A simulation approach based on a full-wave numerical method is presented to study electromagnetic characteristics by complex targets. How to validate simulation results is considered thoroughly under no analytical and...A simulation approach based on a full-wave numerical method is presented to study electromagnetic characteristics by complex targets. How to validate simulation results is considered thoroughly under no analytical and measured data, where a double-check criterion is designed for our simulation approach. As an example, the scattering of F-117A is studied by using our simulation approach under all polarizations, different frequency bands, incident and scattering directions, etc., some of which, such as cross-polarization, bistatic RCS, have not been considered in the previous literature.展开更多
The electromagnetic scattering computation has developed rapidly for many years; some computing problems for complex and coated targets cannot be solved by using the existing theory and computing models. A computing m...The electromagnetic scattering computation has developed rapidly for many years; some computing problems for complex and coated targets cannot be solved by using the existing theory and computing models. A computing model based on data is established for making up the insufficiency of theoretic models. Based on the ＂support vector regression method＂, which is formulated on the principle of minimizing a structural risk, a data model to predicate the unknown radar cross section of some appointed targets is given. Comparison between the actual data and the results of this predicting model based on support vector regression method proved that the support vector regression method is workable and with a comparative precision.展开更多
OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic tar...OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 2(PI3K/Akt/m TORC2)signaling pathway.METHODS:CAG was induced in rats and treated with high-,medium-,or low-dose Jiawei Huangqi Guizhi decoction.Gastric histopathology was observed by hematoxylin and eosin staining.Serum levels of gastrin,PI3K,Akt,and m TORC2 were detected by enzyme-linked immunosorbent assay.Gene and protein expression levels were analyzed by reverse transcription polymerase chain reaction and western blot.RESULTS:The decoction alleviated gastric mucosal injury,reduced inflammation,and restored epithelial structure.It regulated PI3K,Akt,and m TORC2 expression at both m RNA and protein levels.CONCLUSION:Jiawei Huangqi Guizhi decoction may prevent CAG progression by improving gastric tissue and modulating the PI3K/Akt/m TORC2 signaling pathway.展开更多
A RCS prediction system named SCTE (Scattering from Complex Target and Environment) for calculating high-frequency electromagnetic scattering from complex target within complex environment is presented. The scattering...A RCS prediction system named SCTE (Scattering from Complex Target and Environment) for calculating high-frequency electromagnetic scattering from complex target within complex environment is presented. The scattering body is described by Computer-Aided-Design (CAD) representations in which the complex body is modeled as NURBS (Non-Uniform Rational B-spline) surfaces. The complex environment (rough surface of sea or ground) is also carefully considered by using fractal function. Scattering fields are calculated by using physical optics and the equivalent currents methods. There is a good agreement between the present results and that from measurements which demonstrates the accuracy of this system.展开更多
A practical approach for calculating the RCS (Radar Cross Section) of complex targets modeled with wire-grid-frame is presented. A way for generating a polyhedron model (facet-wedge model) with the wire-grid-frame dat...A practical approach for calculating the RCS (Radar Cross Section) of complex targets modeled with wire-grid-frame is presented. A way for generating a polyhedron model (facet-wedge model) with the wire-grid-frame data is described. For storing and reading the data of the polyhedron model in an easy way, a data structure is given.展开更多
The defining neuropathological feature of Parkinson＇s disease （PD） is the loss of nigrostriatal dopaminergic （DA） projections. This results in striatal dopamine levels and a biochemical reduction of movement diso...The defining neuropathological feature of Parkinson＇s disease （PD） is the loss of nigrostriatal dopaminergic （DA） projections. This results in striatal dopamine levels and a biochemical reduction of movement disorders, such as a tremor at rest, rigidity of the limbs, bradykinesia, and postural instability （Kim et al., 2011; Kim et al., 2012; Burke and O＇Malley, 2013; Leem et al., 2014; Namet al., 2014）.展开更多
