On the right path—Stat3 signalling controls the ARF–Mdm2–p53 tumour-suppressor pathway
miRNA对心肌细胞缺血再灌注损伤的干预作用机制研究进展
miRNA对心肌细胞缺血再灌注损伤的干预作用机制研究进展符珍珍1，彭瑜2，张钲21 兰州大学第一临床医学院心脏中心，兰州730000；2 兰州大学第一医院心脏中心摘要：心肌缺血再灌注损伤（MIRI）是急性心肌梗死患者预后不良的主要因素，也是血流再通治疗所面临的主要挑战。
现有研究表明，部分miRNA能够通过抑制程序性细胞死亡因子4、磷酸酶和紧张素同源物、Toll样受体4、肿瘤坏死因子超家族家族成员FASLG蛋白、分泌型磷蛋白1等蛋白表达，减少凋亡蛋白的活性及表达量，减少细胞凋亡，从而减轻MIRI。
miRNA还可通过调节氧化应激和线粒体能量代谢、调节细胞自噬和细胞增殖等机制，达到减轻MIRI的目的。
实验研究发现，多种手段调节miRNA表达，有助于减轻MIRI动物心肌细胞凋亡。
然而目前相关技术并不完善，基于miRNA治疗方案的临床应用尚有待进一步研究。
关键词：微小RNA；心肌缺血再灌注损伤；细胞凋亡；细胞自噬；细胞增殖doi：10.3969/j.issn.1002-266X.2023.32.027中图分类号：R542.2 文献标志码：A 文章编号：1002-266X（2023）32-0112-04急性心肌梗死（AMI）是全球心血管疾病患者死亡的主要原因之一［1］，随着各种药物和再灌注技术的应用，AMI患者急性期病死率有所下降，但仍然高，高病死率与心肌梗死面积的增加密切相关［2］。
研究表明，心肌缺血再灌注损伤（MIRI）是导致再灌注后心肌梗死面积增加的主要原因［3-4］。
MIRI可引发一系列不良生物学效应，包括氧化应激和炎症反应加剧、凋亡相关信号通路激活、细胞内钙超载、线粒体功能障碍、细胞膜功能损害及微血管损伤等，这些因素加重组织缺氧损伤并扩大了梗死面积［5-7］。
微小RNA（miRNA）是一类分子量在21~25 nt的非编码RNA［8］，参与基因转录后表达调控，能通过促进体内各种mRNA的降解和沉默［9］，导致细胞生理功能改变，并最终影响疾病的发生发展［10］。
碧云天 GFP抗体(小鼠单抗)说明书
碧云天生物技术/Beyotime Biotechnology 订货热线：400-168-3301或800-8283301 订货e-mail ：****************** 技术咨询：***************** 网址：碧云天网站 微信公众号GFP 抗体(小鼠单抗)产品编号 产品名称包装 AG281GFP 抗体(小鼠单抗)>40次产品简介：来源 用途 抗体识别位点抗体类型 GFP 分子量MouseWB, IP, IFFull length GFP IgG2a~27kDWB, Western blot; IP, Immunoprecipitation; IF, Immunofluorescence. 本GFP 抗体(小鼠单抗)，即mouse monoclonal GFP antibody ，为进口分装，用全长的来源于水母的GFP (green fluorescent protein)作为抗原制备得到的抗GFP 小鼠单克隆抗体。
克隆号为B-2。
本GFP 抗体可以识别GFP以及GFP 的一些突变体例如EGFP (enhanced green fluorescent protein)。
GFP 或其突变体EGFP 等被广泛用于基因表达效率的检测，以及和目的蛋白融合表达用于检测目的蛋白的表达和分布。
本GFP 抗体不仅可以检测GFP 或其适当的突变体，也可以检测和GFP 或其适当的突变体融合表达的蛋白。
配套提供了Western 一抗稀释液，可以用于Western 检测时的一抗稀释。
)：40次。
包装清单：产品编号 产品名称包装 AG281-1 GFP 抗体(小鼠单抗) 40µl AG281-2 Western 一抗稀释液40ml —说明书1份保存条件：GFP 抗体(小鼠单抗)-20ºC 保存，Western 一抗稀释液-20ºC 或4ºC 保存，一年有效。
斑马技术公司DS8108数字扫描仪产品参考指南说明书
myMerlin for Confirm Rx ICM Mobile App Support Gui
SUPPORT GUIDEWELCOME TO THE myMERLIN ™ FOR CONFIRM Rx ™ ICM MOBILE APP SUPPORT GUIDE FOR iPHONE ‡ MOBILE DEVICEYour new Confirm Rx ™ ICM continuously monitors your heart’s rhythm and can automatically send that information to your doctor through the myMerlin ™ mobile app—without disrupting your daily life. For simplicity, this guide will use myMerlin ™ app instead of myMerlin ™ for Confirm Rx ™ ICM mobile app.This guide will help you understand how to download and install the myMerlin ™ app , how to pair your Confirm Rx ™ ICM heart monitor to the myMerlin ™ app, how to record your symptoms and more. In the back of this guide is a glossary of “Terms To Know”, in case you would like an explanation for an unfamiliar word.TABLE OF CONTENTSConnecting to the internet 5Downloading the app 7 