Ch03Ad hoc Dynamic Macroeconomics The AS-AD Model(高级宏观经济学-柏林洪堡大学,Michael C. Burda)

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糖代谢重编程与巨噬细胞表型的研究进展

糖代谢重编程与巨噬细胞表型的研究进展①陈娟周永学闫曙光②李京涛③魏海梁④王文霸（陕西中医药大学，咸阳 712046）中图分类号R392.12 文献标志码 A 文章编号1000-484X（2023）10-2098-06［摘要］巨噬细胞是组织防御前线的哨兵，是机体对抗入侵病原体的重要武器，其代谢方式和功能与疾病的发展转归密切相关。

通常，巨噬细胞优先选择葡萄糖氧化磷酸化（OXPHOS）途径代谢产能，在缺氧环境下则以糖酵解为主。

而肿瘤巨噬细胞在氧气充足的情况下也通过糖酵解产能，这便是经典的“沃博格效应”。

研究表明，M1型巨噬细胞的糖代谢重编程与肿瘤细胞类似，表现为以有氧糖酵解为主和OXPHOS为辅，而M2型则恰好相反，因此阻断糖代谢重编程可有效抑制炎症反应。

本文重点阐述了巨噬细胞在炎症疾病调控中的关键作用及其糖代谢重编程的可能机制。

以期为免疫和代谢性相关疾病的防治提供新策略。

［关键词］巨噬细胞；重编程；糖酵解；氧化磷酸化Advances in glycometabolic reprogramming and macrophage phenotypesCHEN Juan， ZHOU Yongxue， YAN Shuguang， LI Jingtao， WEI Hailiang， WANG Wenba. Shaanxi University of Chinese Medicine， Xianyang 712046， China［Abstract］Macrophages are sentinels on the front line of tissue defense and an important weapon for the body to fight against invading pathogens. Their metabolic patterns and functions are closely related to the development and outcome of diseases. In general，macrophages preferentially select the oxidative phosphorylation of glucose （OXPHOS） pathway to metabolize energy production， and in hypoxic environments， glycolysis is the predominant. However， tumor macrophages can also produce energy through glycolysis in the presence of sufficient oxygen， which is the classic "Warburg effect". Studies have shown that the reprogramming of glucose metabo‑lism in M1 type macrophages is similar to that of tumor cells， showing that aerobic glycolysis is dominant and OXPHOS is supplemented，while M2 type macrophages are just the opposite， so blocking glucose metabolism reprogramming can effectively inhibit inflammation reaction. This review focuses on the key role of macrophages in the regulation of inflammatory diseases and the possible mechanism of there programming of glucose metabolism， in order to provide new strategies for the prevention and treatment of immune and metabolic related diseases.［Key words］Macrophages；Reprogramming；Glycolysis；Oxidative phosphorylation巨噬细胞是先天的免疫细胞，在炎症和肿瘤环境中扮演重要角色，具有较高的可塑性并在功能上产生极化，根据微环境的不同，巨噬细胞会呈现不同的表型，经典激活的M1型和交替激活的M2型，糖代谢重编程是其主要的影响因素。

Business_Cycles(Ch03)

Points to be Clarified and Emphasized
• 3. Comovement. • Expansions or contractions “occur at about the same time in many economic activities.” Many economic variables have regular and predictable patterns of behavior over the course of the business cycle. The tendency of economic variables to move together in a predictable way over the business cycle is called comovement.
Points to be Clarified and Emphasized
• Temporary deviations from the average, normal growth path of the aggregate economic activity. However, part of the output losses and gains that occurs during a business cycle may become permanent. • Peaks and troughs in the business cycle are known collectively as turning points.
• Classical economists view business cycles representing the economy’s best, efficient response to disturbances (in production and spending). Therefore, they do not see much, if any, need for government action to counteract fluctuations. • In contrast, the Keynesians argue that, because wages and prices adjust slowly, disturbances may drive the economy away from its most desirable level of output and employment for long periods of time. So, government should intervene to smooth business cycle fluctuations.

An Efficient Distributed Verification Protocol for Data Storage Security in Cloud Computing