The mammalian target of rapamycin(mTOR)acts in two structurally and functionally distinct protein complexes,mTOR complex 1(mTORC1)and mTOR complex 2(mTORC2).Upon deregulation,activated mTOR signaling is associated wit...The mammalian target of rapamycin(mTOR)acts in two structurally and functionally distinct protein complexes,mTOR complex 1(mTORC1)and mTOR complex 2(mTORC2).Upon deregulation,activated mTOR signaling is associated with multiple processes involved in tumor growth and metastasis.Compared with mTORC1,much less is known about mTORC2 in cancer,mainly because of the unavailability of a selective inhibitor.However,existing data suggest that mTORC2 with its two distinct subunits Rictor and mSin1 might play a more important role than assumed so far.It is one of the key effectors of the PI3K/AKT/mTOR pathway and stimulates cell growth,cell survival,metabolism,and cytoskeletal organization.It is not only implicated in tumor progression,metastasis,and the tumor microenvironment but also in resistance to therapy.Rictor,the central subunit of mTORC2,was found to be upregulated in different kinds of cancers and is associated with advanced tumor stages and a bad prognosis.Moreover,AKT,the main downstream regulator of mTORC2/Rictor,is one of the most highly activated proteins in cancer.Primary and secondary liver cancer are major problems for current cancer therapy due to the lack of specific medical treatment,emphasizing the need for further therapeutic options.This review,therefore,summarizes the role of mTORC2/Rictor in cancer,with special focus on primary liver cancer but also on liver metastases.展开更多
The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ（RNAPⅡ）in all eukaryotes（Allen and Taatjes,2015）.This complex,which consist...The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ（RNAPⅡ）in all eukaryotes（Allen and Taatjes,2015）.This complex,which consists of at least 30 polypeptides,can be divided into four structurally distinct sub-modules including the head,middle,tail,and cyclin-dependent kinase 8（CDK8）modules （CKM） （Fig. 1A） （Yin and Wang, 2014; Allen and Taatjes, 2015）.展开更多
During the last two centuries, there have been many spectacular advances in medical science, the main consequence of which has been the dramatically reduced burden of infectious diseases. While in the 1800s many peopl...During the last two centuries, there have been many spectacular advances in medical science, the main consequence of which has been the dramatically reduced burden of infectious diseases. While in the 1800s many people died before reaching adult- hood, nowadays most people survive. Hence average life ex- pectancy in 1800s was around 30-40, which was barely higher than it had been in Greek and Roman times （Finch, 2010）, but nowadays life expectancy in most modernised economies is around 75 - 80. This demographic shift, which has happened in only 200 years, has created a dramatic change in the causes of mortality. The major killers in the modern world are non- communicable diseases （NCDs）： principally cardiovascular disease, cancer and neurodegenerative disorders such as Alz- heimer＇s disease. A major factor that influences susceptibility to all these diseases is age. As we get older, our risk of developing these NCDs increases enormously. For example, the rate of breast cancer in females at age 15-19 is less than 10 per 100,000 population, but this increases to 100 at age 40-44, 275 at age 55--59 and 450 at age 85 ＋ （http：//www.cancerresearchuk.org/ cancer-info/cancerstats/types/breast/incidence/#age）. Ageing has consequently become a major medical, social and economic burden to many countries.展开更多
BACKGROUND 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid(BT2)is a benzothiophene carboxylate derivative that can suppress the catabolism of branched-chain amino acid(BCAA)-associated mammalian target of rapamycin co...BACKGROUND 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid(BT2)is a benzothiophene carboxylate derivative that can suppress the catabolism of branched-chain amino acid(BCAA)-associated mammalian target of rapamycin complex 1(mTORC1)activation.Previous studies have demonstrated the therapeutic effects of BT2 on arthritis,liver cancer,and kidney injury.However,the effects of BT2 on ulcerative colitis(UC)are unknown.AIM To investigate the anti-UC effects of BT2 and the underlying mechanism.METHODS Mouse UC models were created through the administration of 3.5%dextran sodium sulfate(DSS)for 7 d.The mice in the treated groups were administered salazosulfapyridine(300 mg/kg)or BT2(20 mg/kg)orally from day 1 to day 7.At the end of the study,all of the mice were sacrificed,and colon tissues were removed for hematoxylin and eosin staining,immunoblot analyses,and immunohistochemical assays.Cytokine levels were measured by flow cytometry.The contents of BCAAs including valine,leucine,and isoleucine,in mouse serum were detected by liquid chromatography-tandem mass spectrometry,and the abundance of intestinal flora was analyzed by 16S ribosomal DNA sequencing.RESULTS Our results revealed that BT2 significantly ameliorated the inflammatory symptoms and pathological damage induced by DSS in mice.BT2 also reduced the production of the proinflammatory cytokines interleukin 6(IL-6),IL-9,and IL-2 and increased the anti-inflammatory cytokine IL-10 level.In addition,BT2 notably improved BCAA catabolism and suppressed mTORC1 activation and cyclooxygenase-2 expression in the colon tissues of UC mice.Furthermore,highthroughput sequencing revealed that BT2 restored the gut microbial abundance and diversity in mice with colitis.Compared with the DSS group,BT2 treatment increased the ratio of Firmicutes to Bacteroidetes and decreased the abundance of Enterobacteriaceae and Escherichia-Shigella.CONCLUSION Our results indicated that BT2 significantly ameliorated DSS-induced UC and that the latent mechanism involved the suppression of BCAA-associated mTORC1 activation and modulation of the intestinal flora.展开更多
