Clinical and genetic characteristics of a child with Sotos syndrome and attention-deficit/hyperactivity disorder:A case report

BACKGROUND Sotos syndrome is an autosomal dominant disorder,whereas attention-deficit/hyperactivity disorder(ADHD)is a neurodevelopmental condition.This report aimed to summarize the clinical and genetic features of a pediatric case of Soros syndrome and ADHD in a child exhibiting precocious puberty.CASE SUMMARY The patient presented with accelerated growth and advanced skeletal maturation;however,she lacked any distinct facial characteristics related to specific genetic disorders.Genetic analyses revealed a paternally inherited heterozygous synonymous mutation[c.4605C>T(p.Arg1535Arg)].Functional analyses suggested that this mutation may disrupt splicing,and bioinformatics analyses predicted that this mutation was likely pathogenic.After an initial diagnosis of Sotos syndrome,the patient was diagnosed with ADHD during the follow-up period at the age of 8 years and 7 months.CONCLUSION The potential for comorbid ADHD in Sotos syndrome patients should be considered to avoid the risk of a missed diagnosis.

A machine learning-based study of multifactor susceptibility and risk control of induced seismicity in unconventional reservoirs

A comprehensive dataset from 594 fracturing wells throughout the Duvernay Formation near Fox Creek, Alberta, is collected to quantify the influences of geological, geomechanical, and operational features on the distribution and magnitude of hydraulic fracturing-induced seismicity. An integrated machine learning-based investigation is conducted to systematically evaluate multiple factors that contribute to induced seismicity. Feature importance indicates that a distance to fault, a distance to basement, minimum principal stress, cumulative fluid injection, initial formation pressure, and the number of fracturing stages are among significant model predictors. Our seismicity prediction map matches the observed spatial seismicity, and the prediction model successfully guides the fracturing job size of a new well to reduce seismicity risks. This study can apply to mitigating potential seismicity risks in other seismicity-frequent regions.

复方血栓通胶囊对高海拔视网膜病变大鼠的保护作用

目的:探讨复方血栓通胶囊对高海拔视网膜病变大鼠的保护作用及其作用机制。方法:雄性SD大鼠24只随机分为6组,分别饲养于模拟高海拔5000m的高原舱内2、4、6、10、24、72h,观察各组大鼠视网膜组织形态,HIF-1α的表达和入舱前后大鼠视网膜电图中暗适应最大反应b波振幅的变化;雄性SD大鼠24只随机分为4组,分别予安慰剂,大花红景天口服液,肌苷片及复方血栓通胶囊灌胃喂药7d后,饲养于模拟海拔为5000m模拟舱内10h,观察各组大鼠视网膜组织形态,HIF-1α的表达和入舱前后大鼠视网膜电图中暗适应最大反应b波振幅的变化。结果:高海拔视网膜病变SD大鼠模型中,结果显示随着各实验时间的增加,神经节细胞层细胞肿胀明显,HIF-1α在神经节细胞及内核层细胞胞浆表达增高,均在10h时最为明显。各组SD大鼠进舱自身前后F-ERG暗适应最大反应b波振幅变化分析,4、6、10、72h组F-ERG暗适应最大反应b波振幅显著降低(P<0.05);2h组和4h组(P=0.007)、6h组(P=0.008)、10h(P=0.002)有差异,24h组和4h组(P=0.035)、6h(P=0.040)、10h组(P=0.012)有差异。复方血栓通对SD大鼠高海拔视网膜病变预防作用研究中,结果显示与安慰剂组相比较,复方血栓通组、红景天组及肌苷组的视网膜水肿均明显减轻,但复方血栓通组与红景天组视网膜水肿程度明显低于肌苷组;复方血栓通组及红景天组HIF-1α在神经节细胞层及内核层表达明显下降;各组SD大鼠进舱后F-ERG暗适应最大反应b波振幅比较显示,安慰剂组与复方血栓通组(P=0.032),红景天组(P=0.001)均有差异。结论:在模拟高海拔环境下,复方血栓通可能是通过抑制HIF-1α的表达对大鼠高海拔视网膜病变有保护作用,但是具体作用机制有待我们进一步研究。

Autophagy and multidrug resistance in cancer

Multidrug resistance(MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence.Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, universally arises during the treatment of sensitive and MDR cancer. Autophagy can be a double-edged sword for MDR tumors: it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive. Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells, facilitating MDR reversal. Therefore, research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important. We summarize advanced studies of autophagy in MDR tumors, including the variable role of autophagy in MDR cancer cells.