An Efficient Distributed Verification Protocol for Data Storage Security in Cloud ComputingAbstract— Data storage is an important application of cloud computing, where clients can remotely store their data into the cloud. By uploading their data into the cloud, clients can be relieved from the burden of local data storage and maintenance. This new paradigm of data storage service also introduces new security challenges. One of these risks that can attack the cloud computing is the integrity of the data stored in the cloud. In order to overcome the threat of integrity of data, the client must be able to use the assistance of a Third Party A uditor (TPA), in such a way that the TPA verifies the integrity of data stored in cloud with the client’s public key on the behalf of the client. The existing schemes with single verifier (TPA) may not scale well for this purpose. In this paper, we propose A n Efficient Distributed Verification Protocol (EDVP) to verify the integrity of data in a distributed manner with support of multiple verifiers (Multiple TPA s) instead of single Verifier (TPA). Through the extensive security, performance and experimental results, we show that our scheme is more efficient than single verifier based scheme. Keywords: cloud storage, Integrity, Client, TPA, SUBTPAs, Verification, cloud computing.I.I NTRODUCTIONCloud computing is a large-scale distributed computing paradigm in which a pool of computing resources is available to Clients via the Internet. The Cloud Computing resources are accessible as public utility services, such as processing power, storage, software, and network bandwidth etc. Cloud storage is a new business solution for remote backup outsourcing, as it offers an abstraction of infinite storage space for clients to host data backups in a pay-as-you-go manner [1]. It helps enterprises and government agencies significantly reduce their financial overhead of data management, since they can now archive their data backups remotely to third-party cloud storage providersrather than maintaining local computers on their own. For example, Amazon S3 is a well known storage service.The increasing of data storage in the cloud has brought a lot of attention and concern over security issues of this data. One of important issue is with cloud data storage is that of data integrity verification at untrusted cloud servers. For example, the storage service provider, which experiences Byzantine failures occasionally, may decide to hide the data loss incidents from the clients for the benefit of their own. What is more serious is that for saving money and storage space the service provider might neglect to keep or deliberately delete rarely accessed data files which belong to thin clients. Consider the large size of the outsourced data and the client’s constrained resource capability, the main problem can be generalized as how can the client find an efficient way to perform periodical integrity verifications without local copy of data files.To verify the integrity of data in cloud without having local copy of data files, recently several integrity verification protocols have been developed under different systems [2-13].A ll these protocols have verified the integrity of data with single verifier (TPA). However, in single auditor verification systems, they use only one Third Party A uditor (TPA) to verify the Integrity of data based Challenge-Response Protocol. In that verification process, the TPA stores the metadata corresponding to the file blocks and creates a challenge and sends to the CSP. The CSP generates the Integrity proof for corresponding challenge, and send back to the TPA. Then, TPA verifies the response with the previously stored metadata and gives the final audit result to the client. However, in this single A uditor system, if TPA system will crash due to heavy workload then whole verification process will be aborted. In addition, during the verification process, the network traffic will be very high near the TPA organization and may create network congestion. Thus, the performance will be degrading in single auditor verification schemes. Therefore, we need an efficient distributed verification protocol to verify the integrity of data in cloud.In this paper, we propose an Efficient Distributed Verification Protocol (EDVP) to verify the integrity of data in a distributed manner with support of multiple verifiers (Multiple TPAs) instead of single Verifier (TPA), which were discussed in existing prior works[2-13]. In our protocol, many number of SUBTPA s concurrently works under the single TPA and workload also must be uniformly distribute among the SUBTPA s, so that each SUBTPA will verify over the whole part, Suppose if TPA fails, one of the SUBTPA will act as TPA. Our protocol would detect the data corruptions in the cloud efficiently when compared to single verifier based protocols.Our protocol design is based on RSA-based Dynamic Public Audit Service for Integrity Verification of data in cloud proposed by Syam et al.[11] in a distributed manner. Here, the n verifiers challenge the n servers uniformly and if m server’s response is correct out of n servers then, we can say that Integrity of data is ensured. To verify the Integrity of the data, our verification process uses multiple TPA s, among theSyam Kumar.P1Dept.of Computer ScinceIFHE(Deemed University)Hyderabad, Indiashyam.553@1,Subramanian. R2, Thamizh Selvam.D3Dept.of Computer Science School of Engineering and Technology,Pondicherry University, Puducherry, India, rsmanian.csc@.in2,dthamizhselvam@32013 Second International Conference on Advanced Computing, Networking and Securitymultiple TPAs, one TPA will act as main TPA and remaining are SUBTPA s. The main TPA uses all SUBTPA s to detect data corruptions efficiently, if main TPA fails, then one of the SUBTPA will act as main TPA. The SUBTPA s do not communicate with each other and they would like to verify the Integrity of the stored data in cloud, and consistency of the provider’s responses. The propose system guarantee the atomic operations to all TPA s; this means that TPA which observe each SUBTPA operations are consistent, in the sense that their own operations plus those operations whose effects they see have occurred atomically in same sequence.In Centrally Controlled and Distributed Data paradigm, where all SUBTPA s are controlled by the TPA and SUBTPA’s communicate to any Cloud Data Storage Server, we consider a synchronous distributed system with multiple TPA s and Servers. Every SUBTPA is connected to Server through a synchronous reliable channel that delivers a challenge to the server. The SUBTPA and the server together are called parties P. A protocol specifies the behaviours of all parties. An execution of P is a sequence of alternating states and state transitions, called events, which occur according to the specification of the system components. A ll SUBTPA s follow the protocol; in particular, they do not crash. Every SUBTPA has some small local trusted memory, which serves to store distribution keys and authentication values. The server might be faulty or malicious and deviate arbitrarily from the protocol; such behaviour is also called Byzantine failure.The Synchronous system comes down to assuming the following two properties:1. Synchronous computation. There is a known upper bound on processing delays. That is, the time taken by any process to execute a step is always less than this bound. Remember that a step gathers the delivery of a message (possibly nil) sent by some other process, a local computation (possibly involving interaction among several layers of the same process), and the sending of a message to some other process.2. Synchronous communication. There is a known upper bound on challenge/response transmission delays. That is, the time period between the instant at which a challenge is sent and the time at which the response is delivered by the destination process is less than this bound.II.RELATED WORKBowers et al. [2] introduced a High Availability Integrity Layer (HAIL) protocol to solve the Availability and Integrity problems in cloud computing using error correcting codes and Universal Hash Functions (UHFs). This scheme achieves the A vailability and Integrity of data. However, this scheme supports private verifiability.To support public verifiability of data integrity, Barsoum et al. [3] proposed a Dynamic Multiple Data Copies over the Cloud Servers, which is based on multiple replicas. This scheme achieves the Availability and Integrity of data stored in cloud. Public verification enables a third party auditor (TPA) to verify the integrity of data in cloud with the data owner's public key on the behalf of the data owner,. Wang et al. [4] designed an Enabling Public Auditability and Data Dynamics for data storage security in cloud computing using Merkle Hash Tree (MHT). It achieves the guarantee of the data Integrity with efficient data dynamic operations and public verifiability. Similarly,Wang et al. [5] proposed a flexible distributed verification protocol to ensure the dependability, reliability and correctness of outsourced data in the cloud by utilizing homomorpic token and distributed erasure coded data. This scheme allow users to audit the outsourced data with less communication and computation cost. Simultaneously, it detects the malfunctioning servers. In their subsequent work, Wang et al. [6] developed a privacy-preserving data storage security in cloud computing. Their construction utilizes and uniquely combines the public key based homomorpic authenticator with random masking while achieving the Integrity and privacy from the auditor. Similarly, Hao et al. [7] proposed a privacy-preserving remote data Integrity checking protocol with data dynamics and public verifiability. This protocol achives the deterministic guaranty of Integrity and does not leak any information to third party auditors. Zhuo et al. [8] designed a dynamic audit service to verify the Integrity of outsourced data at untrusted cloud servers. Their audit system can support public verifiability and timely abnormal detection with help of fragment structure, random sampling and index hash table. Yang et al. [9] proposed a provable data possession of resource-constrained mobile devices in cloud computing. In their framework, the mobile terminal devices only need to generate some secret keys and random numbers with the help of trusted platform model (TPM) chips, and the needed computing workload and storage space is fit for the mobile devices by using bilinear signature and Merkle hash tree (MHT), this scheme aggregates the verification tokens of the data file into one small signature to reduce the communication and storage burden.Although, all these schemes achieved the Integrity of remote data assurance under different systems, they do not provide a strong integrity assurance to the clients because their verification process using pseudorandom sequence. If we use pseudorandom sequence to verify the remote data Integrity, sometimes they may not detect the data modifications on data blocks. Since pseudorandom sequence is not uniform (uncorrelated numbers), it does not cover the entire file while generating Integrity proof for a challenge. Therefore, probabilistic Integrity checking methods using pseudorandom sequence may not provide strong Integrity assurance to user’s data stored in remotely.To provide better Integrity assurance, Syam et al. [10] proposed a homomorpic distributed verification protocol using Sobol sequence instead of pseudorandom sequence [2-9]. Their protocol ensures the A vailability, Integrity of data and also detects the data corruption efficiently. In their subsequent work, Syam et al. [11] described a RSA-based Dynamic Public Audit protocol for integrity verification of data stored in cloud. This scheme gives probabilistic proofs based on random challenges and like [10] it also detects the data modification on file. Similarly, Syam et al. [12] developed an Efficient and Secure protocol for both Confidentiality andIntegrity of data with public verifiability and dynamic operations. Their construction uses Elliptic Curve Cryptography instead of RSA because ECC offers same security as RSA with small key size. Later, Syam et al.[13] proposed a publicly verifiable Dynamic secret sharing protocol for A vailability, Integrity, Confidentiality of data with public verifiability.Although all these schemes achieved the integrity of remote data under different systems with Single TPA, but in single auditor verification protocols, they use only one Third Party A uditor (TPA) to verify the Integrity of data based Challenge-Response Protocol. However, in this single Auditor system, if TPA system will crash due to heavy workload then whole verification process will be aborted.III.PROBLEM STATEMENTA.Problem DefinitionIn cloud data storage, the client stores the data in cloud via cloud service provider. Once data moves to cloud he has no control over it i.e. no security for outsourced data stored in cloud, even if Cloud Service Provider (CSP) provides some standard security mechanism to protect the data from attackers but still there is a possibility threats from attackers to cloud data storage, since it is under the control of third party provider, such as data leakage, data corruption and data loss. Thus, how can user efficiently and frequently verify that whether cloud server storing data correctly or not? A nd will not be tampered with it. We note that the client can verify the integrity of data stored in cloud without having a local copy of data and any knowledge of the entire data. In case clients do not have the time to verify the security of data stored in cloud, they can assign this task to trusted Third Party Auditor (TPA). The TPA verifies the integrity of data on behalf of clients using their public key.B.System ArchitectureThe network representation architecture for cloud data storage, which consists four parts: those are Client, Cloud Service Provider (CSP), Third Party A uditors (TPA s) and SUBTPAS as depicted in Fig 1:Fig 1: Cloud Data Storage Architecture Client: - Clients are those who have data to be stored, and accessing the data with help of Cloud Service Provider (CSP). They are typically desktop computers, laptops, mobile phones, tablet computers, etc.Cloud Service Provider (CSP):- Cloud Service Providers (CSPs) are those who have major resources and expertise in building, managing distributed cloud storage servers and provide applications, infrastructure, hardware, enabling technology to customers via internet as a service.Third Party Auditor (TPA):- Third Party Auditor (TPA) who has expertise and capabilities that users may not have and he verify the security of cloud data storage on behalf of users. SUBTPAS: the SUBTPA s verifies the integrity of data concurrently under the control of TPAThroughout this paper, terms verifier or TPA and server or CSP are used interchangeablyC.Security ThreatsThe cloud data storage mainly facing data corruption challenge:Data Corruption: cloud service provider or malicious cloud user or other unauthorized users are self interested to alter the user data or deleting.There are two types of attackers are disturbing the data storage in cloud:1) Internal Attackers: malicious cloud user, malicious third party user (either cloud provider or customer organizations) are self interested to altering the user’s personal data or deleting the user data stored in cloud. Moreover they decide to hide the data loss by server hacks or Byzantine Failure to maintain its reputation2) External Attackers: we assume that an external attacker can compromise all storage servers, so that he can intentionally modify or delete the user’s data as long as they are internally consistent.D.GoalsIn order to address the data integrity stored in cloud computing, we propose an Efficient Distribution Verification Protocol for ensuring data storage integrity to achieve the following goals:Integrity: the data stored safely in cloud and maintain all the time in cloud without any alteration.Low-Overhead: the proposed scheme verifies the security of data stored in cloud with less overhead.E.Preliminaries and Notations•f key(.)- Sobol Random Function (SRF) indexed on some key, which is defined asf : {0,1}* ×key-GF (2w).•ʌkey– Sobol Random Permutation (SRP) indexed under key, which is defined asʌ : {0,1}log2(l) × key –{0,1}log2(l) .IV. EFFICENT DISTRIBUTION VERIFICATIONPROTOCOL:EDVP The EDVP protocol is designed based on RSA -based Dynamic Public A udit Protocol (RSA -DPA P), which is proposed by Syam et al.[11]. In EDVP, we are mainly concentrating on verification phase of RSA -DPA P. The EDVP contains three phases: 1) Key Distribution, 2) Verification Process 3) Validating Integrity. The process of EDVP is: first, the TPA generates the keys and distribute to SUBTPA s. Then the SUBTPA s verify the integrity of data and gives result to main TPA. Finally, the main TPA validates the integrity by observing the report from SUBTPAs.A. Key DistributionIn key distribution, the TPA generates the random keyand distributes it to his SUBTPAs as follows:The TPA first generates the Random key by using SobolRandom Function [15] then Compute)(1i f K k =Where1 i n and the key is indexed on some (usually secret) key: f :{0,1}*× keyĺZ p Then, employ (m, n ) secret sharing scheme [14] andpartition the random key K into n pieces. To divide K into npieces, the client select a polynomial a(x) with degree m-1andcomputes the n pieces: 1221....−++++=m j i i a i a i a K K (2)¦−=+=11m j j j i i a K K (3)A fter that TPA chooses nSUBTPA s and distributes n pieces to them. The procedure of key distribution is given in algorithm 1.Algorithm 1: Key Distribution1.1. Generates a random key K using Sobol Sequence. )(1i f K k =2. Then, the TPA partition the K into n pieces using (m,n) secret sharing scheme3. TPA select the Number of SUBTPAs: n, and threshold value m;4. for i ĸ1 to n do5. TPA sends k i to the all SUBTPA i s6. end for7. endB. Verification ProcessIn verification process, all SUBTPAs verify the Integrity of data and give results to the TPA, if m SUBTPAs responses meet the threshold value then TPA says that Integrity of data is valid. At a high level, the protocol operates like this: A TPA assigns a local timestamp to every SUBTPA of its operations. Then, every SUBTPA maintains a timestamp vector T in itstrusted memory. A t SUBTPA i , entry T[j] is equal to thetimestamp of the most recently executed operation by SUBTPA j in some view of SUBTPA i .To verify the Integrity of data, each SUBTPA creates a challenge and sends to the CSP as follows: first SUBTPA generates set of Random indices c of set [1, n] using Sobol Random Permutation (SRP) with random key)(c j j K π= (4) Where 1 c l and ʌkey (.) is a Sobol Random Permutation (SRP), which is indexed under key: ʌ : {0,1}log2(l ) ×key–{0,1} log2(l ).Next, each SUBTPA also chooses a fresh random key r j, wherer j = )(2l f k (5)Then, creates a challenge chal ={j, r j } is pairs of random indices and random values. Each SUBTPA sends a challenge to the CSP and waits for the response. The CSP computes a response to the corresponding SUBTPA challenges and send responses back to SUBTPAs.When the SUBTPA receives the response message, first he checks the timestamp, it make sure that V T (using vectorcomparison) and that V [i] = T[i]. If not, the TPA aborts theoperation and halts; this means that server has violated the consistency of the service. Otherwise, the SUBTP COMMITS the operation and check if stored metadata and response (integrity proof) is correct or not? If it is correct,then stores TRUE in its table and sends true message to TPA, otherwise store FALSE and send a false signal to the TPA for corrupted file blocks. The detailed procedure of verification processes is given in algorithm 2. Algorithm 2: Verification Process 1. Procedure: Verification Process 2. Timestamp T3. Each SUBTPA i computes4. Compute )(c j SRPk π=5. the Generate the sobol random key r j6. Send (Chal=(j, r j ) as a challenge to the CSP;7. the server computes the Proof PR i send back to theSUBTPAs;8. PR i ĸReceive(V);9. If (V T V [i] = T[i]) 10. return COMMIT then11. if PR i equals to Stored Metadata then 12. return TRUE;13. Send Signal, (Packet j , TRUE i ) to theTPA14. else15. return FALSE;16. Send Signal, (Packet i , FALSE i ) to the TPA; 17. end if 18. else19. ABORT and halt the process 20. e nd if 21. e nd(1)C.Validating IntegrityTo validate the Integrity of the data, the TPA will receive the report from any subset m out of n SUBTPAs and validates the Integrity. If the m SUBTPA s give the TRUE signal to TPA, then the TPA decides that data is not corrupted otherwise he decides that data has been corrupted. In the final step, the TPA will give an A udit result to the Client. In algorithm 3, we given the process of validating the Integrity, in which, we generalize the Integrity of the verification protocol in a distributed manner. Therefore, we can use distribution verification on scheme [11].Algorithm 3: Validating Integrity1.Procedure: validation(i)2.TPA receives the response from the m SUBTPAs3.for iĸ1 to m do4.If(response==TRUE)5. Integrity of data is valid6. else if(response==FALSE)7. Integrity is not valid8.end if9.end for10.endV.A NALYSIS OF EDVPIn this section, we analyse the security, and performance of EDVP.A.Security AnalysisIn security analysis, we analyze the Integrity of the data in terms of probability detection.Probability Detection:It is very natural that verification activities would increase the communication and computational overheads of the system. To enhance the performance, we used Secret sharing technique [14] to distribute the Key k that provides minimum communication and tractable computational complexity. Thus, it reduces the communication overhead between TPA and SUBTPAs. For a new verification, the TPA can change the Key K for any SUBTPA and send only the different part of the multiset elements to the SUBTPA. In addition, we used probabilistic verification scheme based on Sobol Sequences that provides uniformity not only for whole sequences but also for each subsequences, so each SUBTPA will independently verify over the entire file blocks. Thus, there is a high probability to detect fault location very quickly. Therefore, a Sobol sequence provides strong Integrity proof for the remotely stored data.The probability detections of data corruptions of this protocol same as previous protocols [9-12].In EDVP, we use Sobol random sequence generator to generate the file block number, because sequence are uniformly distributed over [0, 1] and cover the whole region. To make integers, we multiply constant powers of two with the generated sequences. Here, we consider one concrete example, taking 32 numbers from the Sobol sequences.B. B. Performance Analysis and Experimental ResultsIn this section, we evaluate the performance of theverification time for validating Integrity and compare theexperimental results with previous single verifier basedprotocol [11] as shown in Tables 1-3. In Table 4 and 5, wehave shown that the Computation cost of the Verifier and CSPrespectively.Table 1: Veri ication times (Sec) with 5 veri iers whendifferent percentages of 100000 blocks are corruptedCorruption data in percentageSingle Verifierbased Protocols[11]EDVP[5 verifiers]1% 25.99 12.145% 53.23 26.55 10% 70.12 38.6315% 96.99 51.2220% 118.83 86.4430% 135.63 102.8940% 173.45 130.8550% 216.11 153.81 Table 2: Verif ication times (Sec) with 10 Verif ierswhen di f f erent percentages o f 100000 blocks are corruptedCorruption data in percentage Single Verifier basedProtocols[11]EDVP[10verifiers]1% 25.9908.14 5% 53.2318.55 10% 70.12 29.63 15% 96.99 42.22 20% 118.83 56.44 30% 135.63 65.89 40% 173.45 80.85 50% 216.11 98.81T able 3: Verification times (Sec) with 20 verifiers when different percentages of 100000 blocks are corruptedCorruption data in percentage Single VerifierbasedProtocols[11]EDVP[20verifiers]1% 25.9904.145% 53.2314.5510% 70.12 21.6315% 96.99 32.2220% 118.83 46.4430% 135.63 55.8940% 173.45 68.8550% 216.11 85.81From Tables 1-3, we can observe that verification time is lessfor detecting data corruptions in cloud when compared to single verifier based protocol [11]Table 4:Verifier computation Time (ms) for the differentfile sizesFile Size Single Verifier basedProtocol[11]EDVP1MB 148.26 80.07 2MB 274.05 192.65 4MB 526.25 447.23 6MB 784.43 653.44 8MB 1083.9 820.87 10MB 2048.26 1620.06Table 5:CSP computation Time (ms) for the different filesizesFile Size Single Verifier basedProtocols[11]EDVP1MB 488.16 356.272MB 501.23 392.554MB 542.11 421.116MB 572.17 448.678MB 594. 15 465.1710MB 640.66 496. 02 From the table 4 & 5, we can observe that computation cost of verifier and CSP is less compared existing scheme[11]VI.C ONCLUSIONIn this paper, we presented an EDVP scheme to verify the Integrity of data stored in the cloud in a distributed manner with support of multiple verifiers (Multiple TPAs) instead of single Verifier (TPA). This protocol use many number of SUBTPA s concurrently works under the single TPA and workload also must be uniformly distribute among SUBTPAs, so that each SUBTPA will verify the integrity of data over the whole part. Through the security and performance analysis, we have proved that an EDVP verification protocol would detect the data corruptions in the cloud efficiently when compared to single verifier verification based scheme.R EFERENCES[1]R. Buyya, C. S. Yeo, S. Venugopal, J. Broberg, and I.Brandic.“Cloud Computing and Emerging IT Platforms: Vision, Hype, and Reality for Delivering Computing as the 5thUtility,” Future Generation Computer Systems, vol. 25, no. 6,June 2009, pp 599–616, Elsevier Science, A msterdam, TheNetherlands.[2]Bowers K. D., Juels A., and Oprea A., (2008) “HAIL: A High-vailability and Integrity Layer for Cloud Storage,”Cryptology ePrint Archive, Report 2008/489.[3]Barsoum, A. F., and Hasan, M. A., “On Verifying DynamicMultiple Data Copies over Cloud Servers”, Technical Report, Department of Electrical and Computer Engineering University of Waterloo, Ontario, Canada, Aug 2011.[4]Wang Q., Wang C., Li J., Ren K., and Lou W., “Enablingpublic veri¿ability and data dynamics for storage security incloud computing”, IEEE Trans. Parallel and Distributed Systems. VOL.22, NO.5. May, 2011,pp.[5]Wang C., Wang Q., Ren K., cao N., and Lou W.,(2012)“Towards Secure and Dependable Storage Services in CloudComputing”, IEEE Trans. Service Computing. VOL. 5, NO. 2,APRIL -JUNE 2012, pp.220-232.[6]Wang, C., Ren, K., Lou,W., and Li, J., “Toward publiclyauditable secure cloud data storage services”, IEEE Networks,Vol. 24, No. 4, 2010, pp. 19–24.[7]Hao Z., Zhong S., Yu N.,(2011) “A Privacy-Preserving RemoteData Integrity Checking Protocol with Data Dynamics andPublic Verifiability”, IEEE Trans Knowledge and DataEngineering,Vol.23, Issue 9,pp.1432 –1437.[8]Zhu Y., Wang H., Hu Z., Ahn G., Hu H., Stephen, and Yau S.,“Dynamic A udit Services for Integrity Verification of Outsourced Storages in Clouds”, Proc. of the 26th A CMSymposium on Applied Computing (SAC), March 21-24, 2011,Tunghai University, TaiChung, Taiwan.[9]Yang J., Wang H., Wang J., Tan C., and Yu D., (2011)“Provable Data Possession of Resource-constrained MobileDevices in Cloud Computing”, JOURNA L OF NETWORKS,VOL. 6, NO. 7, July,, 2011,pp.1033-1040[10]P. Syam Kumar, R. Subramanian, “Homomorpic DistributedVerification Ptorotocol for Ensuring Data Storage in CloudComputing”. Journal of Information, Vol. 14, No.10, Oct-2011, pp.3465-3476.[11]P. Syam Kumar, R. Subramanian, “RSA-based DynamicPublic A udit Service for Integrity Verification of DataStorage in Cloud Computing using Sobol Sequence” SpecialIssue Security, Privacy and Trust in Cloud Systems, International Journal of Cloud Computing(IJCC) in InderScience Publications, Vol. 1 No.2/3, 2012, pp.167-200. [12]P. Syam Kumar, R. Subramanian, “A n effiecent and Secureprotocol for Ensuring Data Storage Security inCloud Computing” publication in International Journal of computerScience Issues(IJCSI), Volume 8, Issue 6, Nov-2011, pp.261-274.[13]P. Syam Kumar, Marie Stanislas Ashok, Subramanian. R, “APublicly Verifiable Dynamic Secret Sharing Protocol forSecure and Dependable Data Storage in Cloud Computing”Communicated for Publication in International Journal ofCloud Applications and Computing (IJCAC).[14]Shamir A.,“How to Share a Secret”, Comm. 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Explicating dynamic capabilities the nature and microfoundations