This review describes the investigations of oscillatory complex networks consisting of excitable nodes, focusing on the target wave patterns or say the target wave attractors. A method of dominant phase advanced drivi...This review describes the investigations of oscillatory complex networks consisting of excitable nodes, focusing on the target wave patterns or say the target wave attractors. A method of dominant phase advanced driving （DPAD） is introduced to reveal the dynamic structures in the networks supporting osciUations, such as the oscillation sources and the main excitation propagation paths from the sources to the whole networks. The target center nodes and their drivers are regarded as the key nodes which can completely determine the corresponding target wave patterns. Therefore, the center （say node A） and its driver （say node B） of a target wave can be used as a label, （A, B）, of the given target pattern. The label can give a clue to conveniently retrieve, suppress, and control the target waves. Statistical investigations, both theoretically from the label analysis and numerically from direct simulations of network dynamics, show that there exist huge numbers of target wave attractors in excitable complex networks if the system size is large, and all these attractors can be labeled and easily controlled based on the information given by the labels. The possible applications of the physical ideas and the mathematical methods about multiplicity and labelability of attractors to memory problems of neural networks are briefly discussed.展开更多
This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulato...This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.展开更多
A new way of acoustic wave imaging was investigated. By using the Green function theory a system of integral equations,which linked wave number perturbation function with wave field, was firstly deduced. By taking var...A new way of acoustic wave imaging was investigated. By using the Green function theory a system of integral equations,which linked wave number perturbation function with wave field, was firstly deduced. By taking variation on these integral equations an inversion equation,which reflected the relation between the little variation of wave number perturbation function and that of scattering field, was further obtained. Finally, the perturbation functions of some identical targets were reconstructed, and some properties of the novel method including converging speed, inversion accuracy and the abilities to resist random noise and identify complex targets were discussed. Results of numerical simulation show that the method based on the variation principle has great theoretical and applicable value to quantitative nondestructive evaluation.展开更多
Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is ...Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.展开更多
A group tracking algorithm for split maneuvering based on complex domain topological descriptions is proposed for the tracking of members in a maneuvering group. According to the split characteristics of a group targe...A group tracking algorithm for split maneuvering based on complex domain topological descriptions is proposed for the tracking of members in a maneuvering group. According to the split characteristics of a group target, split models of group targets are established based on a sliding window feedback mechanism to determine the occurrence and classification of split maneuvering, which makes the tracked objects focus by group members effectively. The track of an outlier single target is reconstructed by the sequential least square method. At the same time, the relationship between the group members is expressed by the complex domain topological description method, which solves the problem of point-track association between the members. The Singer method is then used to update the tracks. Compared with classical multi-target tracking algorithms based on Multiple Hypothesis Tracking （MHT） and the Different Structure Joint Probabilistic Data Association （DS-JPDA） algorithm, the proposed algorithm has better tracking accuracy and stability, is robust against environmental clutter and has stable time-consumption under both classical radar conditions and partly resolvable conditions.展开更多