Insulin-like growth factor binding protein-7 induces activation and transdifferentiation of hepatic stellate cells in vitro

AIM:To investigate the role of insulin-like growth factor binding protein-7 (IGFBP-7) in the activation and transdifferentiation of hepatic stellate cells (HSC) in vitro.METHODS:Rat HSC-T6 cells were cultured in separate dishes and treated with various concentration of transforming growth factor (TGF)-β1,IGFBP-7 or antiIGFBP-7 antibody for 24 h.The supernatant or a cytoplasm suspension was obtained from cultured HSC,followed by transfer of cells to form cell-coated dishes.Immunocytochemistry and Western blotting were used to analyze the expression of IGFBP-7 induced by TGF-β1 and the level of fibronectin,collagen and α-smooth muscle actin (SMA).The pro-apoptotic effect of antiIGFBP-7 antibody was determined by flow cytometry.RESULTS:Immunocytochemistry and Western blotting revealed that the expression of IGFBP-7 in TGF-β1 treated HSC was significantly up-regulated compared to that in the control group.In addition,fibronectin,collagen and α-SMA also showed enhanced expression in accordance with the transdifferentiation process in a dose-dependent manner to some extent.Moreover,flow cytometry suggested that anti-IGFBP-7 antibody induced apoptosis of activated HSC,which is responsible for the development of liver fibrosis,and may represent a novel pathway and target for therapeutic intervention.CONCLUSION:IGFBP-7 showed increased expression in activated HSC and played an important role in the activation and transdifferentiation process of HSC.AntiIGFBP-7 antibody may ameliorate liver fibrogenesis.

(5R)-5-hydroxytriptolide inhibits the inflammatory cascade reaction in astrocytes

Many studies have shown that(5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether(5R)-5-hydroxytriptolide has preventive effects on neuroinflammation is unclear. This study was designed to pretreat primary astrocytes from the brains of neonatal Sprague-Dawley rats with 20, 100 and 500 nM(5R)-5-hydroxytriptolide for 1 hour before establishing an in vitro neuroinflammation model with 1.0 μg/mL lipopolysaccharide for 24 hours. The generation of nitric oxide was detected by Griess reagents. Astrocyte marker glial fibrillary acidic protein was measured by immunohistochemical staining. The levels of tumor necrosis factor-α and interleukin-1β in the culture supernatant were assayed by enzyme linked immunosorbent assay. Nuclear factor-κB/p65 expression was examined by immunofluorescence staining. The phosphorylation of inhibitor of nuclear factor IκB-α and the location of nuclear factor-κB/P65 were determined using western blot assay. Our data revealed that(5R)-5-hydroxytriptolide inhibited the generation of nitric oxide, tumor necrosis factor-α and interleukin-1β from primary astrocytes activated by lipopolysaccharide, decreased the positive reaction intensity of glial fibrillary acidic protein, reduced the expression of tumor necrosis factor alpha and interleukin-1β in culture supernatant, inhibited the phosphorylation of IκB-α and the translocation of nuclear factor-κB/P65 to the nucleus. These results have confirmed that(5R)-5-hydroxytriptolide inhibits lipopolysaccharide-induced glial inflammatory response and provides cytological experimental data for(5R)-5-hydroxytriptolide in the treatment of neurodegenerative diseases.

Autosomal dominant tubulointerstitial kidney disease with a novel heterozygous missense mutation in the uromodulin gene: A case report

BACKGROUND Autosomal dominant tubulointerstitial kidney disease(ADTKD)is a progressive chronic disease that is inherited in an autosomal dominant fashion.Symptoms include hyperuricemia,gout,interstitial nephritis,renal cysts,and progressive renal damage that can lead to end-stage renal disease.Mutations in the uromodulin gene(UMOD)characterize the ADTKD-UMOD clinical subtype of this disease.To date,>100 UMOD mutations have been identified.Early diagnosis of ADTKD-UMOD is important to treat the disease,slow down disease progression,and facilitate the identification of potentially affected family members.CASE SUMMARY We report a 40-year-old man harboring a novel heterozygous missense mutation in UMOD(c.554G>T;p.Arg185Leu).The patient had hyperuricemia,gout,and chronic kidney disease.The same mutation was detected in his daughter,aunt and cousin.CONCLUSION A single nucleotide substitution in exon 3 of UMOD was responsible for the heterozygous missense mutation(c.554G>T,p.Arg185Leu).

