunction as well as expression of the apoptotic protein caspase-3. Meanwhile, diabetes alleviated mitophagy-associated protein expression in rats subjected to I/R, including expression of PINK1 and Parkin. Transmission electron microscopy indicated that the mitophagosome could be hardly observed and that mitochondrial morphology and structure were obviously damaged in the diabetes + I/R group. In conclusion, our results, for the first time, indicate that diabetes could aggravate I/R injury by repressing mitochondrial function and PINK1/Parkin-mediated mitophagy in vivo and in vitro.

The aim of the present study was to investigate whether the diabetic kidney is more susceptible to ischemia/reperfusion (I/R) injury, and identify the potential mechanisms involved. An animal model of type 1 diabetes was created by treating rats with streptozotocin (STZ). This model was then used, along with healthy controls, to investigate the effect of diabetes mellitus (DM) on renal I/R injury. After 45 min of ischemia and 24 h of reperfusion, kidney and serum samples were acquired and used to evaluate function and histopathological injury in the kidneys. Western blotting was also used to determine the expression levels of key proteins. Rats experiencing renal I/R exhibited significant characteristics of renal dysfunction, reduced levels of Sirtuin 1 (SIRT1) protein (a key signaling protein in the kidneys), increased endoplasmic reticulum stress (ERS) and pyroptosis. Furthermore, diabetic rats exhibited further reductions in the levels of SIRT1 in response to renal I/R injury and an increase in the levels of ERS. These effects were all alleviated by the administration of a SIRT1 agonist. The present analysis revealed that the SIRT1-mediated activation of ER stress and pyroptosis played a pivotal role in diabetic rats subjected to renal I/R injury. Downregulation of the SIRT1 signaling pathway were exacerbated in response to renal I/R injury-induced acute kidney injury (AKI). The present data indicated that DM enhanced ER stress and increased pyroptosis by downregulating the SIRT1 signaling pathway.

CoxCrCuFeMnNi high-entropy alloys (HEAs) were prepared by vacuum hot pressing sintered. The corrosion behavior has been evaluated using potentiodynamic polarization measurements and electrochemical impedance spectra (EIS). The corrosion current density (icorr) and average corrosion rate (Vcorr) of the alloys decreased with the increase of Co content. When the Co content increased to 2.0 mol from 0.5 mol, the values of icorr and Vcorr decreased to 6.95 × 10−6 A cm−2 and 0.07 mm year−1 from 4.04 × 10−5 A cm−2 and 0.43 mm year−1, respectively. EIS results reveal that the thickness and resistance of the passive films of CoxCrCuFeMnNi HEAs increased with the increasing of Co content, indicating the alloy with high Co content had a good corrosion resistance. The reasons for the improvement of corrosion resistance are related to higher the content of passivation elements and FCC2 phase. Keywords: High-entropy alloy, Hot pressing sintered, Polarization, EIS, Corrosion behavior

There is an urgent need to apply basic research achievements to the clinic. In particular, mechanistic studies should be developed by bench researchers, depending upon clinical demands, in order to improve the survival and quality of life of cancer patients. To date, translational medicine has been addressed in cancer biology, particularly in the identification and characterization of novel tumor biomarkers. This review focuses on the recent achievements and clinical application prospects in tumor biomarkers based on translational medicine.

A room-temperature Ni-catalyzed reductive approach to homocoupling of unactivated primary, secondary, and tertiary alkyl bromides is described. The catalytic system can be easily generated from air-stable and cheap materials and demonstrates broad functional group tolerance, thus allowing facile access to useful dimeric triterpene and lignan-like molecules. Moreover, the dimerization of tertiary bromide 6 efficiently establishes sterically hindered vicinal quaternary carbons (C3a and C3a'), which is a key linkage of intriguing bispyrrolo[2,3-b]indoline alkaloids, thereby enabling us to complete the total syntheses of racemic chimonanthine (9) and folicanthine (10). In addition, this dimerization method can be expanded to the highly stereoselective synthesis of bisperhydrofuro[2,3-b]furan (5a) and the dimeric spiroketal 5b, signifying the involvement of possible radical species.

PubChem (https://pubchem.ncbi.nlm.nih.gov) is a public repository for information on chemical substances and their biological activities, launched in 2004 as a component of the Molecular Libraries Roadmap Initiatives of the US National Institutes of Health (NIH). For the past 11 years, PubChem has grown to a sizable system, serving as a chemical information resource for the scientific research community. PubChem consists of three inter-linked databases, Substance, Compound and BioAssay. The Substance database contains chemical information deposited by individual data contributors to PubChem, and the Compound database stores unique chemical structures extracted from the Substance database. Biological activity data of chemical substances tested in assay experiments are contained in the BioAssay database. This paper provides an overview of the PubChem Substance and Compound databases, including data sources and contents, data organization, data submission using PubChem Upload, chemical structure standardization, web-based interfaces for textual and non-textual searches, and programmatic access. It also gives a brief description of PubChem3D, a resource derived from theoretical three-dimensional structures of compounds in PubChem, as well as PubChemRDF, Resource Description Framework (RDF)-formatted PubChem data for data sharing, analysis and integration with information contained in other databases.