By applying the ＇theory of synchronization＇ from the science of complexity to studying the regional regularity of ore formation within the Nanling region of South China,a characteristic target-pattern regional ore z...By applying the ＇theory of synchronization＇ from the science of complexity to studying the regional regularity of ore formation within the Nanling region of South China,a characteristic target-pattern regional ore zonality has been discovered.During the early and late Yanshanian epoch （corresponding respectively to the Jurassic and Cretaceous periods）,two centers of ore formation emerged successively in the Nanling region;the former is mainly for rare metals（W,Sn,Mo,Bi,Nb） and one rare-earth element（La） and was generated in the Jurassic period;whereas the latter is mainly for base metals （Cu,Pb,Zn,Sb,Hg）,noble metals（Au,Ag）,and one radioactive element（U） and was generated in the Cretaceous period.Centers of ore formation were brought about by interface dynamics respectively at the Qitianling and Jiuyishan districts in southern Hunan Province.The characteristic giant nonlinear target-pattern regional ore zonality was generated respectively from the two centers of ore formation by the spatio-temporal synchronization process of the Nanling complex metallogenic system.It induced the collective dynamics and cooperative behavior of the system and displayed the configuration of the regional ore zonality.Then dynamical clustering transformed the configuration into rudimentary ordered coherent structures.Phase dynamics eventually defined the spatio-temporal structures of the target-pattern regional ore zonality and determined their localization and distribution.The integral successive processes of synchronization-dynamical clustering-phase dynamics accomplished the regional ore zonality by way of ＂multiple field dynamics＂ of spatio-temporal superposition of multiple coupled pulsatory solitary wave trains of the zonal sequences of different ores.A new methodology for revealing regional ore zonality is developed,which will encourage further investigation of the formation of deep-seated ore resources and the onset of large-scale mineralization.展开更多
By applying the ＇theory of synchronization＇ from the science of complexity to studying the regional regularity of ore formation within the Nanling region of southern China, a characteristic targetpattern regional or...By applying the ＇theory of synchronization＇ from the science of complexity to studying the regional regularity of ore formation within the Nanling region of southern China, a characteristic targetpattern regional ore zonality has been discovered. During the early and late Yanshanian epoch （corresponding respectively to the Jurassic and Cretaceous periods）, two centers of ore formation emerged successively in the Nanling region; the former is mainly for rare metals （W, Sn, Mo, Bi, Nb） and one rare-earth element （La） and was generated in the Jurassic period; whereas the latter is mainly for base metals （Cu, Pb, Zn, Sb, Hg）, noble metals （Au, Ag）, and one radioactive element （U） and was generated in the Cretaceous period. Centers of ore formation were brought about by interface dynamics respectively at the Qitianling and Jiuyishan districts in southern Hunan Province. The characteristic giant nonlinear target-pattern regional ore zonality was generated by spatio-temporal synchronization process of the Nanling complex metallogenic system. It induced the collective dynamics and cooperative behavior of the system and displayed the configuration of the regional ore zonality. Then dynamical clustering transformed the configuration into rudimentary ordered coherent structures. Phase dynamics eventually defined the spatio-temporal structures of the target-pattern regional ore zonality and determined their localization and distribution. A new methodology for revealing regional ore zonality is developed, which will encourage further investigation of the formation of deep-seated ore resources and the onset of large-scale mineralization.展开更多
With the vigorous development and construction of tourism complex, tourism enterprises under the new business situation and new situation are faced with different problems and development opportunities. This study foc...With the vigorous development and construction of tourism complex, tourism enterprises under the new business situation and new situation are faced with different problems and development opportunities. This study focuses on the development characteristics and current problems of the tourism complex, and combines the analysis of the consumption characteristics of the target consumers of the complex to discuss the management innovation of the tourism complex development and operation enterprises and find a reasonable management innovation path.展开更多
Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attent...Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90 N-RJ19 was determined by X-ray diffraction(resolution limit, 2.0 A, PDB code 4 L90). The crystal structure of Hsp90 N-RJ19 was analyzed in detail and compared with that of native Hsp90 N, Hsp90 N-ATP, and Hsp90 N-GDM,respectively. It was indicated that RJ19 interacted with Hsp90~N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90~N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90~N-RJ 19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90~N provide a rational basis for the design and optimization of novel anticancer drugs.展开更多
文摘A simulation approach based on a full-wave numerical method is presented to study electromagnetic characteristics by complex targets. How to validate simulation results is considered thoroughly under no analytical and measured data, where a double-check criterion is designed for our simulation approach. As an example, the scattering of F-117A is studied by using our simulation approach under all polarizations, different frequency bands, incident and scattering directions, etc., some of which, such as cross-polarization, bistatic RCS, have not been considered in the previous literature.