Strategic Management JournalStrat.Mgmt.J.(2007)Published online in Wiley InterScience ()DOI:10.1002/smj.640Received 16February 2004;Final revision received 20June 2007EXPLICATING DYNAMIC CAPABILITIES:THE NATURE AND MICROFOUNDATIONS OF (SUSTAINABLE)ENTERPRISE PERFORMANCEDAVID J.TEECE*Institute of Management,Innovation and Organization,Haas School of Business,University of California,Berkeley,California,U.S.A.This paper draws on the social and behavioral sciences in an endeavor to specify the nature and microfoundations of the capabilities necessary to sustain superior enterprise performance in an open economy with rapid innovation and globally dispersed sources of invention,innova-tion,and manufacturingcapability.Dynamic capabilities enable business enterprises to create,deploy,and protect the intangible assets that support superior long-run business performance.The microfoundations of dynamic capabilities—the distinct skills,processes,procedures,orga-nizational structures,decision rules,and disciplines—which undergird enterprise-level sensing,seizing,and reconﬁguring capacities are difﬁcult to develop and deploy.Enterprises with strong dynamic capabilities are intensely entrepreneurial.They not only adapt to business ecosystems,but also shape them through innovation and through collaboration with other enterprises,enti-ties,and institutions.The framework advanced can help scholars understand the foundations of long-run enterprise success while helping managers delineate relevant strategic considerations and the priorities they must adopt to enhance enterprise performance and escape the zero proﬁt tendency associated with operating in markets open to global competition.Copyright 2007John Wiley &Sons,Ltd.INTRODUCTIONRecent scholarship stresses that business enter-prises consist of portfolios of idiosyncratic and difﬁcult-to-trade assets and competencies (’re-sources’).1Within this framework,competitive advantage can ﬂow at a point in time from the ownership of scarce but relevant and difﬁcult-to-imitate assets,especially know-how.However,inKeywords:cospecialization;intangible assets;innovation;business ecosystems;entrepreneurship;managerial capi-talism;global competitiveness*Correspondence to:David J.Teece,F402Haas School of Business #1930,University of California,Berkeley,California 94720-1930,U.S.A.E-mail:teece@ 1The reference here is to the resource-based theory of the enterprise advanced by Rumelt (1984),Wernerfelt (1984),Amit and Schoemaker (1993),and others.Some of my earlier work (Teece,1980,1982)was also in this vein.fast-moving business environments open to global competition,and characterized by dispersion in the geographical and organizational sources of inno-vation and manufacturing,sustainable advantage requires more than the ownership of difﬁcult-to-replicate (knowledge)assets.It also requires unique and difﬁcult-to-replicate dynamic capabili-ties.These capabilities can be harnessed to con-tinuously create,extend,upgrade,protect,and keep relevant the enterprise’s unique asset base.For analytical purposes,dynamic capabilities can be disaggregated into the capacity (1)to sense and shape opportunities and threats,(2)to seize opportunities,and (3)to maintain competitiveness through enhancing,combining,protecting,and,when necessary,reconﬁguring the business enter-prise’s intangible and tangible assets.Dynamic capabilities include difﬁcult-to-replicate enterpriseCopyright 2007John Wiley &Sons,Ltd.D.J.Teececapabilities required to adapt to changing cus-tomer and technological opportunities.They also embrace the enterprise’s capacity to shape the ecosystem it occupies,develop new products and processes,and design and implement viable busi-ness models.It is hypothesized that excellence in these‘orchestration’2capacities undergirds an enterprise’s capacity to successfully innovate and capture sufﬁcient value to deliver superior long-termﬁnancial performance.The thesis advanced is that while the long-run performance of the enter-prise is determined in some measure by how the (external)business environment rewards its her-itage,the development and exercise of(internal) dynamic capabilities lies at the core of enterprise success(and failure).This paperﬁrst describes the nature of dynamic capabilities,and then explicates their microfoundations.The ambition of the dynamic capabilities frame-work is nothing less than to explain the sources of enterprise-level competitive advantage over time, and provide guidance to managers for avoiding the zero proﬁt condition that results when homoge-neousﬁrms compete in perfectly competitive mar-kets.A framework,like a model,abstracts from reality.It endeavors to identify classes of relevant variables and their interrelationships.A framework is less rigorous than a model as it is sometimes agnostic about the particular form of the theoreti-cal relationships that may exist.Early statements of the dynamic capabilities framework can be found in Teece,Pisano,and Shuen(1990a,1990b,1997) and Teece and Pisano(1994).An extensive lit-erature on dynamic capabilities now exists(e.g., Helfat et al.,2007)that can be organized and inte-grated into the general framework offered here. As indicated,the possession of dynamic capabil-ities is especially relevant to multinational enter-prise performance in business environments that display certain characteristics.Theﬁrst is that the environment is open to international commerce and fully exposed to the opportunities and threats asso-ciated with rapid technological change.The sec-ond is that technical change itself is systemic in 2The management functions identiﬁed are analogous to that of an orchestra conductor,although in the business context the ‘instruments’(assets)are themselves constantly being created, renovated,and/or replaced.Moreover,completely new instru-ments appear with some frequency,and old ones need to be abandoned.Whileﬂexibility is certainly an element of orches-tration,the latter concept implies much more.that multiple inventions must be combined to cre-ate products and/or services that address customer needs.The third is that there are well-developed global markets for the exchange of(component) goods and services;and the fourth is that the busi-ness environment is characterized by poorly devel-oped markets in which to exchange technological and managerial know-how.These characteristics can be found in large sectors of the global econ-omy and especially in high-technology sectors.In such sectors,the foundations of enterprise success today depend very little on the enterprise’s abil-ity to engage in(textbook)optimization against known constraints,or capturing scale economies in production.Rather,enterprise success depends upon the discovery and development of opportuni-ties;the effective combination of internally gener-ated and externally generated inventions;efﬁcient and effective technology transfer inside the enter-prise and between and amongst enterprises;the protection of intellectual property;the upgrading of‘best practice’business processes;the inven-tion of new business models;making unbiased decisions;and achieving protection against imita-tion and other forms of replication by rivals.It also involves shaping new‘rules of the game’in the global marketplace.The traditional elements of business success—maintaining incentive align-ment,owning tangible assets,controlling costs, maintaining quality,‘optimizing’inventories—are necessary but they are unlikely to be sufﬁcient for sustained superior enterprise performance. Executives seem to recognize new challenges in today’s globally competitive environments and understand how technological innovation is nec-essary but not sufﬁcient for ﬂey, CEO of Proctor&Gamble,notes that‘the name of the game is innovation.We work really hard to try to turn innovation into a strategy and a process ...‘.3Sam Pamisano,CEO of IBM,remarks that ‘innovation is about much more than new prod-ucts.It is about reinventing business processes and building entirely new markets that meet untapped customer demand.’4Put differently,there is an emerging recognition by managers themselves that the foundations of enterprise success transcend simply being productive at R&D,achieving new product introductions,adopting best practice,and delivering quality products and services.Not only 3Fortune,December11,2006:4.4Business Week,April24,2004:64.Explicating Dynamic Capabilities:Nature and Microfoundationsmust the innovating enterprise spend heavily on R&D and assiduously develop and protect its intel-lectual property;it must also generate and imple-ment the complementary organizational and man-agerial innovations needed to achieve and sustain competitiveness.As indicated,not all enterprise-level responses to opportunities and threats are manifestations of dynamic capabilities.As Sidney Winter(2003: 991)notes,‘ad hoc problem solving’isn’t neces-sarily a capability.Nor is the adoption of a well-understood and replicable‘best’practice likely to constitute a dynamic capability.Implementing best practice may help an enterprise become or remain viable,but best practices that are already widely adopted cannot by themselves in a competitive market situation enable an enterprise to earn more than its cost of capital,or outperform its competi-tors.Likewise,invention and innovation by them-selves are insufﬁcient to generate success(Teece, 1986).Two yardsticks can be proposed for calibrating capabilities:‘technical’ﬁtness and‘evolutionary’ﬁtness(Helfat et al.,2007).Technicalﬁtness is deﬁned by how effectively a capability performs its function,regardless of how well the capability enables aﬁrm to make a living.Evolutionary or externalﬁtness refers to how well the capability enables aﬁrm to make a living.Evolutionaryﬁt-ness references the selection environment.Helfat et al.(2007)further note that both technical and evolutionaryﬁtness range from zero to some pos-itive value.These yardsticks are consistent with the discussion here.Dynamic capabilities assist in achieving evolutionaryﬁtness,in part by helping to shape the environment.The element of dynamic capabilities that involves shaping(and not just adapting to)the environment is entrepreneurial in nature.Arguably,entrepreneurialﬁtness ought to have equal standing with evolutionaryﬁtness. Dynamic capabilities have no doubt been rele-vant to achieving competitive advantage for some time.However,their importance is now ampli-ﬁed because the global economy has become more open and the sources of invention,innovation,and manufacturing are more diverse geographically and organizationally(Teece,2000),and multiple inventions must be combined to achieve market-place success(Somaya and Teece,2007).Achiev-ing evolutionaryﬁtness is harder today than it was before the millennium.Moreover,regulatory and institutional structures must often be reshaped for new markets to emerge;and as discussed later,the ubiquity of‘platforms’must now be recognized (Evans,Hagiu,and Schmalensee,2006).While the development and astute management of intangible assets/intellectual capital is increas-ingly recognized as central to sustained enter-prise competitiveness,the understanding of why and how intangibles are now so critical still remains opaque and is not addressed by orthodox frameworks.What is needed is a new framework for business and economic analysis.As former U.S.Federal Reserve Chairman Alan Greenspan remarked,‘we must begin the important work of developing a framework capable of analyzing the growth of an economy increasingly dominated by conceptual products.’5The dynamic capabilities approach developed here endeavors to be respon-sive to this challenge at the enterprise level.In an earlier treatment(Teece et al.,1997:530) it was noted that‘we have merely sketched an out-line for a dynamic capabilities approach.’In what follows,the nature of various classes of dynamic capabilities is identiﬁed,and an effort is made to separate the microfoundations of dynamic capa-bilities from the capability itself.Put differently, important distinctions are made between the orga-nizational and managerial processes,procedures, systems,and structures that undergird each class of capability,and the capability itself.One should note that the identiﬁcation of the microfounda-tions of dynamic capabilities must be necessarily incomplete,inchoate,and somewhat opaque and/or their implementation must be rather difﬁcult.Oth-erwise sustainable competitive advantage would erode with the effective communication and appli-cation of dynamic capability concepts.Of course,the existence of processes,proce-dures,systems,and structures already ubiquitously adopted by competitors does not imply that these have not in the past been the source of competitive advantage,or might not still be a source of compet-itive advantage in certain contexts.For example, studies of the diffusion of organizational innova-tions(e.g.,Armour and Teece,1978;Teece,1980) 5Chairman Alan Greenspan also noted recently,‘over the past half century,the increase in the value of raw materials has accounted for only a fraction of the overall growth of U.S.gross domestic product(GDP).The rest of that growth reﬂects the embodiment of ideas in products and services that consumers value.This shift of emphasis from physical materials to ideas as the core of value creation appears to have accelerated in recent decades.’(Remarks of Alan Greenspan,Stanford Institute for Economic Policy Research,2004.)D.J.Teeceindicate that diffusion is by no means instanta-neous,and that proﬁts can persist for many years before being competed away.Decade-long adop-tion cycles for new business structures and pro-cedures(e.g.,performance measurement systems) are not uncommon.Uncertain imitability(Lippman and Rumelt,1982)may also serve to slow the dif-fusion process and support persistent differential performance.Fortunately,the existing literature on strategy, innovation,and organization and the new literature on dynamic capabilities have identiﬁed a panoply of processes and routines that can be recognized as providing certain microfoundations for dynamic capabilities.For instance,Eisenhardt and Martin (2000)identify cross-functional R&D teams,new product development routines,quality control rou-tines,and technology transfer and/or knowledge transfer routines,and certain performance mea-surement systems as important elements(micro-foundations)of dynamic capabilities.The effort here is not designed to be comprehensive,but to integrate the strategy and innovation literature and provide an umbrella framework that highlights the most critical capabilities management needs to sus-tain the evolutionary and entrepreneurialﬁtness of the business enterprise.SENSING(AND SHAPING) OPPORTUNITIES AND THREATS Nature of the capabilityIn fast-paced,globally competitive environments, consumer needs,technological opportunities,and competitor activity are constantly in a state ofﬂux. Opportunities open up for both newcomers and incumbents,putting the proﬁt streams of incum-bent enterprises at risk.As discussed in Teece et al.(1997),some emerging marketplace trajecto-ries are easily recognized.In microelectronics this might include miniaturization,greater chip density, and compression and digitization in information and communication technology.However,most emerging trajectories are hard to discern.Sensing (and shaping)new opportunities is very much a scanning,creation,learning,and interpretive activ-ity.Investment in research and related activities is usually a necessary complement to this activity. Opportunities get detected by the enterprise because of two classes of factors.First,as stressed by Kirzner(1973),entrepreneurs can have differ-ential access to existing information.Second,new information and new knowledge(exogenous or endogenous)can create opportunities,as empha-sized by Schumpeter(1934).Kirzner stressed how the entrepreneurial function recognizes any dise-quilibrium and takes advantage of it.The Kirzner-ian view is that entrepreneurship is the mechanism by which the economy moves back toward equi-librium.Schumpeter,on the other hand,stressed upsetting the equilibrium.As Baumol(2006:4) notes,‘the job of Schumpeter’s entrepreneur is to destroy all equilibria,while Kirzner’s works to restore them.This is the mechanism under-lying continuous industrial evolution and revolu-tion.’Equilibrium is rarely if ever achieved(Shane, 2003).Both forces are relevant in today’s econ-omy.To identify and shape opportunities,enterprises must constantly scan,search,and explore across technologies and markets,both‘local’and‘dis-tant’(March and Simon,1958;Nelson and Winter, 1982).This activity not only involves investment in research activity and the probing and reprob-ing of customer needs and technological possibili-ties;it also involves understanding latent demand, the structural evolution of industries and mar-kets,and likely supplier and competitor responses. To the extent that business enterprises can open up technological opportunities(through engaging in R&D and through tapping into the research output of others)while simultaneously learning about customer needs,they have a broad menu of commercialization opportunities.Overcoming a narrow search horizon is extremely difﬁcult and costly for management teams tied to established problem-solving competences.Henderson(1994) notes that General Motors(GM),IBM,and Dig-ital Equipment Corporation(DEC)encountered difﬁculties because they became prisoners of the deeply ingrained assumptions,informationﬁlters, and problem-solving strategies that made up their world views,turning the solutions that once made them great into strategic straitjackets.When opportunities areﬁrst glimpsed,entrepre-neurs and managers mustﬁgure out how to inter-pret new events and developments,which tech-nologies to pursue,and which market segments to target.They must assess how technologies will evolve and how and when competitors,suppli-ers,and customers will petitors may or may not see the opportunity,and even if theyExplicating Dynamic Capabilities:Nature and Microfoundationsdo they may calibrate it differently.Their actions, along with those of customers,suppliers,standard-setting bodies,and governments,can also change the nature of the opportunity and the manner in which competition will unfold.There are also constraints on the rules by which competitive forces will play out.These constraints are imposed by regulators,standard-setting bod-ies,laws,social mores,and business ethics.The shape of the‘rules of the game’is thus the result of co-evolution and complex interaction between what might be thought of as(business) ecosystem participants.Because of uncertainty, entrepreneurs/managers must make informed con-jectures about the path ahead.These conjectures become working hypotheses that can be updated as evidence emerges.Once a new evolutionary path becomes apparent,quick action is needed. MicrofoundationsThe literature on entrepreneurship emphasizes that opportunity discovery and creation can originate from the cognitive and creative(’right brain’) capacities of individual(s).However,discovery can also be grounded in organizational processes,such as research and development activity.The ability to create and/or sense opportunities is clearly not uniformly distributed amongst individuals or enter-prises.Opportunity creation and/or discovery by individuals require both access to information and the ability to recognize,sense,and shape devel-opments.The ability to recognize opportunities depends in part on the individual’s capabilities and extant knowledge(or the knowledge and learning capacities of the organization to which the indi-vidual belongs)particularly about user needs in relationship to existing as well as novel solutions. This requires speciﬁc knowledge,creative activity, and the ability to understand user/customer deci-sion making,and practical wisdom(Nonaka and Toyama,2007).It involves interpreting available information in whatever form it appears—a chart, a picture,a conversation at a trade show,news of scientiﬁc and technological breakthroughs,or the angst expressed by a frustrated customer.One must accumulate and thenﬁlter information from profes-sional and social contacts to create a conjecture or a hypothesis about the likely evolution of technolo-gies,customer needs,and marketplace responses. This task involves scanning and monitoring inter-nal and external technological developments and assessing customer needs,expressed and latent. It involves learning,interpretation,and creative activity.While certain individuals in the enterprise may have the necessary cognitive and creative skills, the more desirable approach is to embed scan-ning,interpretative,and creative processes inside the enterprise itself.The enterprise will be vulner-able if the sensing,creative,and learning functions are left to the cognitive traits of a few individuals.6 Organizational processes can be put in place inside the enterprise to garner new technical information, tap developments in exogenous science,monitor customer needs and competitor activity,and shape new products and processes r-mation must beﬁltered,and mustﬂow to those capable of making sense of it.Internal argument and discussion about changing market and tech-nological reality can be both inductive and deduc-tive.Hypothesis development,hypothesis‘testing,’and synthesis about the meaning of information obtained via search are critical functions,and must be performed by the top management team.The rigorous assembly of data,facts,and anecdotes can help test beliefs.Once a synthesis of the evidence is achieved,recurrent synthesis and updating can be embedded in business processes designed by middle management and/or the planning unit in the business organization(Casson,1997).If enter-prises fail to engage in such activities,they won’t be able to assess market and technological devel-opments and spot opportunities.As a consequence, they will likely miss opportunities visible to others. As noted in Teece et al.(1997),more decen-tralized organizations with greater local autonomy are less likely to be blindsided by market and technological developments.Because of the prob-lem of information decay as information moves up(and down)a hierarchy,businesses must devise mechanisms and procedures to keep management informed.Bill Hewlett and David Packard devel-oped‘management by walking about’(Packard, 1995)as a mechanism to prevent top management at Hewlett-Packard from becoming isolated from 6In a limited sense,that is about decision making under uncer-tainty.As Knight observes,with uncertainty there is‘a necessity to act upon opinion rather than knowledge’(Knight,1921:268). The problem is not just about knowledge asymmetries and incen-tive problems as Alchian and Demsetz(1972)seem to suggest. Rather,it involvesﬁltering and interpreting information about evolving technologies and marketplaces.D.J.Teecewhat was going on at lower levels in the enter-prise,and outside the enterprise as well.In other organizations(e.g.,professional services)the man-agement ranks can beﬁlled by leading profession-als who remain involved with professional work. This protects them from the hazards of managerial isolation.The search activities that are relevant to‘sens-ing’include information about what’s going on in the business ecosystem.With respect to technolo-gies,R&D activity can itself be thought of as a form of‘search’for new products and processes. However,R&D is too often usually a manifesta-tion of‘local’search.‘Local’search is only one component of relevant search.In fast-paced envi-ronments,with a large percentage of new prod-uct introductions coming from external sources, search/exploration activity should not just be local. Enterprises must search the core as well as to the periphery of their business ecosystem.Search must embrace potential collaborators—customers, suppliers,complementors—that are active in inno-vative activity.Customers are sometimes amongst theﬁrst to perceive the potential for applying new technol-ogy.Visionary members of customer organizations are often able to anticipate the potential for new technology and possibly even begin rudimentary development activities.Moreover,if the suppli-ers of new technology do not succeed in properly understanding user/customer needs,it is unlikely that new products they might develop will be suc-cessful.Indeed,one of the most consistentﬁndings from empirical research is that the probability that an innovation will be successful commercially is highly correlated with the developers’understand-ing of user/customer needs(Freeman,1974).Elec-tronic computing and the Internet itself can rightly be viewed as having a signiﬁcant component of user-led innovations.Business enterprises that are alert and sense the opportunity are often able to leverage customer-led efforts into new products and services,as the users themselves are frequently ill prepared to carry initial prototypes further for-ward.Suppliers can also be drivers of innovation important in theﬁnal product.Innovation in micro-processor and DRAMs is a classic case.This upstream or‘component’innovation has impacted competition and competitive outcomes in personal computers,cellular telephony,and consumer elec-tronics more generally.Failure to‘design in’new technology/components in a timely fashion will lend to failure;conversely,success can some-times be achieved by continuous rapid‘design in.’Indeed,continuous and rapid design around new technology/components developed elsewhere can itself be a source of durable competitive advan-tage.Put differently,with rapid innovation by com-ponent suppliers,downstream competitive success canﬂow from the ability of enterprises to continu-ously tap into such(external)innovation ahead of the competition.External search and acquisition of technology have been going on for decades,but as Chesbrough(2003)explains,‘Open Innovation’is now a mandate for enterprise success.The concept and practice of open innovation underscore the importance of broad-based external search and subsequent integration involving cus-tomers,suppliers,and complementors.Establish-ing linkages between corporations and universities assists broad-based search,as university programs are usually unshackled from the near at hand. Indeed,a recent study of patenting in the opti-cal disk industry(Rosenkopf and Nerkar,2001) seems to suggest that exploration that is more con-ﬁned generates lower impacts,and that the impact of exploration is highest when exploration spans organizational(but not technological)boundaries. However,it is not just a matter of searching for external inventions/innovations that represent new possibilities.Frequently it is a matter of combining complementary innovations so as to create a solu-tion to a customer problem.The systemic nature (Teece,2000)of many innovations compounds the need for external search.Sensing opportunities and threats can also be facilitated if the enterprise and/or the entrepreneur explicitly or implicitly employ some kind of ana-lytical framework,as this can help highlight what is important.Theﬁeld of strategic management has been stranded for some time with a frame-work that implicitly assumes that industry struc-ture(and product market share),mediated by enterprise behavior,determines enterprise perfor-mance.In Porter’s(1980)Five Forces frame-work,a good strategy involves somehow picking an attractive industry and positioning oneself to be shielded from competition.Porter’s approach mandates‘industry’analysis7and the calibration ofﬁve distinct industry-level forces:the role of 7The Five Forces framework undergirds‘industry’analysis in business school curriculum and in practice.However,the very。