The mechanism of Wumei Wan on treating diabetes enteropathy based on the network pharmacology

Objective:To explore the potential mechanism of Wumei Wan(WMW)in treating diabetes enteropathy(DE)basing on network pharmacology.Methods:The effective compound of WMW were collected by TCMSP,the potential target of WMW was obtained by means of PubChem and Swiss target prediction online tools,and the disease target of DE was obtained by Genecards,TTD and DisGeNET databases,Cytoscape 3.7.2 software was used to construct active ingredients of WMW-potential target-DE network,protein interaction network(PPI)was constructed by STRING database.In order to understanding the mechanism of WMW treating in DE,Omicshare platform was used for GO analysis and KEGG pathway enrichment analysis.The analysis results were verified through docking by Discovery Studio 2016.Results:Total of 128 active components and 139 targets of WMW were screened out from the ten drugs.A total of 714 disease targets were screened out from the disease databases.24 common targets were identified from both WMW and DE.AKT1,MMP9,SRC,PTGS2,PPARG,NOS2,etc.are potential major targets of WMW in the treatment of DE.61 entries(p<0.05)were enriched in GO biological process function related to fatty acid anabolism and ligand receptor binding,as unsaturated fatty acid metabolic process,icosanoid metabolic process,enzyme linked receptor protein signaling pathway,protein amino acid phosphorylation,cellular response to insulin stimulus.A total of 72 signaling pathways were obtained through KEGG pathway analysis(p<0.05).The signaling pathways closely related to DE are including relaxin signaling pathway,EGFR tyrosine kinase inhibitor resistance,CLRs signaling pathway,and VEGF signaling pathway.Conclusion:This study preliminarily revealed the material basis and mechanism of WMW in the treatment of DE from the synergistic aspects of intestinal immune balance,gastrointestinal wall structure reconstruction,intestinal microvascular disorder and neuronal activity.

Prokaryotic expression, purification of a novel candidate tumor suppressor gene FUS1 and characterization of its polyclonal antibodies

FUS1 is a novel candidate tumor suppressor gene identified in human chromosome 3p21.3. Its expression showed significantly reduction or even loss in lung cancer and other types of cancers. In order to further investigate the biological function of FUS1 protein, FUS1 cDNA from MRC-5 cells was amplified by RT-PCR and cloned into prokaryotic expression vector pQE-30. The recombinant expression plasmids were transformed into M15 strain and grown at 20℃ or 37℃. SDS–PAGE analysis revealed that the accumulation of the recombinant protein FUS1 (rFUS1) in inclusion body forms reached maxium amount when induced with 0.5 mM IPTG for 5 h at 37℃. The inclusion bodies were solubilized in 2M urea and purified by a 6 &#215;His tagged affinity column under denaturing condition. The purified rFUS1 was identified by electrospray ionization-mass spectrometry (ESI-MS) and tested for purity by HPLC chromatography. The purified rFUS1 proteins were then used to immunize rabbits to obtain anti-human FUS1 polyclonal antibodies, which were suitable to detect both the recombinant exogenous FUS1 and the endogenous FUS1 from tissues and cells by western blot and immunohistochemistry, Available purified rFUS1 proteins and self-prepared polyclonal antibodies against FUS1 may provide effective tools for further studies on biological function and application of FUS1.

Local search yields a PTAS for fixed-dimensional k-means problem with penalties

We study a problem called the k-means problem with penalties(k-MPWP),which is a natural generalization of the typical k-means problem.In this problem,we have a set D of client points in R^(d),a set F of possible centers in R^(d),and a penalty cost Pj>O for each point j∈D.We are also given an integer k which is the size of the center point set.We want to find a center point set S■F with size k,choose a penalized subset of clients P■D,and assign every client in D\P to its open center.Our goal is to minimize the sum of the squared distances between every point in D\P to its assigned centre point and the sum of the penalty costs for all clients in P.By using the multi-swap local search technique and under the fixed-dimensional Euclidean space setting,we present a polynomial-time approximation scheme(PTAS)for the k-MPWP.