文摘The electromagnetic scattering computation has developed rapidly for many years; some computing problems for complex and coated targets cannot be solved by using the existing theory and computing models. A computing model based on data is established for making up the insufficiency of theoretic models. Based on the ＂support vector regression method＂, which is formulated on the principle of minimizing a structural risk, a data model to predicate the unknown radar cross section of some appointed targets is given. Comparison between the actual data and the results of this predicting model based on support vector regression method proved that the support vector regression method is workable and with a comparative precision.
基金Supported by Guangzhou Science and Technology Bureau Research Fund:the Mechanism of Action of Huangqi Guizhi Decoction on Precancerous Lesions in Cag Rats was Studied based on the Phosphatidylinositol 3-Kinase-Protein Kinase B-Mechanistic Target of Rapamycin Complex 2 Pathway(No.202102080643)Guangzhou Traditional Chinese Medicine and Integrative Medicine Research Project:Observation on the Therapeutic Effect of Wenyang Jianpi Ointment on Chronic Atrophic Gastritis of Spleen and Stomach Weakness Type and Study on its Regulatory Effect on Transforming Growth Factor Beta 3(No.20222A010079)Panyu District Science and Technology Project:the Mechanism by which the Modified Huangqi Guizhi Decoction Regulates the Transforming Growth Factor-β3 Signaling Pathway to Improve Precancerous Lesions in Rats with Chronic Atrophic Gastritis(No.2020-Z04-025)。
文摘OBJECTIVE:To investigate the effects of Jiawei Huangqi Guizhi decoction(加味黄芪桂枝汤)on chronic atrophic gastritis(CAG)in rats and its modulation of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 2(PI3K/Akt/m TORC2)signaling pathway.METHODS:CAG was induced in rats and treated with high-,medium-,or low-dose Jiawei Huangqi Guizhi decoction.Gastric histopathology was observed by hematoxylin and eosin staining.Serum levels of gastrin,PI3K,Akt,and m TORC2 were detected by enzyme-linked immunosorbent assay.Gene and protein expression levels were analyzed by reverse transcription polymerase chain reaction and western blot.RESULTS:The decoction alleviated gastric mucosal injury,reduced inflammation,and restored epithelial structure.It regulated PI3K,Akt,and m TORC2 expression at both m RNA and protein levels.CONCLUSION:Jiawei Huangqi Guizhi decoction may prevent CAG progression by improving gastric tissue and modulating the PI3K/Akt/m TORC2 signaling pathway.
文摘A RCS prediction system named SCTE (Scattering from Complex Target and Environment) for calculating high-frequency electromagnetic scattering from complex target within complex environment is presented. The scattering body is described by Computer-Aided-Design (CAD) representations in which the complex body is modeled as NURBS (Non-Uniform Rational B-spline) surfaces. The complex environment (rough surface of sea or ground) is also carefully considered by using fractal function. Scattering fields are calculated by using physical optics and the equivalent currents methods. There is a good agreement between the present results and that from measurements which demonstrates the accuracy of this system.
文摘A practical approach for calculating the RCS (Radar Cross Section) of complex targets modeled with wire-grid-frame is presented. A way for generating a polyhedron model (facet-wedge model) with the wire-grid-frame data is described. For storing and reading the data of the polyhedron model in an easy way, a data structure is given.
文摘The defining neuropathological feature of Parkinson＇s disease （PD） is the loss of nigrostriatal dopaminergic （DA） projections. This results in striatal dopamine levels and a biochemical reduction of movement disorders, such as a tremor at rest, rigidity of the limbs, bradykinesia, and postural instability （Kim et al., 2011; Kim et al., 2012; Burke and O＇Malley, 2013; Leem et al., 2014; Namet al., 2014）.