生物英语单词

生命科学导论词汇表整理北医临床五班郑汉龙Unit 1 计算生物学computational biology 系统生物学systems biology 生物信息学bioinformatics 理论生物学theoretical biology 生物医学工程学biomedical engineering 数码生物学digital biology 人工生命artificial life 纳米生物学nanobiology 微胶囊microcapsuleUnit 2碳水化合物carbohydrates单糖monosaccharide 旋光异构体optical isomer 手性分子chiral molecule葡萄糖glucose寡糖oligosaccharide 双糖disaccharide 多糖polysaccharide（多糖分为energy-storage 或structural）淀粉starch 直链淀粉amylase 支链淀粉amylopectin 糖原glycogen 纤维素cellulose 纤维素酶cellulase 几丁质chitin 果胶pectin 琼脂agar 脂质lipid脂肪fat磷脂phospholipids 卵磷脂lecithin脑磷脂cephalin 丝氨酸磷脂phosphatidylserine 衍生脂质derived lipid 高胆固醇血症hypercholesteremia 蛋白质protein肽键peptide bond 寡肽oligopeptide 多肽polypeptide螺旋helix 折叠sheet 二硫键disulfide bond 氢键hydrogenbond 范德华力van der waalsforce 离子键ionic bond 变性denaturation 复性renaturation酶enzyme 核酶rybozyme 单纯蛋白质simple protein 结合蛋白质conjugated protein 辅酶coenzyme 辅基prostheticgroup 契合假说induced-fit hypothesis 活性中心active center抑制剂inhibitor 激活剂activator核酸nucleic acid 腺嘌呤ademine 鸟嘌呤guanine 胞嘧啶cytosine 胸腺嘧啶thymine 尿嘧啶uracil 核糖ribose 脱氧核糖deoxyrybose上游upstream下游downstream小沟minorgroove大沟major groove构象conformation阿尔茨海默氏病Alzheimer’s disease 前体蛋白amyloid precursor protein （APP）分泌酶secretaseUnit 3细胞学说cell theory原核细胞prokaryotic cell原核生物prokaryote真核细胞eukaryotic cell真核生物eukaryote 古细菌archaea 真细菌bacteria 细胞膜plasma membrane 糖脂glycolipid 胆固醇cholesterol 甘油磷脂glycerophospholipid 鞘磷脂sphingomyelin不对称性单位膜asymmetric unit membrane （AUM）胞外基质extra cellular matrix （ECM）细胞间连接intercellular junctions 紧密连接tight junctions 桥粒desmosomes 斑点桥粒spot desmosomes 间隙连接gap junctions 胞间连丝plasmodesma 连接子connexon 简单扩散simple diffusion 协助扩散facilitated diffusion 载体蛋白carrier protein 通道蛋白channel protein 水通道蛋白aquapotin 主动运输active transport 协同运输cotransport 电化学梯度electrochemical gradient 共运输symport 对向运输antiport 膜转运蛋白membrane transport protein 离子通道ion channel 离子泵ion pump 胞吞作用endocytosis 胞吞泡endocytic vesicle 膜下网格蛋白clathrin 结合蛋白dynamin接合蛋白adapter protein受体介导的胞吞作用receptor-mediated endocytosis低密度脂蛋白low-density lipoproteins 胞吐作用exocytosis 细胞质基质cytoplasmic matrix =cytomatrix胞质溶胶cytosol 内质网endoplasmic reticulum （ER）糙面内质网roughER （RER）光面内质网smooth ER （SER）核糖体ribosome 高尔基复合体golgi complex 信号识别颗粒signal recognition particle（SRP）共转移cotranslocation停止转移锚序列stop-transfer anchor sequence扁平膜囊saccules 溶酶体lysosome 过氧化物酶体peroxisome 微体microbody自体吞噬autophage 液泡vacuole 线粒体mitochondria 心磷脂cadiolipin 氢化酶体hydrogenosome 纺锤剩体mitosome 叶绿体chloroplast 微管microtubule 秋水仙素colchicine 紫杉醇taxol 纤毛cilia 鞭毛flagella 基体basal body 基粒basalgranule 菌毛fimbriae 菌毛蛋白pilin 微丝microphilament （MF）肌动蛋白actin 细胞松弛素cytochalasins 鬼笔环肽phillodin 中间纤维intermediate filament （IF）核纤层nuclear lamins 角蛋白纤维keratins filament 波形蛋白vimentin结蛋白desmin胶质原纤维酸性蛋白glial fibrillary acidic protein中间丝蛋白peripherin 神经丝neurofilaments 中间连接蛋白internexin 微管马达蛋白microtubule motor proteins 驱动蛋白kinesin 动力蛋白dynein 胞质动力蛋白cytosolic dynein 轴心动力蛋白axonemal dynein 分子马达蛋白molecular motor proteins 重链heavy chain 中间链intermediate chains 轻链light chains动力蛋白激活蛋白dynactin 轴动力蛋白构造：stalk，head，stem，base 微丝马达蛋白myosin motor proteins肌球蛋白myosin肌质网sarcoplasmic reticulum肌原纤维myofibril 肌节sarcomere 原肌球蛋白tropomyosinT-管transverse tubules 钙火花calcium sparks 细胞核nucleus 核被膜nuclear envelope 核孔复合体nuclear core complex （NPC）中央装运体central transporter 染色质chromatin 染色体chromosome 染色单体sister chromatid 组蛋白histone 非组蛋白nohistone 着丝粒centromere 着丝点（动粒）kinetochore 核仁nucleolus 广义核骨架nuclear skeletonUnit 4NAD 烟酰胺腺嘌呤二核苷酸Nicotinamide ademine dinucleotideNADP 烟酰胺腺嘌呤二核苷酸磷酸Nicotinamide ademine dinucleotide Phosphate FAD 黄素腺嘌呤二核苷酸Flavin ademine denucleatide光合作用Photosynthesis 叶绿素Chlorophyll 类胡萝卜素carotenoids 光系统photosystem PS 环式光合磷酸化cyclic photophosphorylationRuBP 核酮糖-1,5-二磷酸Ribulose-1,5-bisphosphate3-甘油三磷酸3-phospho-glycerate 光呼吸photorespirationCAM 植物景天科酸代谢crassulacean acid metabolism 细胞呼吸cellular respiration 糖酵解glycolysis 三羧酸循环tricarboxylic acid cycle =柠檬酸循环citric acid cycle 电子传递链electron transport chain 氧化磷酸化oxidative phosphorylation ATP合成酶ATP sythentase 质子半通道proton half channel 酸中毒acidosisUnit5细胞周期cell cycle 细胞周期时相phases of the cell cycle 黏合蛋白cohesin 凝缩蛋白condensin多蛋白黏合复合体multiprotein cohesion complex染色体结构维持蛋白SMC structural maintenanc of choromosomes浓缩condensation纺锤体微管APC anaphase-promoting complex紧固蛋白securin 泛素化ubiquination 中心体centrosome微观组织中心MTOC检验点checkpoint周期蛋白依赖性蛋白激酶CDKcyclin-dependent kinase促成熟因子MTF maturation promoting factor限制点restriction point 周期蛋白cyclin Unit 6 信号转导signal transduction 信号分子signal molecule 第二信使second messenger 级联放大作用cascade amplificationGTP 酶开关蛋白GTPase switch proteins二磷酸磷脂酰肌醇PIP2 三磷酸肌醇IP3 二酰基甘油DAG生长素抑制素somatostatin应答元件结合蛋白CREB基础转录装置basal transcriptional machinery味蕾taste bud 视感细胞rod视锥细胞cone激活结构域AD activation domain DNA 结合结构域DBD DNA-binding domain 配合体结合结构域LBD ligand-bindingdomain 糖皮质激素受体GR glucocorticoid receptor G 蛋白偶联受体GPCR G-protein-coupledreceptor乙酰胆碱ACh神经元neurocyte 神经信号neuronal signaling 突触synapse 脑干brain stem 延脑medullo 脑桥pons中脑midbrain 小脑cerebellum 间脑diencephalon 上丘脑epithalamus 丘脑thalamus 下丘脑hypothalamus 松果腺pincal gland 脉络丛choroidplexus 大脑cerebrum 基底神经节basal ganglion 大脑皮层cerebralcortex 新皮质neocortex 胼胝体corpus callosum 初级感受区primary sensory areas 联络区association area皮质祖细胞cortical progenitors 觉醒arousal 血清素serotonin 褪黑激素melatonin 近似昼夜规律cricadian rythmsUnit 7卵原细胞genia分离定律law of segregation基因型genotype 等位基因alleles 显性等位基因dominant allele 隐形等位基因recessive allele 纯合体homozygote 杂合体heterozygote 测交test cross自由组合定律law of independent assortment庞纳特方格Punnett square 遗传的颗粒假说 “particulate” hypothesisof inheritance混合遗传模型blending model完全连锁complete linkage 不完全连锁incomplete linkage 重组recombination 连锁图linkage mapping 重组频率recombination frequency 不完全显性incomplete dominance 并显性codominant 复等位基因multiple alleles 恒河猴Rhesus monkey 基因多效型pleiotropy多基因遗传polygenic inheritance 加性效应additiveeffectUnit 8常染色体显性遗传autosomal dominant inheritance AD常染色体隐性遗传autosomal recessive inheritance AR 性决定sex determination 性分化sex differentiation剂量补偿效应dosagecompensation effectX 染色质失活中心X-choromosome inactivation centerSRY 基因sex-determining region of the Y 睾丸决定因子TDF testis determining factor 睾丸女性化综合症androgen insensitivity syndrome AIS androgen 雄性激素性连锁显性遗传sex-linked dominant inheritance XD性连锁隐性遗传sex-linked recessive inheritance XR 血友病hemophilia 自毁容貌综合症Lesch-Nyhan syndrome Y 连锁遗传Y-linked inheritance （与上同）holandric inheritance 毛耳缘hairy ear rims 多倍体polyploid 同源多倍体autopolyploid 异源多倍体allopolyploid唐氏综合症Down syndrome智商intelligence quotient染色体缺失deletion，deficiency染色体重复duplication，repeat猫眼综合症cat-eye syndrome染色体倒位inversion染色体异位Unit 9translocation烟草花叶病毒TMV单链结合蛋白SSB引物primer脱氧核苷三磷酸dNTP引物酶primase 前导链leading strand 后随链lagging strand 聚合酶链反应Polymerase chain reaction PCR 端粒telomere 端粒酶telomerase 简并degeneracy 赭石型三联体密码子ochre triple codon 琥珀型三联体密码子amber triple codon 蛋白石型三联体密码子opal ～～转录transcription 下游downstream 上游upstream启动子promotermRNA messenger ribonucleic acid tRNA transfer ribonucleic acid 加工processing 拼接splicing 聚腺苷化信号polyadenylation signal 内含子intron 外显子extron 间断基因interrupted gene 拼接体spliceosome氨酰-tRNA 合成酶aminoacyl-tRNAsynthetase焦磷酸PPi起始因子initiation factor 位点exit site 延长因子elongation factor 多聚核糖体polyribosomes 释放因子release factor 无义突变nonsense mutation 基因表达调控gene regulation 结构基因structural gene 操作基因operator gene 启动基因promoter gene 操纵子opreon 调节基因regulator gene 阻遏蛋白repressor protein 正基因调节positive gene regulation 分解代谢物激活蛋白catabolite activator protein CAP 基因丢失gene elimination 免疫球蛋白immunoglobulin Ig 重链heavy chain 轻链light chain 转录因子transcription factorsDNA 结合基序motif螺旋-转角-螺旋基序helix-turn-helix motif 锌指基序zinc-finger motif 亮氨酸拉链基序leucine zipper motif 增强子enhancer绝缘子insulator 沉默子silencer 5-甲基胞嘧啶thylcytosine 可变的RNA 剪接alternative RNA splicing 小RNA micro RNA miRNA RNA 干扰RNA interference RNAi转录后基因沉默（就植物而言）posttranscriptional gene silenceP TGS 转铁蛋白transferrin 铁蛋白ferritin 干一环stem loop 铁应答元件iron response element IREUnit 10 点突变pointmutation 同义突变samesense mutation 错义突变missense ~ 无义突变nonsense~ 自发突变spontaneous ~ 诱变剂mutagent控制因子controlling elements 转座因子transposable elements 转座子transposons 逆转座子retrotransposons 三核苷酸重复trinucleotide repeats 恶性肿瘤malignancy 肿瘤细胞tumor cell 扩散metastasis犬类传染性生殖器官肿瘤canine transmissible venereal tumor疱疹病毒herpesvirus 肿瘤抑制基因tumor suppressor gene 等位基因杂合型丢失loss of heterozygosity 细胞信号通路cell-signaling pathways 衰老标记senescence markers 人类基因组计划Human genome project （HGP）细胞遗传图cytogenetic map 核苷酸短串重复序列short tandem repeat STR单核苷酸多态性标记single nucleotide polymorphism STR DNA 测序DNA sequencing 限制性内切核酸酶restriction endonuclease 限制酶restriction enzyme 回文结构palindrome 粘性末端stickyend 平末端blunt end 重组DNA recombinant DNA 载体vector 质粒plasmid 探针probe 菌落colony DNA 文库DNAlibrary 质粒不相容性plasmid incompatibility 基因组文库genomic library 凝胶电泳gel electrophoresis 互补complementaryUnit 11 受精作用fertilization 顶体反应acrosomal reaction 顶体泡acrosomal vesicle 皮层反应cortical reaction 基因组印记genomic imprinting 卵裂cleavage桑葚胚morula囊胚腔blastocoel 囊胚期blatula 卵黄yolk向里凹陷invaginate 卷入involute原肠胚gastrula 原肠archenteron原口动物protosome 后口动物deuterostome 体节somites 诱导作用induction 形态原morphogen 锚状细胞anchorcell 尾bicaudal 间隙基因gapgenes 成对规则基因pair-rulegene 体节性基因segmentpolarity gene 同源异型基因homeotic gene 同源异型homeosis分生组织meristems 花分生组织floral meristems 营养分生组织vegetative ~ 心皮carpel 花瓣petal 雄蕊stamen 花萼sepal簇生fascinated 奢侈基因luxurygene 组织特异性基因tissue specificgene 管家基因housekeeping gene祖细胞progenitor cell 前体细胞precursor cell 胚胎干细胞embryonic stem cell ESC 成体干细胞somatic stem cell体细胞核移植技术somatic cell nuclear transfer SCNT 全能干细胞totipotent stem cell 多组织潜能干细胞pluripotent stem cell 多细胞潜能肝细胞multipotent ~~ 造血干细胞hematopoietic ~~ 粒性白细胞granulocyte macrophage 白细胞介素interleukin 嗜酸性粒细胞eosinophil 红细胞erythrocyte 肿瘤坏死因子tumor necrosis factor 单能干细胞unipotent stem cell 终末分化terminal differentiation 细胞凋亡apoptosis 细胞程序性死亡programmed cell death 凋亡小体blebbing （细胞内）损耗wear-terar 双性恋bisexual 印随imprinting 领域行为territorialityUnit 12---Unit 20盖亚假说Gaia hypothesis拉马克进化学说Lamarck’s theory of evolution达尔文自然选择学说Darwin’s theory of natural selection基因型频率genotype frequency等位基因alleles frequency 遗传平衡genetic equilibrium 遗传漂变genetic drift 建立者效应foundereffect瓶颈效应bottle neck effect定向选择directional selection频率曲线frequency curve分裂选择disruptive selection稳定选择stabilizing selection小进化microevolution 大进化macroevolution 异域种形成allopatric speciation 同域种形成sympatric speciation 同源多倍体autopolyploids 中性选择学说neutral selection 物种species 分类学taxonomy 进化谱系phylogency 衣壳capsid 包膜envelope 糖蛋白glycoprotein 核蛋白nucleoproteinAIDS acquired immunodeficiency syndrome 反转录酶reverse transcriptase类病毒viroid阮病毒prion瘙痒病scrapie微生物microorganisms支原体mycoplasma立克次体rickettsia 衣原体chlamydia 革兰氏染色法Gramstain 内生孢子endospores 微丝蛋白基质层actincortex 细胞向前突出protrusion 无性生殖asexual reproduction 有性生殖sexual reproduction 变态metamorphosis 蝗虫grasshopper 若虫nymphs脊索chorda dorsalis 多区域进化multiregional evolution蒙古利亚人种Mongloid 高加索人种Caucasoid 尼格罗人种Negroid澳大利亚人种Australoid 生态学ecology 非生物因子abiotic factors生物因子biotic factors 种群populatioin 集群分布clumped distribution 均匀分布uniform distribution 随机分布random distribution 出生率natality 死亡率mortality 性比sex ratio 代间距generation time 生存曲线survivorship curve 指数增长exponential growth 逻辑斯蒂增长logistic growth 容纳量carrying capacity 物种多样性biodiversity物种丰度species richness 物种均匀度species eveness 优势种dominant species 最高生物量biomass关键中keystone species食物网food web （由chain 组成）群落交错区ecotone种间竞争interspecific competition生态位niche 群落community 协同进化coevolution 捕食作用predation 植食herbivory 保护色cryptic coloration 警戒色warning coloration 拟态mimicry 共栖commensalism 海葵anemone 互利共生mutualism 寄生parasitism 群落演替community succession 顶级群落climax community 非生物环境abiotic environment 生产者producer 消费者consumer 分解者decomposer食草性动物herbivores 一级消费者primary consumers 食肉动物carnivores 二级消费者secondary consumers 三级消费者tertiary consumers 营养级trophic level 自养生物autotroph 同化assimilation 分解作用decomposition 食微生物动物microbivores 矿化作用mineralization 固定作用immobilization 净矿化作用net mineralization 内循环internal cycling 生物地化循环biogeochemical cycles 气态物循环gaseous cycle 沉积型循环sedimentary cycle 外来物种入侵alien species invasion 保护生物学conservation biology。