Mangiferin is a major bioactive ingredient in Mangifera indica Linn. (Anacardiaceae) leaves. Aqueous extract of such leaves have been used as an indigenous remedy for respiratory diseases like asthma and coughing in traditional Chinese medicine. However, underlying molecular mechanisms of mangiferin on anti-asthma remain unclear. In our present study, we investigated the anti-asthmatic effect of mangiferin on Th1/Th2 cytokine profiles and explored its underlying immunoregulatory mechanism in mouse model of allergic asthma. Mangiferin significantly reduced the total inflammatory cell counts and eosinophil infiltration, decreased the production of ovalbumin-specific IgE in serum and PGD2 in BALF. The antibody array analysis showed that mangiferin down-regulated the levels of one group of cytokines/chemokines including Th2-related IL-4, IL-5, IL-13, and others IL-3, IL-9, IL-17, RANTES, TNF-α, but simultaneously up-regulated Th1-related IFN-γ, IL-2 and IL-10 and IL-12 expression in serum. Thus it attenuates the imbalance of Th1/Th2 cells ratio by diminishing the abnormal mRNA levels of Th1 cytokines (IFN-γ and IL-12) and Th2 cytokines (IL-4, IL-5 and IL-13). Finally, mangiferin substantially inhibited the activation and expression of STAT-6 and GATA-3 in excised lung tissues. Our results suggest that mangiferin can exert anti-asthmatic effect. The underlying mechanism may attribute to the modulation of Th1/Th2 cytokine imbalance via inhibiting the STAT6 signaling pathway.

The Protein Ontology (PRO; http://proconsortium.org) formally defines protein entities and explicitly represents their major forms and interrelations. Protein entities represented in PRO corresponding to single amino acid chains are categorized by level of specificity into family, gene, sequence and modification metaclasses, and there is a separate metaclass for protein complexes. All metaclasses also have organism-specific derivatives. PRO complements established sequence databases such as UniProtKB, and interoperates with other biomedical and biological ontologies such as the Gene Ontology (GO). PRO relates to UniProtKB in that PRO’s organism-specific classes of proteins encoded by a specific gene correspond to entities documented in UniProtKB entries. PRO relates to the GO in that PRO’s representations of organism-specific protein complexes are subclasses of the organism-agnostic protein complex terms in the GO Cellular Component Ontology. The past few years have seen growth and changes to the PRO, as well as new points of access to the data and new applications of PRO in immunology and proteomics. Here we describe some of these developments.

Glucokinase (GK) is a glycolytic enzyme that plays an important role in regulating blood glucose level, thus acting as a potentially attractive target for drug discovery in the treatment of diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the activation mechanism of GK from the super-open state (inactive state) to the closed state (active state), a series of conventional molecular dynamics (MD) and targeted MD (TMD) simulations were performed on this enzyme. Conventional MD simulation showed a specific conformational ensemble of GK when the enzyme is inactive. Seven TMD simulations depicted a reliably conformational transition pathway of GK from the inactive state to the active state, and the components important to the conformational change of GK were identified by analyzing the detailed structures of the TMD trajectories. In combination with the inactivation process, our findings showed that the whole conformational pathway for the activation-inactivation-activation of GK is a one-direction circulation, and the active state is less stable than the inactive state in the circulation. Additionally, glucose was demonstrated to gradually modulate its binding pose with the help of residues in the large domain and connecting region of GK during the activation process. Furthermore, the obtained energy barriers were used to explain the preexisting equilibrium and the slow binding kinetic process of the substrate by GK. The simulated results are in accordance with the recent findings from the mutagenesis experiments and kinetic analyses. Our observations reveal a complicated conformational process in the allosteric protein, resulting in new knowledge about the delicate mechanisms for allosteric biological macromolecules that will be useful in drug design for targeting allosteric proteins.

An optical sensor based on the coupling between the plasmonic and photonic resonance modes in metallic photonic crystals is investigated. Large-area metallic photonic crystals consisting of periodically arranged gold nanostructures with dimensions down to sub-100 nm are fabricated using solution-processible gold nanoparticles in combination with interference lithography or interference ablation, which introduces a variety of fabrication techniques for the construction of this kind of sensor device. Sensitivity of the plasmonic response of the gold nanostructures to the changes in the environmental refractive index is enhanced through the coupling between the narrow-band photonic resonance mode and the relatively broad-band plasmon resonance, which is recognized as a Fano-like effect and is utilized to explore sensors. Theoretical modeling shows the characterization and the optimization of the sensitivity of this kind of sensor device. Theoretical and experimental results are demonstrated for the approaches to improve the sensitivity of the sensor device.