文摘The mammalian target of rapamycin(mTOR)acts in two structurally and functionally distinct protein complexes,mTOR complex 1(mTORC1)and mTOR complex 2(mTORC2).Upon deregulation,activated mTOR signaling is associated with multiple processes involved in tumor growth and metastasis.Compared with mTORC1,much less is known about mTORC2 in cancer,mainly because of the unavailability of a selective inhibitor.However,existing data suggest that mTORC2 with its two distinct subunits Rictor and mSin1 might play a more important role than assumed so far.It is one of the key effectors of the PI3K/AKT/mTOR pathway and stimulates cell growth,cell survival,metabolism,and cytoskeletal organization.It is not only implicated in tumor progression,metastasis,and the tumor microenvironment but also in resistance to therapy.Rictor,the central subunit of mTORC2,was found to be upregulated in different kinds of cancers and is associated with advanced tumor stages and a bad prognosis.Moreover,AKT,the main downstream regulator of mTORC2/Rictor,is one of the most highly activated proteins in cancer.Primary and secondary liver cancer are major problems for current cancer therapy due to the lack of specific medical treatment,emphasizing the need for further therapeutic options.This review,therefore,summarizes the role of mTORC2/Rictor in cancer,with special focus on primary liver cancer but also on liver metastases.
基金partially supported by the National Institutes of Health(R21CA185833 and R01GM113242 to H.S.)the National Natural Science Foundation of China(Nos.81660041 and 81260021 to L.D.)the Education Department of Jiangxi Province(GJJ150219to X.T.)
文摘The Mediator co-activator complex is a highly conserved,multisubunit protein complex required for gene transcription by RNA polymerase Ⅱ（RNAPⅡ）in all eukaryotes（Allen and Taatjes,2015）.This complex,which consists of at least 30 polypeptides,can be divided into four structurally distinct sub-modules including the head,middle,tail,and cyclin-dependent kinase 8（CDK8）modules （CKM） （Fig. 1A） （Yin and Wang, 2014; Allen and Taatjes, 2015）.
文摘During the last two centuries, there have been many spectacular advances in medical science, the main consequence of which has been the dramatically reduced burden of infectious diseases. While in the 1800s many people died before reaching adult- hood, nowadays most people survive. Hence average life ex- pectancy in 1800s was around 30-40, which was barely higher than it had been in Greek and Roman times （Finch, 2010）, but nowadays life expectancy in most modernised economies is around 75 - 80. This demographic shift, which has happened in only 200 years, has created a dramatic change in the causes of mortality. The major killers in the modern world are non- communicable diseases （NCDs）： principally cardiovascular disease, cancer and neurodegenerative disorders such as Alz- heimer＇s disease. A major factor that influences susceptibility to all these diseases is age. As we get older, our risk of developing these NCDs increases enormously. For example, the rate of breast cancer in females at age 15-19 is less than 10 per 100,000 population, but this increases to 100 at age 40-44, 275 at age 55--59 and 450 at age 85 ＋ （http：//www.cancerresearchuk.org/ cancer-info/cancerstats/types/breast/incidence/#age）. Ageing has consequently become a major medical, social and economic burden to many countries.