BIO-DYNAMIC-WGSN：生物动力学WGSN

BIO-DYNAMICNEW SYSTEMS SUBLIME SLIME FREE-FORMERNO.1NO.2NO.3Basic biological life forms are inspiring current science, cultural thinking and innovation. They reveal new ways of understanding interconnections, micro-networks, organic pattern structures and the make-up of the human body. Our new appreciation of all things bacterial and slime-oriented sees artists and designers creating work that questions dichotomies such as beauty and repulsion, solid and fluid, clean and dirty, and healthy and germ-free.Inspired by the endless mutation in microbiology, we celebrate the merging and mingling of styles. What we know as tropical, urban, rural or coastal become a fluid mix of influences.melted, morphed and liquefied.coastal become a fluid blend of categories.KEYTAKEAWAYSBasic life forms teach us about networking and navigating big dataHuman biology is revolutionised with the human microbiomeThink fluid and free-flowingClinical modernism is replaced by an organic and gloopy aesthetic We celebrate the “ickiness” and unpleasant nature of bacteria andslimeLIVING DATA PROCESSORS HUMAN MICROBIOME PROJECT MOULD NETWORK RAILWAYS YOUR MICROBIOME SLIME DYNAMICS Brainless, single-celled slime moulds can be programmed to function like biological computers. A group of scientists are claiming that these living cells may be the revolutionary future of data processing. Already, these biocomputers can make maps, run logic programmes and perform basic calculations.The US-based Human Microbiome Project is a research project that aims to understand how the human microbiome relates to health. Essentially, this is an enormous data analysis project that maps out the complex ecosystem of micro organisms found in the body and provides new analysis of human An Oxford University research team analysing networks created by slime moulds has compared these networks to the complexity of the Tokyo rail system, concluding that the sophistication matches human network designers. These findings can be applied to mobile communication and transport networks and even human blood flow.Recently, the New York Times published an article explaining the newly discovered fact that we are in some sense “only 10% human” - 90% of our bodies are made of bacterial species and 99% of our genetic information is microbial. This is a huge paradigm shift, as the last century was spent fighting off bacteria. Slime Dynamics is a new cultural theory by Ben Woodard that looks towards the vibrancy and vitality of basic life forms such as bacteria and mould as a way to understand the connections between digital technology, cybernetics and biological evolution. It celebrates the dark vitality and unpleasantness of life.Slime Dynamics by Ben Woodard (ISBN:9781780992488)THE DA VINCI UPGRADE Science writer Carl Zimmer has proposed that artists develop a new model to represent the perfect man, replacing Leonardo da Vinci’s Vitruvian man. This comes as our understanding of the human body makes a revolutionary move from “sterile mammal” to “microbial rainforest”.THE SILK PAVILION PLASTINATIONS MOULD NETWORK RAILWAYS ALTERNATIVE ENERGY THE SPACE BETWEEN MY TOES Researchers at MIT look to the methods of simple organisms such as silkworms to learn new methods of 3D printing, enabling additive manufacturing to build complex, free-form biological structures on a large scale. As an illustration of this, they are 3D-printing a life-size pavilion.Artist Stefan Gross makes melted plastic statues called Plastinations from found objects - in this instance, children’s plastic toys. The results are fluid forms with an aspect of the grotesque and gritty.www.stefangross.nl Designer Ross Lovegrove unveiled his Renault Twin ‘Z car at this year’s Milan Design Week. By examining nature, its systems and energy transactions, he has created a compact organic car that uses responsive LED lighting, seamless form and an all-electric motor.Curator Samantha Culp has noticed the art world’s recent interest in mutated energy drinks - in digital collages, installations, conceptual works, performance, video and photography. It seems to express or symbolise our deep anxieties about petroleum dependence, dirty energy and power.Maastricht University’s recent design focus was on hygiene as it moves away from the stark clinical aesthetic we typically associate with bacteria-free environments. Graduate Anne Buscher’s slippers use a silicon imprint of the foot to fill in the vulnerable spaces between the toes. CONTAMINATED CONSUMABLES Artist Vibha Galhotra carefully studied the contamination on the shores around Delhi’s Yamuna river and in response created a new body of work, Sediments and Other Untitled. Galhotra said: “By collecting the sediments from the river, I employed them as Indian ink, charcoal or colour”. LIVING DATA PROCESSORS HODGEPODGE HETEROTOPIA ELECTRIC JUNGLE TURING PATTERNS STEAMY REGIONS In A Thousand Years of Non-linear History, artist and philosopher Manuel DeLanda offers a fresh take on objects, ideas and social structures, suggesting that all of these things are part of a continuous evolution, a fluid state.A Thousand Years of Non-linear History by Manuel DeLanda (ISBN: 9780942299328)Artist Sumitro Basak paints the vibrancy and filth of Kolkata – celebrating what he calls the “hodgepodge heterotopian world” - through free-flowing forms, narrative images and the bright colours of city advertisements. For its womenswear resort collection 2013, Kenzo launched an animated lookbook video Electric Jungle, directed by illustrator Mat Maitland. This visual frenzy of animal print, variegated pattern and fluid overlays is a mutation of traditional print categories./5965364160 years ago, mathematician Alan Turing proposed mathematical equations showing how microorganisms create regular repeating patterns in nature, resulting in the stripes on tigers and the spots on leopards. These patterns inspire fresh print directions based on biological mutation and differentiation. Ceramic sculptor Ron Nagle’s drippy “ooze” aesthetic - simple amorphic forms, a combination of basic textures and the energy of his objects - connects to the themes of the Bio-dynamic trend: the primordial substances and simple organisms that form the basis of life on IMPROMPTU CITYSCAPE Graffiti artist Hense has just finished his largest mural to date, in the city of Lima, Peru. His colourful and expressionistic style and impromptu patterns contrast and enhance the surrounding urban BIO-DYNAMIC INDUSTRIAL EVOLUTION NEO GEOS/S 15A/W 14/15S/S 14Bio-dynamic sees the way we understand form, structures and even our own bodies completely revolutionised. It inspires us to create bacteria-friendly products and systems based on the fluid intelligence of the most basic life forms - microbes. In Industrial Evolution, we highlighted designers as they pioneered today’s industrial evolution. Using new craft-machines and 3D printing, these designers created improvised products with a focus on biology and the molecular. As a new geological era was announced, Neo-Geo investigated revolutionary ways of designing cities and public systems. It looked at the re-use of post-industrial waste, visionary combinations of plastic and natural materials.。

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用于治疗癌症、视网膜病症和心肌病的三取代嘧啶化合物和组合物[

专利名称：用于治疗癌症、视网膜病症和心肌病的三取代嘧啶化合物和组合物
专利类型：发明专利
发明人：马尔科·德·维沃,阿南德·加内桑,乔斯·安东尼奥·奥尔特加·马丁内斯,苏海尔·贾希德
申请号：CN201880042801.0
申请日：20180502
公开号：CN110799505A
公开日：
20200214
专利内容由知识产权出版社提供
摘要：本公开涉及式(I)的化合物或其药学上可接受的盐或溶剂化物。

其还公开了包括式(I)化合物的药物组合物及其用途，特别是在治疗与相对于生理学或期望的RhoI/Cdc42表达或功能水平增加相关的疾病或病症中的用途。

申请人：意大利学院科技基金会,加利福尼亚大学董事会
地址：意大利热那亚
国籍：IT
代理机构：北京康信知识产权代理有限责任公司
代理人：殷爽
更多信息请下载全文后查看。

宏观经济学课件(英文版)

GDP Composition
The breakdown of GDP into its various components, such as consumption, investment, government spending, and net exports.
VS
A measure of the percentage of the labor force that is jobless and actively seeking employment.
04
Fiscal Policy and Government Speing is a significant component of the economy, representing a significant share of GDP.
Government spending can also act as a stabilizer during economic downturns, stimulating growth and absorbing economic shocks.
05
Monetary Policy and Central Bank Operations
The main monetary policy tools used by central banks are open market operations, reserve requirements, and interest rate policy.
02
Examples include stimulus packages during the Great Recession, infrastructure spending programs, and social welfare policies.