Mitochondrial Autophagy and NLRP3 Inflammasome in Pulmonary Tissues from Severe Combined Immunodeficient Mice after Cardiac Arrest and Cardiopulmonary Resuscitation

Background：The incidence of cancer,diabetes,and autoimmune diseases has been increasing.Furthermore,there are more and more patients with solid organ transplants.The survival rate of these immunocompromised individuals is extremely low when they are severely hit-on.In this study,we established cardiac arrest cardiopulmonary resuscitation （CPR） model in severe combined immunodeficient （SCID） mice,analyzed the expression and activation of mitochondrial autophagy and NLRP3 inflammasome/caspase-1,and explored mitochondrial repair and inflammatory injury in immunodeficiency individual during systemic ischemia-reperfusion injury.Methods：A potassium chloride-induced cardiac arrest model was established in C57BL/6 and nonobese diabetic/SCID （NOD/SCID） mice.One hundred male C57BL/6 mice and 100 male NOD/SCID mice were randomly divided into five groups （control,2 h post-CPR,12 h post-CPR,24 h post-CPR,and 48 h post-CPR）.A temporal dynamic view of alveolar epithelial cells,macrophages,and neutrophils from bronchoalveolar lavage fluid （BALF） was obtained using Giemsa staining.Spatial characterization ofphenotypic analysis of macrophages in the lung interstitial tissue was analyzed by flow cytometry.The morphological changes ofmitochondria 48 h after CPR were studied by transmission electron microscopy and quantified according to the Flameng grading system.Western blotting analysis was used to detect the expression and activation of the markers of mitochondrial autophagy,NLRP3 inflammasome,and caspase-1.Results：（1） In NOD/SCID mice,macrophages were disintegrated in BALF,and many alveolar epithelial cells were shed at 48 h after resuscitation.Compared with C57BL/6 mice,the ratio of macrophages/total cells peaked at 12 h and was significantly higher in NOD/SCID mice （31.17 ± 4.13 vs.49.69 ± 2.43,t =14.46,P =0.001）.After 24 h,the results showed a downward trend.Furthermore,a large number of macrophages were disintegrated in the BALF.（2） Mitochondrial autophagy was present in both C57BL/6 and NOD/SCID mice after CPR,but it began late in the NOD/SCID mice.Compared with C57BL/6 mice,phos-ULK1 （Ser327） expression was significantly lower at 2 h and 12 h after CPR （2 h after CPR：1.88 ± 0.36 vs.1.12 ± 0.11,t =-1.36,P 〈 0.01 and 12 h after CPR：1.52 ± 0.16 vs.1.05 ± 0.12,t =-0.33,P 〈 0.01）,whereas phos-ULK1 （Ser757） expression was significantly higher at 2 h and 12 h after CPR in NOD/SCID mice （2 h after CPR：1.28 ± 0.12 vs.1.69 ± 0.14,t =1.7,P 〈 0.01 and 12 h after CPR：1.33 ± 0.l 0 vs.1.94 ± 0.13,t =2.75,P 〈 0.01）.（3） Furthermore,NLRP3 inflammasome/caspase-1 activation in the pulmonary tissues occurred early and for only a short time in C57BL/6 mice,but this phenomenon was sustained in NOD/SCID mice.The expression of the NLRP3 inflammasome increased modestly in the C57 mice,but the increase was higher in the NOD/SCID mice than in the C57BL/6 mice,especially at 12,24,48 h after CPR （48 h after CPR：1.46 ± 0.13 vs.2.97 ± 0.19,t =5.34,P =0.001）.The expression ofcaspase-l-20 generally followed the same pattem as the NLRP3 inflammasome.Conclusions：There is a regulatory relationship between the NLRP3 inflammasome and mitochondrial autophagy after CPR in the healthy mice.This regulatory relationship was disturbed in the NOD/SCID mice because the signals for mitochondrial autophagy occurred late,and NLRP3 inflammasome-and caspase-1-dependent cell injury was sustained.