基金Supported by National Natural Science Foundation of ChinaNo. 82074241+1 种基金Project of Jiangsu Province Hospital of Traditional Chinese Medicine Peak TalentNo. y2021rc36
文摘BACKGROUND 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid(BT2)is a benzothiophene carboxylate derivative that can suppress the catabolism of branched-chain amino acid(BCAA)-associated mammalian target of rapamycin complex 1(mTORC1)activation.Previous studies have demonstrated the therapeutic effects of BT2 on arthritis,liver cancer,and kidney injury.However,the effects of BT2 on ulcerative colitis(UC)are unknown.AIM To investigate the anti-UC effects of BT2 and the underlying mechanism.METHODS Mouse UC models were created through the administration of 3.5%dextran sodium sulfate(DSS)for 7 d.The mice in the treated groups were administered salazosulfapyridine(300 mg/kg)or BT2(20 mg/kg)orally from day 1 to day 7.At the end of the study,all of the mice were sacrificed,and colon tissues were removed for hematoxylin and eosin staining,immunoblot analyses,and immunohistochemical assays.Cytokine levels were measured by flow cytometry.The contents of BCAAs including valine,leucine,and isoleucine,in mouse serum were detected by liquid chromatography-tandem mass spectrometry,and the abundance of intestinal flora was analyzed by 16S ribosomal DNA sequencing.RESULTS Our results revealed that BT2 significantly ameliorated the inflammatory symptoms and pathological damage induced by DSS in mice.BT2 also reduced the production of the proinflammatory cytokines interleukin 6(IL-6),IL-9,and IL-2 and increased the anti-inflammatory cytokine IL-10 level.In addition,BT2 notably improved BCAA catabolism and suppressed mTORC1 activation and cyclooxygenase-2 expression in the colon tissues of UC mice.Furthermore,highthroughput sequencing revealed that BT2 restored the gut microbial abundance and diversity in mice with colitis.Compared with the DSS group,BT2 treatment increased the ratio of Firmicutes to Bacteroidetes and decreased the abundance of Enterobacteriaceae and Escherichia-Shigella.CONCLUSION Our results indicated that BT2 significantly ameliorated DSS-induced UC and that the latent mechanism involved the suppression of BCAA-associated mTORC1 activation and modulation of the intestinal flora.
基金supported by the National Natural Science Foundation of China(Grant Nos.11174034,11135001,11205041,and 11305112)the Natural ScienceFoundation of Jiangsu Province,China(Grant No.BK20130282)
文摘This review describes the investigations of oscillatory complex networks consisting of excitable nodes, focusing on the target wave patterns or say the target wave attractors. A method of dominant phase advanced driving （DPAD） is introduced to reveal the dynamic structures in the networks supporting osciUations, such as the oscillation sources and the main excitation propagation paths from the sources to the whole networks. The target center nodes and their drivers are regarded as the key nodes which can completely determine the corresponding target wave patterns. Therefore, the center （say node A） and its driver （say node B） of a target wave can be used as a label, （A, B）, of the given target pattern. The label can give a clue to conveniently retrieve, suppress, and control the target waves. Statistical investigations, both theoretically from the label analysis and numerically from direct simulations of network dynamics, show that there exist huge numbers of target wave attractors in excitable complex networks if the system size is large, and all these attractors can be labeled and easily controlled based on the information given by the labels. The possible applications of the physical ideas and the mathematical methods about multiplicity and labelability of attractors to memory problems of neural networks are briefly discussed.
基金Supported by Hubei Provincial Natural Science Foundation,No.2025AFB845Graduate Innovation and Entrepreneurship Fund of Wuhan University of Science and Technology,No.JCX2024044.
文摘This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.
文摘A new way of acoustic wave imaging was investigated. By using the Green function theory a system of integral equations,which linked wave number perturbation function with wave field, was firstly deduced. By taking variation on these integral equations an inversion equation,which reflected the relation between the little variation of wave number perturbation function and that of scattering field, was further obtained. Finally, the perturbation functions of some identical targets were reconstructed, and some properties of the novel method including converging speed, inversion accuracy and the abilities to resist random noise and identify complex targets were discussed. Results of numerical simulation show that the method based on the variation principle has great theoretical and applicable value to quantitative nondestructive evaluation.
文摘Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.
基金co-supported by the National Natural Science Foundation of China(Nos.61471383,61531020,61471379 and 61102166)
文摘A group tracking algorithm for split maneuvering based on complex domain topological descriptions is proposed for the tracking of members in a maneuvering group. According to the split characteristics of a group target, split models of group targets are established based on a sliding window feedback mechanism to determine the occurrence and classification of split maneuvering, which makes the tracked objects focus by group members effectively. The track of an outlier single target is reconstructed by the sequential least square method. At the same time, the relationship between the group members is expressed by the complex domain topological description method, which solves the problem of point-track association between the members. The Singer method is then used to update the tracks. Compared with classical multi-target tracking algorithms based on Multiple Hypothesis Tracking （MHT） and the Different Structure Joint Probabilistic Data Association （DS-JPDA） algorithm, the proposed algorithm has better tracking accuracy and stability, is robust against environmental clutter and has stable time-consumption under both classical radar conditions and partly resolvable conditions.