Recursive Macroeconomic Theory (Sargent, 3rd edition)

Exercises1197last period’s wage oﬀer;(ii)a previously employed worker sets a reservation wage for continuing working at last period’s wage.For a given value ofμ,compare these two reservation wages.d.Show that an unemployed worker’s reservation wage for a short-lasting job exceeds her reservation wage for a long-lasting job.e.Let¯w s and¯w l be an unemployed worker’s reservation wages for short-lasting jobs and long-lasting jobs,respectively.In period t,let N st and N lt be the fractions of workers employed in short-lasting jobs and long-lasting jobs, respectively.Let U t be the fraction of workers unemployed in period t.Derive diﬀerence equations for N st,N lt and U t in terms of the parameters of the model and the reservation wages,{F,μs,μl,πs,πl,¯w s,¯w l}.Exercise28.8Productivity shocks,job creation,and job destruction, donated by Rodolfo ManuelliConsider an economy populated by a large number of identical individuals.The utility function of each individual is∞βt x t,t=0where0<β<1,β=1/(1+r),and x t is income at time t.All individuals are endowed with one unit of labor that is supplied inelastically:If the individual is working in the market,its productivity is y t,while if he or she works at home, productivity is z.Assume that z<y t.Individuals who are producing at home can also,at no cost,search for a market job.Individuals who are searching and jobs that are vacant get randomly matched.Assume that the number of matches per period is given byM(u t,x t),where M is concave,increasing in each argument,and homogeneous of degree 1.In this setting,u t is interpreted as the total number of unemployed workers, and v t is the total number of vacancies.Letθ≡v/u,and let q(θ)=M(u,v)/v be the probability that a vacant job(orﬁrm)will meet a worker.Similarly,let θq(θ)=M(u,v)/u be the probability that an unemployed worker is matched with a vacant job.Jobs are exogenously destroyed with probability s.In order to create a vacancy,aﬁrm must pay a cost c>0per period in which the1198Equilibrium Search and Matchingvacancy is“posted”(i.e.,unﬁlled).There is a large number of potentialﬁrms (or jobs),and this guarantees that the expected value of a vacant job,V,is zero.Finally,assume that when a worker and a vacant job meet,they bargain according to the Nash bargaining solution,with the worker’s share equal toϕ. Assume that y t=y for all t.a.Show that the zero-proﬁt condition implies thatw=y−(r+s)c/q(θ).b.Show that if workers andﬁrms negotiate wages according to the Nash bar-gaining solution(with worker’s share equal toϕ),wages must also satisfyw=z+ϕ(y−z+θc).c.Describe the determination of the equilibrium level of market tightness,θ.d.Suppose that at t=0,the economy is at its steady state.At this point, there is a once-and-for-all increase in productivity.The new value of y is y >y. Show how the new steady-state value ofθ,θ ,compares with the previous value. Argue that the economy“jumps”to the new value right away.Explain why there are no“transitional dynamics”for the level of market tightness,θ.e.Let u t be the unemployment rate at time t.Assume that at time0the economy is at the steady-state unemployment rate corresponding toθ,the“old”market tightness,and display this rate.Denote this rate as u0.Letθ0=θ . Note that change in unemployment rate is equal to the diﬀerence between job destruction at t,JD t and job creation at t,JC t.It follows thatJD t=(1−u t)s,JC t=θt q(θt)u t,u t+1−u t=JD t−JC t.Go as far as you can characterizing job creation and job destruction at t=0 (after the shock).In addition,go as far as you can describing the behavior of both JC t and JD t during the transition to the new steady state(the one corresponding toθ ).。

Ad-hoc on-demand distance vector routing

tery power, users are free to move about at their convenience without being constrained by wires. The idea of forming an on-the- y ad-hoc network of mobile nodes dates back to DARPA packet radio network days 11, 12]. More recently the interest in this subject has grown due to availability of license-free, wireless communication devices that users of laptop computers can use to communicate with each other. Several recent papers on this topic have focused on the algorithmic complexity of choosing the optimal set of ad-hoc routers 6, 8, 15], while others have proposed new routing solutions 4, 7, 10, 14, 16, 18] leveraging features from the existing Internet routing algorithms. Interest within the Internet Engineering Task Force (IETF) is also growing as is evidenced by the formation of a new working group (manet 5, 13]) whose charter is to develop a solution framework for routing in ad-hoc networks. The manet working group has goals that are quite distinct from the goals of the IETF mobileip working group, and make little or no use of Mobile IP 20] or any of its forerunners (e.g., 9, 22]). The Destination-Sequenced Distance Vector (DSDV) algorithm has been proposed 18] as a variant of the distance vector routing method by which mobile nodes cooperate to form an ad-hoc network. DSDV is e ective for creating ad-hoc networks for small populations of mobile nodes, but it is a fairly brute force approach because it depends for its correct operation on the periodic advertisement and global dissemination of connectivity information. Frequent system-wide broadcasts limit the size of ad-hoc networks that can e ectively use DSDV because the control message overhead grows as O(n2 ). DSDV also requires each mobile node to maintain a complete list of routes, one for each destination within the ad-hoc network. This almost always exceeds the needs of any particular mobile node. Keeping a complete routing table does reduce route acquisition latency before transmission of the rst packet to a destination. It is, however, possible to design a sys-