To examine the antitumor activity of IL-13PE38 on solid malignant glioma cells in vitro and to investigate its relationship between the antitumor activity of IL-13PE38 and the expression level of IL-13Rα2 in malignant glioma.Ten fresh tissues of anaplastic glioma and 11 fresh tissues of glioblastoma multiforme were obtained during craniotomy at First Affiliated Hospital, Wenzhou Medical College between June 2009 and December 2010. All fresh glioma cells were cultured in vitro with IL-13PE38. Then the cytotoxicity of IL-13PE38 was determined by colorimetric MTS proliferation assay and the SR (survival rate) calculated. The expression level of IL-13Rα2 was studied by immunohistochemical SABC method in 21 cases of malignant glioma. And the value of integrated optical density (IOD) was examined by computer assisted pathological image analysis system. The correlation between the IOD of IL-13Rα2 and the SR of malignant glioma cells was also studied.(1) There were strongly positive expression of IL-13Rα2 in most cases (19/21, 90%). And the expression level of IL-13Rα2 in glioblastoma multiforme was higher than the expression level of IL-13Rα2 in anaplastic glioma (P0.05). (2) As the fresh malignant glioma cells were cultured with IL-13PE38 of same concentration, the number of surviving cells decreased in different degrees. The survival rate of 14 cases were70% and 9 cases50%. And the survival rate of anaplastic glioma cells was higher than that of glioblastoma multiforme cells (P0.05). (3) The IOD of IL-13Rα2 and the SR of malignant glioma cells were strongly negatively correlated (r = -0.093, P0.01).A low concentration of IL-13PE38 shows a high level of cytotoxicity for solid malignant glioma cells. And its cytotoxic efficiency depends on the expression level of IL-13Rα2.

Sleep is a fundamental biological process conserved across the animal kingdom. The study of how sleep regulatory networks are conserved is needed to better understand sleep across evolution. We present a detailed description of a sleep state in adult zebrafish characterized by reversible periods of immobility, increased arousal threshold, and place preference. Rest deprivation using gentle electrical stimulation is followed by a sleep rebound, indicating homeostatic regulation. In contrast to mammals and similarly to birds, light suppresses sleep in zebrafish, with no evidence for a sleep rebound. We also identify a null mutation in the sole receptor for the wake-promoting neuropeptide hypocretin (orexin) in zebrafish. Fish lacking this receptor demonstrate short and fragmented sleep in the dark, in striking contrast to the excessive sleepiness and cataplexy of narcolepsy in mammals. Consistent with this observation, we find that the hypocretin receptor does not colocalize with known major wake-promoting monoaminergic and cholinergic cell groups in the zebrafish. Instead, it colocalizes with large populations of GABAergic neurons, including a subpopulation of Adra2a-positive GABAergic cells in the anterior hypothalamic area, neurons that could assume a sleep modulatory role. Our study validates the use of zebrafish for the study of sleep and indicates molecular diversity in sleep regulatory networks across vertebrates., Author Summary Sleep disorders are common and poorly understood. Further, how and why the brain generates sleep is the object of intense speculations. In this study, we demonstrate that a bony fish used for genetic studies sleeps and that a molecule, hypocretin, involved in causing narcolepsy, is conserved. In humans, narcolepsy is a sleep disorder associated with sleepiness, abnormal dreaming, and paralysis and insomnia. We generated a mutant fish in which the hypocretin system was disrupted. Intriguingly, this fish sleep mutant does not display sleepiness or paralysis but has a 30% reduction of its sleep time at night and a 60% decrease in sleep bout length compared with non-mutant fish. We also studied the relationships between the hypocretin system and other sleep regulatory brain systems in zebrafish and found differences in expression patterns in the brain that may explain the differences in behavior. Our study illustrates how a sleep regulatory system may have evolved across vertebrate phylogeny. Zebrafish, a powerful genetic model that has the advantage of transparency to study neuronal networks in vivo, can be used to study sleep., Zebrafish sleep, and have the receptor for the wake-inducing molecule hypocretin. While mutation in this receptor causes narcolepsy in mammals, in fish, sleep is fragmented, demonstrating differences in sleep control in vertebrates.

There are over 100 genes that have been reported to be associated with asthma or related phenotypes. In 2006–2007 alone there were 53 novel candidate gene associations reported in the literature. Replication of genetic associations and demonstration of a functional mechanism for the associated variants are needed to confirm an asthma susceptibility gene. For most of the candidate genes there is little functional information. In a previous review by Hoffjan et al. published in 2003, functional information was reported for 40 polymorphisms and here we list another 22 genes which have such data. Some important genes such as filaggrin, interleukin-13, interleukin-17 and the cysteinyl leukotriene receptor-1 which not only were replicated by independent association studies but also have functional data are reviewed in this article.

Background Despite our increasing recognition of the mechanisms that specify and propagate epigenetic states of gene expression, the pattern of how epigenetic modifications contribute to the overall genetic variation of a phenotypic trait remains largely elusive. Results We construct a quantitative model to explore the effect of epigenetic modifications that occur at specific rates on the genome. This model, derived from, but beyond, the traditional quantitative genetic theory that is founded on Mendel’s laws, allows questions concerning the prevalence and importance of epigenetic variation to be incorporated and addressed. Conclusions It provides a new avenue for bringing chromatin inheritance into the realm of complex traits, facilitating our understanding of the means by which phenotypic variation is generated.