基金supported by China Geological Survey grant nos 1212010561603 and 1212011121101(2005)
文摘By applying the ＇theory of synchronization＇ from the science of complexity to studying the regional regularity of ore formation within the Nanling region of South China,a characteristic target-pattern regional ore zonality has been discovered.During the early and late Yanshanian epoch （corresponding respectively to the Jurassic and Cretaceous periods）,two centers of ore formation emerged successively in the Nanling region;the former is mainly for rare metals（W,Sn,Mo,Bi,Nb） and one rare-earth element（La） and was generated in the Jurassic period;whereas the latter is mainly for base metals （Cu,Pb,Zn,Sb,Hg）,noble metals（Au,Ag）,and one radioactive element（U） and was generated in the Cretaceous period.Centers of ore formation were brought about by interface dynamics respectively at the Qitianling and Jiuyishan districts in southern Hunan Province.The characteristic giant nonlinear target-pattern regional ore zonality was generated respectively from the two centers of ore formation by the spatio-temporal synchronization process of the Nanling complex metallogenic system.It induced the collective dynamics and cooperative behavior of the system and displayed the configuration of the regional ore zonality.Then dynamical clustering transformed the configuration into rudimentary ordered coherent structures.Phase dynamics eventually defined the spatio-temporal structures of the target-pattern regional ore zonality and determined their localization and distribution.The integral successive processes of synchronization-dynamical clustering-phase dynamics accomplished the regional ore zonality by way of ＂multiple field dynamics＂ of spatio-temporal superposition of multiple coupled pulsatory solitary wave trains of the zonal sequences of different ores.A new methodology for revealing regional ore zonality is developed,which will encourage further investigation of the formation of deep-seated ore resources and the onset of large-scale mineralization.
基金supported by China Geological Survey Grants No. 1212010561603(2005)
文摘By applying the ＇theory of synchronization＇ from the science of complexity to studying the regional regularity of ore formation within the Nanling region of southern China, a characteristic targetpattern regional ore zonality has been discovered. During the early and late Yanshanian epoch （corresponding respectively to the Jurassic and Cretaceous periods）, two centers of ore formation emerged successively in the Nanling region; the former is mainly for rare metals （W, Sn, Mo, Bi, Nb） and one rare-earth element （La） and was generated in the Jurassic period; whereas the latter is mainly for base metals （Cu, Pb, Zn, Sb, Hg）, noble metals （Au, Ag）, and one radioactive element （U） and was generated in the Cretaceous period. Centers of ore formation were brought about by interface dynamics respectively at the Qitianling and Jiuyishan districts in southern Hunan Province. The characteristic giant nonlinear target-pattern regional ore zonality was generated by spatio-temporal synchronization process of the Nanling complex metallogenic system. It induced the collective dynamics and cooperative behavior of the system and displayed the configuration of the regional ore zonality. Then dynamical clustering transformed the configuration into rudimentary ordered coherent structures. Phase dynamics eventually defined the spatio-temporal structures of the target-pattern regional ore zonality and determined their localization and distribution. A new methodology for revealing regional ore zonality is developed, which will encourage further investigation of the formation of deep-seated ore resources and the onset of large-scale mineralization.
文摘With the vigorous development and construction of tourism complex, tourism enterprises under the new business situation and new situation are faced with different problems and development opportunities. This study focuses on the development characteristics and current problems of the tourism complex, and combines the analysis of the consumption characteristics of the target consumers of the complex to discuss the management innovation of the tourism complex development and operation enterprises and find a reasonable management innovation path.
基金supported by the National Natural Science Foundation of China(Nos.31401185 and 81402850)the Introduced talents Foundation of Xi'an Medical University(No.2015 RCYJ 01)
文摘Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90 N-RJ19 was determined by X-ray diffraction(resolution limit, 2.0 A, PDB code 4 L90). The crystal structure of Hsp90 N-RJ19 was analyzed in detail and compared with that of native Hsp90 N, Hsp90 N-ATP, and Hsp90 N-GDM,respectively. It was indicated that RJ19 interacted with Hsp90~N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90~N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90~N-RJ 19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90~N provide a rational basis for the design and optimization of novel anticancer drugs.