103 Epithelial-Mesenchymal Transition, At the Crossroads of Development and Tumor Metastasis

Epithelial-Mesenchymal Transition:At the Crossroadsof Development and Tumor MetastasisJing Yang1,*and Robert A.Weinberg2,3,*1Department of Pharmacology and Pediatrics,School of Medicine,University of California,San Diego,9500Gilman Drive,La Jolla,CA92093-0636,USA2Whitehead Institute for Biomedical Research,9Cambridge Center,Cambridge,MA02142,USA3Department of Biology,Massachusetts Institute of Technology,77Massachusetts Avenue,Cambridge,MA02139,USA*Correspondence:jingyang@(J.Y.),weinberg@(R.A.W.)DOI10.1016/j.devcel.2008.05.009The epithelial-mesenchymal transition is a highly conserved cellular program that allows polarized,immotile epithelial cells to convert to motile mesenchymal cells.This important process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting car-cinoma invasion and metastasis.In this review,we summarize and compare major signaling pathways that regulate the epithelial-mesenchymal transitions during both development and tumor metastasis.Studies in bothﬁelds are critical for our molecular understanding of cell migration and morphogenesis.An Overview of Epithelial-Mesenchymal TransitionThe development of metazoan organ systems starts with a single layer of epithelial cells,which constitutes the primary building block for constructing organismic complexity.Epithelial cells form a sheet or layers of cells that are tightly connected laterally by specialized junction structures,including adherens junctions, desmosomes,tight junctions,and gap junctions.Among these, adherens junctions play a particularly important role in assem-bling and constructing lateral cell-cell adhesions in epithelial cell sheets(Yap et al.,1997).Epithelial cells establish an aligned apical-basal polarity through their association with a lamina layer at their basal surface,often called the basement membrane.Un-der normal conditions,this anchoring to the basement mem-brane ensures that epithelial cells can only migrate laterally along the basal surface,thereby maintaining their positioning within the epithelium and precluding their entrance into the underlying extracellular matrix(ECM).During early embryogenesis of most metazoans,mesenchy-mal cells arise from the primitive epithelium.In contrast to epithe-lial cells,mesenchymal cells exhibit a front-back end polarity and rarely establish direct contacts with neighboring mesenchymal cells(Hay,1995).Unlike epithelial cells,mesenchymal cells can invade as individual cells through ECM constructed by epithelial sheets and by mesenchymal cells themselves.While epithelial and mesenchymal cell types have long been recognized in early embryos,the conversion of epithelial cells into mesenchymal cells was only deﬁned as a distinct cellular program in1980s.In a series of elegant experiments,Greenburg and Hay showed that when epithelial cells from embryonic and adult anterior lens were cultured in3D collagen gels,these cells elongated,detached from the explants,and migrated as individ-ual cells(Greenburg and Hay,1982,1986,1988).Based on the mesenchymal morphology and the pseudopodia andﬁlopodia structures of these migrating cells,they concluded that differen-tiated epithelial cells could be transformed into mesenchymal cells through a cellular program they named Epithelial-Mesen-chymal Transition(EMT).Subsequent cell-biological and molecular studies of EMT resulted in this program being loosely deﬁned by three major changes in cellular phenotype(Boyer and Thiery,1993;Hay, 1995):(1)morphological changes from a cobblestone-like mono-layer of epithelial cells with an apical-basal polarity to dispersed, spindle-shaped mesenchymal cells with migratory protrusions;(2)changes of differentiation markers from cell-cell junction proteins and cytokeratin intermediateﬁlaments to vimentinﬁla-ments andﬁbronectin(in addition,certain integrins[Zuk and Hay,1994]and splicing variants of FGFR2[Savagner et al., 1994]switch from epithelial to mesenchymal subtypes);and(3) the functional changes associated with the conversion of sta-tionary cells to motile cells that can invade through ECM.Not all three changes are invariably observed during an EMT;how-ever,acquisition of the ability to migrate and invade ECM as single cells is considered a functional hallmark of the EMT program.The EMT program is activated at multiple steps of embryonic development to enable the conversion of various types of epithe-lial cells into mesenchymal cells.Passage through an EMT,how-ever,does not necessarily represent an irreversible commitment to switch differentiation lineages.Thus,the reverse program, termed the Mesenchymal-Epithelial Transition(MET),also oc-curs both during embryonic development and during several pathological processes(Boyer and Thiery,1993;Davies,1996). The reversibility of this process underscores the enormous plas-ticity of certain embryonic and adult cells that participate in pro-cesses of disease pathogenesis.EMT in DevelopmentDuring development,the EMT program has been observed to underlie a variety of tissue remodeling events,including mesoderm formation,neural crest development,heart valve818Developmental Cell14,June2008ª2008Elsevier Inc.development,secondary palate formation,and male Mu¨llerian duct regression.In this section,we discuss in more detail four examples of the best-studied EMT events that occur during embryogenesis (Figure 1).Mesoderm formation and neural crest development represent the key EMT programs that occur during early embryonic development,and the resulting mesenchymal and neural crest cells maintain oliogopotentiality,enabling them to further differentiate into various cell types.In contrast,heart valve development and secondary palate formation occur in relatively well-differentiated epithelial cells that are destined to become deﬁned mesenchymal cell types.The latter two pro-cesses,which occur in well-differentiated epithelia,raise the possibility that EMTs may also be induced under certain physio-logical or pathological conditions in adult tissues,including tumor invasion and metastasis processes that will be discussed below.Mesoderm FormationThe earliest example of an EMT program participating in em-bryogenesis is the formation of mesoderm from the primitive ectoderm,a process that is initiated during gastrulation.Most of our molecular understanding of the EMT program during gas-trulation is derived from model organisms,including Drosophila and amphibian and avian embryos (Kimelman,2006).More re-cent studies indicate that the same basic principles apply to mammalian embryos (Viebahn,1995).The induction of mesoderm begins in a speciﬁc area of the primitive ectoderm,termed the ventral furrow in Drosophila ,the blastopore lip in Xenopus ,and the primitive streak in birds and mammals.The ﬁrst event in mesoderm formation is the in-vagination of the epithelial cells.This step is characterized by drastic morphological changes in a small population of epithelial cells,which include the narrowing of their apical compartments,the redistribution of organelles to the apical location,and the bulging of the basal compartments.When the epithelial cells are ready to ingress,the basement membrane is breached locally.At this point,the ingressing epithelial cells lose their tight cell-cell adhesions and remain attached to neighboring cells only by sparsely distributed focal contacts.Subsequently,these cells undergo mesenchymal differentiation and migrate along the narrow extracellular space underneath the ectoderm (Viebahn,1995).The newly gained ability for such ectoderm-derived cells to migrate along and through ECM marks the completion of the EMT program during gastrulation.Neural Crest FormationAnother dramatic example of EMT participating in embryogene-sis involves the generation of the neural crest,a deﬁning tissue of vertebrates.The neural crest is composed of a population of pre-cursor cells that are equipped with the ability to migrate over ex-traordinarily long distances in the embryo.Based on certain sim-ilarities,formation of the neural crest has been portrayed as a second gastrulation event in vertebrates (Duband et al.,1995).The neural crest develops at the boundary between the neural plate and the epidermal ectoderm.The emergence of neural crest cells begins with the presence of a distinct population of cells with rounded and pleiomorphic shapes,which contrast with those of the polarized neural tube cells that form nearby.Like the EMT program during gastrulation,the presumptive neu-ral crest cells proceed to lose N-cadherin-mediated cell-cell adhesion while becoming excluded from the neural epithelium (Tucker et al.,1988).Detailed immunolabeling and electron microscopic studies revealed that disruption of the basal lamina occurs immediately before or at the onset of neural crest cell migration in the cranial regions of avian and mouseembryosFigure 1.Images of EMT Processes during Embryogenesis(A)Primitive streak formation.The top panel shows the posterior third of a midsagittal 1m m plastic section from early streak stage rabbit embryo at 6.6days post coitum (d.p.c.)with three deﬁnitive mesoderm cells (blue arrow)between epiblast and hypoblast and a bottle-shaped epiblast cell (red arrow),which is about to ingress to become a deﬁnitive mesoderm cell (Viebahn,1995).The lower panel shows the center of a transverse 1m m plastic section through the center of the primitive streak of a full primitive streak stage rabbit embryo at 6.7d.p.c.with multiple bottle-shaped epiblast cells near the primitive pit (center of the picture)and mesoderm cells ﬁlling the space between epiblast and hypoblast (Viebahn et al.,1995).Imageis courtesy of Christoph Viehahn (University of Go¨ttingen,Go ¨ttingen,Germany)and S.Karger AG,Basel.(B)Neural crest formation.Immunoﬂuorescence image showing that neural crest cells (light blue)emerge from the neural epithelium (yel-low).Neural crest cells are stained with SOX9antibody (light blue);neural epithelia cells are stained with N-cadherin (yellow).Phalloidin (red)is used to label all cells,and DAPI (deep blue)is used to label cell nuclei.Image is courtesy of James Briscoe (National Institute for Medical Research,London,UK).(C)Cardiac valve formation.Light microscopy on a section of the atrium and ventricular ﬂow of an E9.5mouse embryo heart.Note that mesenchymmal cells (Mes)are emerging from the cardial endo-thial cell layer (Endo).Image is courtesy of Raymond B.Runyan (University of Arizona,Tucson,Arizona,USA).(D)Secondary palate formation.A hematoxylin-and eosin-stained section of rodent palate during palatogenesis in vitro is shown.The palatal seam begins to disintegrate and epithelial cells break away from the intact seam to become mesenchymal within 24hr (ar-rowhead).Image is courtesy of Ali Nawshad (University of Nebraska Medical Center,Lincoln,Nebraska,USA).Developmental Cell 14,June 2008ª2008Elsevier Inc.819(Duband and Thiery,1987;Nichols,1981).These observations indicate that neural crest cells actively invade through the basal lamina,just as in the case of gastrulation.However,in the trunk region of both avian and mouse embryos,a basal lamina is not present at the neural fold before the onset of neural crest migra-tion,obviating a rate-limiting step in the release of neural crest cells(Martins-Green and Erickson,1987).Theseﬁndings sug-gest that the cranial and trunk neural crest cells might employ distinct types of subcellular machinery to initiate EMT,invade the ECM,and migrate.As presumptive neural crest cells are released from the neural epithelium,they concomitantly upregulate genes required for mesenchymal phenotype and migratory ability.One critical com-ponent of neural crest migration is ECM that is laid down along the migratory path,helping to ensure that these cells reach appropriate destinations.Studies of this process have revealed that high levels ofﬁbronectin and hyaluronan appear in the pre-sumptive neural crest area before the onset of migration(Poel-mann et al.,1990),which raises the intriguing possibility that expression of these molecules is critical to the subsequent migratory ability of these cells.Cardiac Valve FormationThe endocardial cushion is the precursor structure to the heart valve in vertebrate embryos and begins to form soon after the primitive linear heart tube begins to loop.Initially,the myocardial cells secrete a large amount of ECM,which displaces the endo-cardium away from the myocardium,thereby creating endocar-dial cushions.After cushion formation,mesenchymal cellsﬁll the cushion space(Markwald et al.,1977).Video microscopy of isolated atrioventricular(AV)canals in culture has demonstrated that these mesenchymal cells derive from the endocardial cell layer by undergoing an EMT(Bolender and Markwald,1979). Through use of an elegant AV canals explant culture system in a3D,type I collagen gel,detailed molecular studies have shown that signals secreted from the AV myocardium are essential for induction of an EMT in the AV endocardial cells(Mjaatvedt and Markwald,1989;Rezaee et al.,1993).After receiving EMT-in-ducing stimuli,AV endocardial cells exhibit decreased expres-sion of N-CAM,lose cell-cell adhesion,and invade the newly deposited endocardial cushion,thereby establishing the pre-sumptive cardiac septa and valves(Person et al.,2005).The ability to model this EMT event in the explant culture has greatly facilitated molecular characterization of individual signals involved in this program.Several inducing signals,transcription factors,and ECM components have been tested for their in-volvement in cardiac valve formation.Below we discuss several EMT-inducing signals that are involved in EMT that occurs during cardiac valve formation.Secondary Palate FormationAnother relatively well-studied EMT event involving differenti-ated epithelial cells involves formation of the secondary oral pal-ate.Dissecting the palatal tissue and introducing it into organ cultures has made it possible to trace the entire program of pal-ate remolding by electron microscopy and immunohistochemis-try.Development of the secondary palate requires fusion of the palatal shelves at the midline.As the shelves approach one another from opposite sides of the developing oral cavity,epithe-lial cells covering the tip of each shelf intercalate and form the medial epithelial seam.Soon after fusion,these medial epithelial cells undergo an EMT and are integrated into the mesenchymal compartment of the palate,thereby completing the program of palatogenesis(Fitchett and Hay,1989).Interestingly,blocking fusion of the palatal shelves has been shown to prevent basal epithelial cells from undergoing an EMT,indicating that signals from the epithelial midline seam are critical to the triggering of the EMT process(Grifﬁth and Hay,1992).MET in DevelopmentDuring embryogenesis,the EMT program does not always repre-sent an irreversible process that permanently commits cells to one or another fate.Instead,in several cases,the converted mesenchymal cells can revert to an epithelial cell state by pass-ing through an MET.The best-studied MET event during em-bryogenesis is the formation of the nephron epithelium in the developing kidney.During this process,nephric mesenchymal cells aggregate around individual branches of the ureteral bud, begin to express laminin,polarize,and eventually develop cell-cell adhesions and differentiate into epithelial cells that form kid-ney tubules(Davies,1996).The ability of a mesenchymal cell to revert to an epithelial identity demonstrates,once again,sub-stantial cell plasticity and additionally suggests that interconver-sion between epithelial and mesenchymal cell states may also occur under certain pathological conditions.Molecular Regulation of EMTBoth developmental studies in various organisms and tissue culture studies have yielded a number of distinct signaling pathways that regulate EMT.Here we focus our discussion on the extracellular signals responsible for inducing EMTs and the key transcriptional factors that respond these signals;such transcription factors function as master regulators of the EMT programs in vertebrates(Table1).TGF-b SignalingMembers of the transforming growth factor-b(TGF-b)super-family have been implicated as major induction signals of EMT during almost all of the morphogenetic events discussed above. Extensive studies in various developmental EMT systems provide convincing evidence that TGF-b signaling is a primary inducer of EMT,although the precise signaling pathways activated by indi-vidual family members may differ during various EMT events.In both Xenopus and zebraﬁsh embryos,mesoderm induction is initiated mainly by members of the Nodal subfamily of TGF-b (Kimelman,2006).Several elegant studies in Xenopus using activin as a Nodal pathway activator or using different doses of Nodal inhibitors indicate that activation of Nodal signaling is es-sential for mesoderm induction in both the dorsal and ventral re-gions(McDowell and Gurdon,1999).Another Nodal family mem-ber,termed Vg1in Xenopus and chicken and GDF3in mice,is also known to play a critical role in mesoderm induction.Overex-pression of chick Vg1on its own is sufﬁcient to induce the forma-tion of a secondary primitive steak(Shah et al.,1997).In mice, Gdf3null mutants frequently exhibit defects in mesoderm forma-tion(Chen et al.,2006).Induction of neural crest requires the activation of BMP, another TGF-b superfamily member.In Xenopus,experiments examining differential activation of the BMP signal indicate that BMPs set up a competency zone between neural plate and ectoderm from which the neural crest can be induced(Raible,820Developmental Cell14,June2008ª2008Elsevier Inc.2006).In chickens and mice,BMPs have also been shown to be required for the induction and/or migration of neural crest cells (Correia et al.,2007).TGF-b signals also play critical roles in the activation of EMT during cardiac valve formation and secondary palate fusion.In a series of elegant antibody-blocking experiments using chicken AV explants,TGF-b2was shown to be essential for the initiation of the EMT program and the separation of endothelial cells;in contrast,TGF-b3was speciﬁcally required for the migration of the separated endothelial cells into ECM(Boyer et al.,1999).In mice,experiments using individual TGF-b1or TGF-b2knockout mice and heart explant culture also revealed the involvement of TGF-b1and TGF-b2in the EMT process occurring during car-diac morphogenesis(Mercado-Pimentel and Runyan,2007).In-terestingly,the TGF-b3knockout mice present a cleft palate phenotype,and the role of this TGF-b variant in initiating EMT to enable palatal fusion has been further conﬁrmed using a TGF-b3-blocking antibody in isolated mouse palatal shelf explants(Ahmed et al.,2007).One of the key questions about the role of TGF-b signaling in EMT is how various TGF-b signals are translated into the tran-scriptional signaling networks and the cellular responses re-quired for EMT and cell migration.In cultured mammary epithe-lial cells,TGF-b receptors are localized at tight junctions and directly interact with two important regulators of epithelial cell polarity and tight-junction assembly,Par6(Ozdamar et al., 2005)and Occludin(Barrios-Rodiles et al.,2005).Phosphoryla-tion of Par6by TGF-b type II receptor leads to a loss of tight junctions and apical-basal polarity(Ozdamar et al.,2005).Most developmental studies also suggest that the TGF-b pathway collaborates with Wnt,Notch,and receptor tyrosine kinase sig-nals to generate the speciﬁcities required for EMT in various mor-phogenetic steps.In cultured MDCK epithelial cells,activation of the TGF-b/Smad pathway has been shown to coordinate with Ras activation to promote a full EMT phenotype(Grunert et al., 2003).Future studies are needed to reveal how these complex networks interact to coordinate and specify individual steps of the EMT program.The Wnt SignalThe canonical Wnt pathway is implicated in the initiation and maintenance of mesoderm formation.In Xenopus and zebraﬁsh, Wnt8is required for the formation of dorsal mesoderm(Kelly et al.,1995;Smith and Harland,1991;Sokol et al.,1991).In mice,Wnt3null mutants show defects in the formation of the primitive streak(Liu et al.,1999).Activation of neural crest cell delamination and migration in-volves both canonical and noncanonical Wnt signaling.In Xeno-pus,gain-of-function experimental approaches demonstrate that activation of Wnt signaling induces ectopic neural crest, while depletion of b-catenin conﬁrms that the canonical Wnt pathway is required for initial neural crest induction(Wu et al., 2005).Furthermore,activation of Wnt11/Frizzled7-mediated noncanonical Wnt signaling also plays an essential and speciﬁc role in neural crest migration in Xenopus(De Calisto et al.,2005). In avian embryos,Wnt is necessary and sufﬁcient to induce neu-ral crest cells(Garcia-Castro et al.,2002).The role of Wnt signaling in heart valve induction is also well documented.b-catenin transcription activity has been observed in the newly formed mesenchyme of cardiac cushions during EMT in both zebraﬁsh(Gitler et al.,2003;Hurlstone et al., 2003)and mouse embryos(Liebner et al.,2004).In mice,inacti-vation of b-catenin in endothelial cells inhibits EMT and cardiac cushion formation both in vivo and in tissue explants(Liebner et al.,2004).The Notch PathwayNotch signaling has also been implicated in modulating the EMT program during embryogenesis.For example,in frog and chick, Notch signaling regulates cranial neural crest cells indirectly through its effect on expression of BMP family members(Cornell and Eisen,2005).Another study identiﬁed a role for Notch in pro-moting EMT during cardiac valve formation and in cultured epi-thelial cells from mammary gland,kidney tubules,and epidermis (Timmerman et al.,2004).In mice and zebraﬁsh,embryos lacking components of the Notch pathway maintain endocardial adhe-sion complexes and fail to undergo endocardial EMT.Con-versely,overexpression of activated Notch1induces EMT in immortalized endothelial cells(Timmerman et al.,2004).Further-more,in epithelial cells from the mammary gland,kidney tubules, and epidermis,the Notch ligand Jagged1and the Notch target Hey1are induced by TGF-b at the onset of EMT in a Smad3-de-pendent fashion(Zavadil et al.,2004).Unlike the TGF-b and Wnt pathways,activation of the Notch signaling pathway is not con-served among all the EMT processes that occur during the course of embryogenesis.It is therefore reasonable to predictTable1.Examples of EMTs during Vertebrate Embryonic Development and the Corresponding Signaling PathwaysDevelopmentalProcess Transition The TGF-ßPathwayThe WntPathwayThe NotchPathwayTyrosine KinaseReceptorsTranscriptionFactorsMesoderm formation primitive ectodermto mesodermNodal canonical Wnts N.D.FGFR Snail,Slug,GoosecoidNeural crest formation neural epitheliumto neural crest cellsBMP canonical Wnts,noncanonicalWnt11/Frizzled7regulateBMP signalingFGFR,PDGFR Snail,Slug,Twist1,SIP1Cardiac valve formation endocardial cellsto cardiac septaand valvesTGF-b1,2,3,BMPcanonical Wnts Jagged1/Notch1ErbB3Snail,SlugSecondary palate formation palatal shelfepithelial cells to palatalmesenchymal cellsTGF-b3N.D.N.D.EGFR,PDGFR N.D.N.D.,not determined.Developmental Cell14,June2008ª2008Elsevier Inc.821that Notch signaling is not sufﬁcient and needs to be coordinated with additional signaling inputs in order to promote an EMT. Signals from Tyrosine Kinase ReceptorsIn addition to TGF-b,several other tyrosine kinase receptors,in-cluding Met,FGF,IGF,EGF family members,and more recently PDGF,also play critical roles in regulating EMT-like morphoge-netic events that occur during development.For example, FGFR1orchestrates the EMT and morphogenesis of mesoderm at the primitive streak by controlling E-cadherin expression in mice(Ciruna and Rossant,2001).In mice,P38MAP kinase downregulates E-cadherin independent of the FGF signaling at the primitive streak(Zohn et al.,2006).Furthermore,activation of ErbB2-ErbB3is required for the EMT program during mouse cardiac valve formation(Camenisch et al.,2002).In mice,abla-tion of the HGF or Met genes results in the complete absence of all muscle groups that are derived from long-range migrating progenitor cells.This defect is due to an absence of delamination by the migratory progenitors(Dietrich et al.,1999).The similarity between muscle progenitor cell release and the EMT program suggests a role for HGF signaling in regulating an EMT-like mor-phological change occurring during this critical developmental step as well.A partial EMT has been implicated in the branching morpho-genesis that occurs during the formation of several organs,in-cluding the trachea,the kidneys,and the mammary glands.Dur-ing Drosophila tracheal development,FGF signaling is essential in guiding the migration of the tracheal cells during branch bud-ding(Ghabrial et al.,2003),and this function of FGF is also con-served in mice.In the mouse mammary gland,overexpression of HGF causes hyperplastic branching morphogenesis,while inhi-bition of HGF/Met signaling blocks the budding of side branches (Rosario and Birchmeier,2003).Therefore,it is likely that recep-tor tyrosine kinase pathways contribute to this EMT-like program during these branching morphogenesis events.Receptor tyrosine kinase pathways are also clearly involved in EMT in certain cell types in culture.The HGF/Met pathway pro-motes the partial EMT(‘‘scattering’’)phenotype of MDCK epithe-lial cells in monolayer culture.Extensive biochemical analyses have shown that multiple downstream signaling pathways,in-cluding Ras,MAP kinase,PI3kinase,and Rac/Cdc42,are acti-vated to coordinate the change in cell adhesion and motility that underlies this scattering(Birchmeier et al.,1997).In a mouse carcinoma cell line,NBT-II,the scattering phenotype induced by FGF1,EGF,or HGF,is due to the delocalization of E-cadherin from adherens junctions,suggesting that receptor tyrosine ki-nases can induce E-cadherin downregulation during an EMT (Boyer et al.,1997).Recently,a PDGF/PDGF receptor autocrine loop was induced during TGF-b-induced EMT,which was es-sential for acquisition of a complete EMT phenotype(Jechlinger et al.,2003).Transcriptional RegulationDuring the execution of the EMT program,many genes involved in cell adhesion,mesenchymal differentiation,cell migration,and invasion are transcriptionally altered.The best-studied transcrip-tional modulation during EMT is that involving the E-cadherin gene promoter.Indeed,functional loss of E-cadherin in an epi-thelial cell has been considered a hallmark of EMT.Detailed anal-yses of the human E-cadherin promoter have identiﬁed E-box elements that are responsible for its transcriptional repression in non-E-cadherin-expressing mesenchymal cells(Giroldi et al., 1997;Hennig et al.,1995).In2000,the zinc-ﬁnger transcription factor Snail was found to directly bind to the E-boxes of the E-cadherin promoter and to repress transcription of this gene (Batlle et al.,2000;Cano et al.,2000).Since this important dis-covery,several additional zinc-ﬁnger transcription factors have been found to be capable of repressing E-cadherin transcription, thereby causing the dissolution of cell-cell adhesion that occurs during EMT;these include Slug,a close relative of Snail(Hajra et al.,2002),and two members of the ZEB family of transcription factors,ZEB1(d EF1)(Eger et al.,2005)and ZEB2(SIP1)(Comijn et al.,2001).More recent studies have found that ZEB1,Snail, and Slug are capable of repressing the transcription of several polarity factors,including Crumbs3and Lgl2(Aigner et al., 2007;Spaderna et al.,2008),indicating their roles in suppressing critical components of epithelial cell traits.These transcription factors are involved in various EMT pro-cesses occurring during embryogenesis.Duringﬂy mesoderm formation,for example,both Snail and Slug are expressed to promote the dissociation of cell adhesion,thereby allowing the migration and differentiation of epithelial cells.This particular function of Snail in gastrulation is also apparent in mice,as Snail knockout mice display a severe defect in mesoderm formation (Carver et al.,2001).In Xenopus and chicken embryos,Snail and Slug are induced in the premigratory neural crest precursor cells and play essential roles in the subsequent delamination and migration of neural crest cells(Nieto,2002).Similarly,SIP1 knockout mice display a delamination arrest of cranial neural crest cells,suggesting SIP1’s involvement in regulating neural crest development(Van de Putte et al.,2003).In addition to these zinc-ﬁnger transcription factors that have a high afﬁnity for the E-box elements of the E-cadherin promoter, transcription factors belonging to other families also regulate EMT in culture and during development.E47,a widely expressed bHLH transcription factor,has been shown to repress E-cad-herin transcription in MDCK cells directly by binding to E-boxes in the E-cadherin promoter(Perez-Moreno et al.,2001),albeit with lower afﬁnity.In a search for genes involved in mouse mam-mary tumor metastasis,the bHLH factor Twist1has been found to be capable of inducing EMT in human mammary epithelial cells(Yang et al.,2004).One unique aspect of Twist1is that it does not seem to directly repress the transcription of E-cadherin (E.Ruiz,E.Danis,and J.Y.,unpublished data).Twist1was orig-inally identiﬁed as being required for mesoderm induction in Drosophila(Thisse et al.,1987;Leptin and Grunewald,1990; Leptin,1991).In vertebrates,Twist1is predominantly expressed in neural crest cells(Gitelman,1997).Twist1mutation in mice causes failure in cranial neural tube closure,indicating its role in proper migration and differentiation of neural crest and head mesenchymal cells(Chen and Behringer,1995;Soo et al., 2002).Like Twist1,two additional embryonic transcription fac-tors,FOXC2(Mani et al.,2007)and Goosecoid(Hartwell et al., 2006),have also been demonstrated to induce EMTs in certain epithelial cells,while they also seem to lack the ability to directly bind to the E-cadherin promoter.All of the aforementioned factors are capable of repressing E-cadherin directly or indirectly when overexpressed in cultured epithelial cells.We still do not understand,however,how these genes are involved in the mesenchymal differentiation,cell822Developmental Cell14,June2008ª2008Elsevier Inc.。