Analysis of cement-treated clay behavior by micromechanical approach

Experimental results show the significant influence of cement content on the mechanical properties of cement-treated clays.Cementation is produced by mixing a certain amount of cement with the saturated clay.The purpose of this paper is to model the cementation effect on the mechanical behavior of cement-treated clay.A micromechanical stress-strain model is developed considering explicitly the cementation at inter-cluster contacts.The inter-cluster bonding and debonding during mechanical loading are introduced in two ways:an additional cohesion in the shear sliding and a higher yield stress in normal compression.The model is used to simulate isotropic compression and undrained triaxial tests under various confining stresses on cement-treated Ariake clay and Singapore clay with various cement contents.The applicability of the present model is evaluated through comparisons between numerical and experimental results.The evolution of local stresses and local strains in inter-cluster planes are discussed in order to explain the induced anisotropy due to debonding at contact level under the applied loads.The numerical simulations demonstrate that the proposed micromechanical approach is well adapted for taking into account the main physical properties of cement-treated clay,including damage and induced anisotropy under mechanical loading.

A practical ANN model for predicting the excavation-induced tunnel horizontal displacement in soft soils

The objective of this study is to propose an artificial neural network(ANN)model to predict the excavation-induced tunnel horizontal displacement in soft soils.For this purpose,a series of finite element data sets from rigorously verified numerical models were collected to be utilized for the development of the ANN model.The excavation width,the excavation depth,the retaining wall thickness,the ratio of the average shear strength to the vertical effective stress,the ratio of the average unloading/reloading Young’s modulus to the vertical effective stress,the horizontal distance between the tunnel and retaining wall,and the ratio of the buried depth of the tunnel crown to the excavation depth were chosen as the input variables,while the excavation-induced tunnel horizontal displacement was considered as an output variable.The results demonstrated the feasibility of the developed ANN model to predict the excavation-induced tunnel horizontal displacement.The proposed ANN model in this study can be applied to predict the excavation-induced tunnel horizontal displacement in soft soils for practical risk assessment and mitigation decision.

New cytotoxic C-3 dehydrated bufadienolides from the venom of Bufo bufo gargarizans

Three new C-3 dehydrated bufadienolides were isolated from the venom of Bufo bufo gargarizans. Their structures were elucidated as 5β,12β-12,14-dihydroxy-11-oxobufa-3,20,22-trienolide （1）, 5β,12β- 12,14-dihydroxy-11 -oxobufa-2,20,22-trienolide （2）, and 5β,12β-12,14-dihydroxy-11 -oxobufa-2,20,22- trienolide （3） on the basis of extensive spectroscopic analysis, especially 1D NMR and 2D NMR data. In addition, all three compounds were tested for their cytotoxic activities against A549 and HepG2 cancer cell lines. Compounds 2 and 3 showed significant cytotoxicities with IC50 values less than 10 μmol/L on both cancer cells.

Two New Coumarins from Fraxinus chinensis Rexb.

The ethanol extract of the stem bark of Fraxinus chinensis Roxb. showed good inhibitory bioactivity against VEGF receptor-1 kinase （IC50：13.8 μg/mL）. In order to find new and bioactive compounds, the chemical constituents of the stem bark of F. chinensis were investigated and two new coumarins, namely 6＇-O-sinapinoyl esculin （compound 1） and 6＇-O-vanillyl esculin （compound 2）, together with eleven known compounds （compounds 3-13） were isolated. The structures of the two new compounds were identified by their physicochemical properties and spectral analysis, particularly one- and two-dimensional nuclear magnetic resonance spectral methods. The known compound, oleuropein （compound 11）, exhibited moderate activity （IC50：（8.7 ± 1.3） μmol/L） to inhibit VEGF receptor- 1 kinase.

Observed response of maglev structure undercrossed by three shield tunnels in soft soil

This paper investigates the response of a maglev structure to three under-crossing tunnels of the Shanghai Metro Line 13.The minimal distance between the tunnels and pile groups of the maglev structure is only 1.5 m,thus the deformations of the maglev structure are strictly controlled for the serviceability of the operating maglev trains.The displacements of maglev piers and ground settlements during different tunnelling stages are monitored with an automatic measuring system.Based on the observed data,the ground settlement trough and displacements of maglev piers caused by the three shield tunnelling procedures are analyzed and discussed.The maximal ground settlement after the completion of the three tunnelling procedures is -43 mm.To operate the existing maglev safely,practical construction control methods are applied,including synchronous grouting,adjustment of the shield status,shield-advancing speed control,and stabilisation of the soil chamber pressure.With these countermeasures,the tunnel-induced deformations of maglev piers are well below the predefined thresholds.All piers heave under the strict deformation criterion of 2.0 mm.The crossing project is finally completed without interruptions of the maglev operations by monitoring the progress.The presented project is a valuable example for the evaluation of shield tunnelling effects on the adjacent maglev structures and establishes criteria for similar projects in the future.