空间宏基因组学-概述说明以及解释

空间宏基因组学-概述说明以及解释1.引言1.1 概述概述空间宏基因组学是一个新兴的领域，结合了宏基因组学和空间科学的概念，致力于研究地球和宇宙中微生物的分布、演化和功能。

通过对微生物群落的高通量测序和生物信息学分析，揭示了地球上不同环境中微生物的多样性和生态功能。

同时，空间宏基因组学也将这些研究拓展到太空环境，探索宇宙中是否存在类似地球生态系统的微生物群落。

这一领域的出现为我们揭示了微生物在生态系统中的重要性，为地球和太空环境的微生物生态学研究提供了新的视角和方法。

通过空间宏基因组学的研究，我们可以更好地了解地球和宇宙中微生物的分布规律和功能作用，为人类生存和探索宇宙提供了重要的科学依据和技术支持。

1.2 文章结构本文主要分为引言、正文和结论三部分。

在引言部分，首先对空间宏基因组学进行了概述，介绍了本文的主题和背景。

然后对文章的结构进行了总体介绍，说明了各部分的内容和组织方式。

最后，明确了本文的目的，即对空间宏基因组学进行系统性的分析和探讨。

在正文部分，主要包括空间宏基因组学的定义和背景、应用领域以及意义和价值。

具体介绍了空间宏基因组学在不同领域的应用，以及其在科学研究和社会发展中的重要作用。

通过这些内容的阐述，读者可以对空间宏基因组学有一个全面的了解。

在结论部分，将对全文进行总结与回顾，对空间宏基因组学进行全面的评价和展望。

进一步探讨空间宏基因组学的发展前景和未来趋势，指出其潜在的重要性和应用价值。

同时，对本文的研究成果进行了回顾和总结，展望未来对该领域的深入探讨和研究方向。

1.3 目的空间宏基因组学作为一门新兴的研究领域，其目的主要在于利用现代高通量测序技术和生物信息学分析手段，探索和揭示宏基因组在不同环境中的结构、功能和演化规律，从而深入理解微生物群落在生态系统中的作用和影响。

通过研究空间宏基因组学，我们可以更好地了解微生物之间的相互关系、协同作用和竞争关系，进而为保护生态环境、提高农业生产效率、开发新型抗生素等方面提供科学依据和技术支持。

美研究者发现调节血管生长的“开关”

管内壁的内皮细胞会暴露在一种具有 “ 开关 ” 效的功物质环境中，致血管开始扩张、导生长。过分析，通研究人员确定这个 “ 关 ”就是微型核糖核酸分子开ｍｉ — ３。负责此项研究的病理学家戴维・Ｒｌ２切雷什
瘤，而副作用更小。
来源：中国广播网
洞。通过电子测量手段检测ＤＡ的易位，再根据ＮＤＡ的４个碱基各自独特的“ Ｎ电子签名 ” 就可以快，
美研究者发现调节血管生长的 “ 开关 ” 美国科研人员发现了一种可调节血管生长的 “ 关” 开 —— 微型核糖核酸分子ｍＲ— ３。并且找到ｉｌ２了控制该 “ 开关 ” 的方法。这一研究成果有望对癌症和心脑血管疾病的治疗产生积极影响。这项研究由美国加州大学圣迭戈分校医学院和密歇根大学癌
如肺、卵巢、肝脏和前列腺的癌细胞。这一发现将可能发展出一种全新的策略来治疗某种类型的淋巴
这个纳米平台由石墨烯制成。研究小组利用电子束技术，石墨烯膜上烧灼出纳米大小的小孑，在Ｌ在电场的作用下．微小的ＤＡ链就可以穿过这些孔Ｎ
症中心的研究人员共同完成。
速完成ＤＡ测序。Ｎ该研究论文的作者、宾夕法尼亚大学文理学院物理和天文系副教授玛丽亚・德恩迪奇说，墨烯是石由单一碳原子层构成的二维结构材料，由于石墨烯

双频激电及其数据处理

工程实例证明时间域与频率域的等效性
甘肃某金银矿点金银矿受断裂带产于绿泥石角闪片岩、绢云母石英片岩内的挤压带中，金、银与铅、锌、黄铁矿化共生，且有正相关关系。黄铁矿化较强处可呈稠密浸染至半块状。图为该矿体IV号剖面综合图。Fs 与 ηs 相似性也是一目了然。
时间域与频率域的差异
频率域电法的主要优点 a.轻便; b.抗干扰能力强。传统频率域电法的主要缺点任何一种频率域电法都是要在不同的频率进行测量，传统的主动源电法勘探（包括激发极化法和电磁法）的工作方式都是“变频法”,变频法是一个频率、一个频率地逐个改变频率进行测量,以致带来了它两大致命弱点. a.变频法的工作效率低(“扫面”的速度更低); b.变频法的相对精度低。 (1)在激电法中区分矿异常性质能力低, (2)在电磁法(CSAMT)中发现深部异常能力低。 (3)不能（像TEM那样）进行近区的频率域电磁测深。
电流脉冲宽度 T（即充电时间长度）对极化强度的影响
ΔV0
电位差ΔV
ΔV0
时间 (t)
T大，二次电位大
电位差ΔV
ΔV0
ΔV0
T小，二次电位小
T
T
二次电位差 ΔVIP
频率域与时间域的等效性
脉冲宽度 (T)
电位差 ΔV
二次电位差 ΔVIP
ΔVIP
时间域
时间域
频率域
二次电位差 ΔVIP
频率域IP与时间域IP的物理实质是一样的，对于寻找金属矿来说它们的能力是等效的。
01
对于线性时不变系统，在理论上二者是可以相互转换的。
02
在实际条件下，一般电流密度都非常小（小于0.01μA/cm2），实际上可以看作线性系统，如果能测量到相当完整的时间响应和频率响应，则它们在一定精度内也是可以相互转换的。

清华大学彭晓峰-微纳尺度传热概述

Particularly for probing buried interfaces
ps
fs
Second order non-linear optical processÆ forbidden in the centrosymmetric bulk phases
VSF spectra of: CCl4/water Hexane/water Vapor/water Æ Indicating differences in hydrogen bonding at the various interfaces
Example:
smaller in scale
Packaging interface
Severe spatial constraints Electronics packages make space very variable more compact electronic heat generating volume
Flowable/deformable matrix materials Silicone oil, etc.
Heat conductive particle fillers
Al2O3, ZnO, BN, etc.
Example:
The ratio between matrix material and particle fillers
Relationship with Heat Conduction
固体导热：微观粒子(声子、电子)的运动。
如果这些微观粒子的运动发生改变，那么必定会从微观的层面影响导热过程。
热流的分布。。。
磁场通过对电子和声子的作用来影响导热。
磁－热效应

奥密克戎分子结构及所用研究方法

奥密克戎分子结构及所用研究方法奥密克戎分子结构及其研究方法奥密克戎(OMe)分子,又称甲基二甲基硅烷或二甲基亚硅酸酯,是一种重要的有机氟化物。

它是一种多环烃,也称甲基二环壬基,由一个氯原子和三个碳原子组成,拥有较低的极性、较高的热稳定性和良好的有机溶剂性。

它的分子结构也在结构有关的有机反应的研究中有着重要的作用。

OMe分子的反应要素主要有:分子质量、极性、热稳定性和溶剂性等。

OMe分子的分子量为100 g/mol,分子量较小,因此其反应比较快,极性则与其他烃分子类似,拥有大量的氟键可以稳定共价键,而OMe分子的热稳定性和溶剂性则使它更加适合用于高温有机反应。

OMe分子分子结构研究可采用多种方法,其中包括:低能电子激发光谱(LEES)、原子吸收光谱(AAS)、核磁共振氢谱(NMR)、电子发射散射法(EDS)、紫外可见光谱(UV-Visible)、质谱(MS)等等,以及X射线衍射法(XRD)、恒电流电化学技术(EDC)等。

其中,核磁共振氢谱是OMe分子结构研究的首要方法,它可以检测出OMe分子的结构特征,包括氢的位置、碳原子的位置及其键角、同位素组成以及极性等。

X射线衍射法可以用来检测OMe分子结构中碳原子之间和氟原子之间的键长及键角,以及奥密克戎分子的空间结构,这种方法具有极低的结构噪声水平,并可以精确地表示OMe分子结构的精细细节。

恒电流电化学技术是OMe分子结构研究中一种比较新的方法,它可以用来检测OMe分子的解离度、光谱特征以及结构特征,它可以用来检测OMe分子极性以及它与其他分子之间的相互作用。

以上就是OMe分子结构研究的几种主要方法,它们可以用来研究OMe分子结构的特征,并能较好地揭示OMe分子构型、结构特征以及与其他分子的相互作用。

OMe分子的研究也有助于深入理解有机化学及其与其他重要分子之间的相互作用。

氘瑞米德韦结构

氘瑞米德韦结构
氘瑞米德韦结构，也被称为“氘瑞米德韦-乔伊氏结构”，是一种新的结构可以被用来构建大规模的有机小分子，可以为生物化学研究带来新的机遇。

氘瑞米德韦结构可以通过微分数据来建立，其中，氘瑞米德韦结构是由一系列可以被自动生成的非标准氢键组成的结构。

氘瑞米德韦结构有两个基本特征：一个结构基元和一些特殊的氢键矩阵。

结构基元是指一系列相连的双键中心，每个双键中心拥有一个碳原子和一个氢原子，双键中心之间通过氢键相连，形成拓扑结构。

特殊的氢键矩阵是指在拓扑结构的基础上，由外层的叶素原子（acidic hydrogen atom）与其他结构基元中的碳原子之间形成的特殊氢键。

氘瑞米德韦结构有许多有趣的物理和化学属性。

它们结构相对稳定，其中的叶素原子和碳原子之间的相互作用给它们带来了极强的空间定向性。

此外，氘瑞米德韦结构的自旋和外部电场的连续改变也可以被用于进一步调节结构的稳定性。

氘瑞米德韦结构已经成功应用于生物化学领域，它可以被用来构建蛋白质，糖基聚合物，小分子药物，抗原抗体结合体以及细胞膜和纳米结构等等。

此外，氘瑞米德韦结构也可以被用来促进介体转化反应，提高反应速率。

由于其复杂的物理和化学属性，氘瑞米德韦结构可以被用来构建复杂的结构，并为许多生物领域的研究提供新的机遇。

此外，氘瑞米德韦结构还可以被用来增强天然小分子的生物活性，帮助开发新的抗
生素，抗癌药物和其他新型的医药制剂。

总而言之，氘瑞米德韦结构是一种具有重要意义的新型结构，可以被用来快速构建大规模的有机小分子，满足生物化学领域越来越复杂的研究需求，帮助开发更强大的药物。

测序周报·科研篇：关注三种大规模单细胞分析方法

测序周报·科研篇：关注三种大规模单细胞分析方法“ 惊蛰一雷惊蛰始，微雨众卉新”关注三种大规模单细胞分析方法导读：近日，美国加州大学圣地亚哥分校张鹍教授在《Nature Methods》发表了评论性文章“Stratifying tissue heterogeneity with scalable single-cell assays”，就全球最新的单细胞分析方法做了点评。

这三种方法能够显著提高单细胞基因组测序和结构分析的规模，允许研究者们对组织内的不同种类的细胞群进行分区（hierarchical partitioning）。

在“大数据”和“深度学习”成为热门词汇的这个时代，生物学家们也毫不例外地需要数据。

研究者面对单细胞检测中的噪音和不完全覆盖时尤其如此：他们想要尽可能多细胞的信息，以便分析细胞之间的异质性，并得出可信的和有普遍代表性的结论。

基于液滴的单细胞转录组测序方法提供了一个良好的示例：即使测序覆盖度相对较低，通过检测更多的细胞也能有很大的收获。

然而，目前除RNA之外其他类型数据分析的进展较慢。

最近发表的三篇论文[1-3]有望将规模的优势带到基因组序列和染色体结构的研究中（见图1）。

1. 直接文库制备（DLP）方法在癌症或脑等组织中，基因组变异是功能异质性的重要来源。

Zahn 等人[1]和Vitak等人[2]采用两种不同的方法来分析异质性，在数百到数千单细胞中分析拷贝数变异（CNV）。

从概念上讲，Zahn等人[1]的直接文库制备（direct library preparation，DLP）方法类似于Quake等人[4]开发的方法。

Quake 等人的方法已经被商业化，开发成了Fluidigm C1单细胞自动制备系统，该系统可以将单细胞限制在单个微流体反应器中来进行一系列酶反应。

然而，DLP方法产生的序列更加均匀，后续CNV识别的灵敏度更佳，对较小的基因组间隔（genomic intervals）或拷贝数变化更是如此。