Soil effect on the bearing capacity of a double-lining structure under internal water pressure

Water conveyance tunnels usually experience high internal water pressures and complex soil conditions.Therefore,shield tunnels with double-lining structure have been adopted because of their high bearing capacity.The effect of the interface between the segmental and inner linings on the bearing capacity has been widely investigated;however,the effect of soil on the internal water pressure bearing capacity has not been emphasized enough.Therefore,in this study,model tests and an analytical solution are presented to elucidate the effect of soil on the internal water pressure bearing capacity.First,model tests are conducted on double-lining models under sandy soil and highly weathered argillaceous siltstone conditions.The internal force and earth pressure under these different soil conditions are then compared to reveal the contribution of soil to the internal water pressure bearing capacity.Following this,an analytical solution,considering the soil–double-lining interaction,is proposed to further investigate the contribution of the soil.The analytical solution is verified with model tests.The analytical solution is in good agreement with the model test results and can be used to evaluate the mechanical behavior of the double-lining and soil contribution.The effect of soil on the bearing capacity is found to be related with the elastic modulus of the soil and the deformation state of the double-lining.Before the double-lining cracks,the sandy soil contributes 3.7%of the internal water pressure but the contribution of the soil rises to 10.4%when it is the highly weathered argillaceous siltstone.After the double-lining cracks,the soil plays an important role in bearing internal water pressure.The soil contributions of sandy soil and highly weathered argillaceous siltstones are 10.5%and 27.8%,respectively.The effect of soil should be considered in tunnel design with the internal water pressure.

Daytime hypercapnia in adult patients with obstructive sleep apnea in China

To the Editor:Obstructive sleep apnea(OSA)is a common sleep-disordered breathing.Previous studies reported that the incidence of daytime hypercapnia in patients with OSA was 26.2%in China[1]and 14%in Japan.[2]However,Weitzenblum et al[3]demonstrated that daytime hypercapnia in patients with OSA might not be secondary to sleep apneas/hypopneas,but might due to the comorbidities,such as chronic obstructive pulmonary disease or severe obesity.Obesity hypoventilation syndrome(OHS)is defined as a conjunction of obesity(body mass index[BMI]≥30 kg/m^(2)),daytime hypercapnia(partial pressure of carbon dioxide in arterial blood[PaCO_(2)]≥45 mmHg)and sleep disordered breathing,after excluding other causes for alveolar hypoventilation.[4]Since patients with OHS were not completely excluded in previous studies,[1,2]we assumed that the incidence of daytime hypercapnia in Chinese patients with OSA might be low.

Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth

Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKIs)have been canonically used in NSCLC treatment.However,prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs.Therefore,the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance.Here,we identified a 23-hydroxybetulinic acid derivative,namely DPBA,as a novel EGFR small-molecule ligand.It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR.Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR.DPBA did not induce EGFR dimerization,phosphorylation,and ubiquitination,but it significantly promoted EGFR degradation and repressed downstream survival pathways.Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs.Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation.The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC,particularly NSCLC with innate or acquired EGFR TKI resistance.DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

Distributed H_∞ PID Feedback for Improving Consensus Performance of Arbitrary-delayed Multi-agent System

The H∞ proportional-integral-differential(PID) feedback for arbitrary-order delayed multi-agent system is investigated to improve the system performance. The closed-loop multi-input multi-output(MIMO) control framework with the distributed PID controller is firstly described for the multi-agent system in a unified way. Then, by using the matrix theory, the prescribed H∞performance criterion of the multi-agent system is shown to be equivalent to several independent H∞ performance constraints of the single-input single-output(SISO) subsystem with respect to the eigenvalues of the Laplacian matrix. Subsequently, for each subsystem,the set of the PID controllers satisfying the required H∞ performance constraint is analytically characterized based on the extended Hermite-Biehler theorem. Finally, the three-dimensional set of the decentralized H∞ PID control parameters is derived by finding the intersection of the H∞ PID regions for all the decomposed subsystems. The simulation results reveal the effectiveness of the proposed method.