Phone Settings 8Setup and Pairing 13Recording symptoms16Troubleshooting and general support 17Contact Us23For simplicity, this guide will use myMerlin ™ app instead of myMerlin ™ for Confirm Rx ™ ICM mobile app.STAYING CONNECTEDFollow these tips to keep the myMerlin app Do notforce close the app. Make sure it is running in the background, and remember to open the Keep your smartphone connected to the internet using Keep your phone near (within 5 feet or 1.5 meters) you overnight and as much If the app doesn’t seem to be working at night, turn OFF otherHOW TOUSE THIS GUIDETo help you understand how to use your iPhone ‡ and the myMerlin ™ app, this guide uses pictures of iPhone ‡ screens and symbols:DOUBLE CIRCLEA green double circle in the picture shows you where to tap your finger on your iPhone When you are asked to tap the screen, do so in one quick, light motion.ARROWA purple arrow in the SINGLERECTANGLEGOOD Y CONNECTING YOUR iPHONE ‡ TO THE INTERNET USING WI-FI ‡Using Wi-Fi ‡ is one of the ways to send your heart monitor information to your doctor. Setting it up on your iPhone ‡ is simple. Here’s how:STEP 1Tap Settings.STEP 2Tap Wi-Fi ‡.STEP 3Turn Wi-Fi ‡ ON by tapping the slider to turn it ON/green (image to left). If it is already ON/green, skip this step. Your phone will automatically search for available Wi-Fi ‡ networks.STEP 5information icon .STEP 4Tap the name of the Wi-Fi ‡ network you want to join. You may need to enter a password (passwords are case sensitive). After joining the network, you will see the Wi-Fi ‡ symbol on the top of your screen.CONNECTING YOUR iPHONE‡ TO THEINTERNET USING CELLULAR DATAIf you are not near a Wi-Fi‡ network, your iPhone‡ can still connect to the internet usingcellular data. Typically, your phone will automatically make this switch for you.You’ll know you’re connected to a cellular data network if you see one of these symbolson the top left corner of your screen: LTE, 4G, 3G.If you do not see any of these symbols, your cellular data may be turned OFF.To turn cellular data ON, follow these steps:STEP 4Tap Cellular DataOptions.STEP 5If using iOS‡ 13 orlater, ensure Low DataMode is OFF.DOWNLOADING THEmyMERLIN™ APP ON iPHONE‡Now that your iPhone‡ is connected to the internet, download the myMerlin™app.You will need a good internet connection, via Wi-Fi‡ or a cellular data network, for thisprocess. These steps will guide you through the download:DON’T FORGET!Once you’ve downloaded themyMerlin™ app, you will need to pairyour iPhone‡ to your heart monitor.STEP 1Open the App Store‡by tapping the AppStoreSTEP 2Tap the Search iconat the bottom of yourscreen (image above).STEP 3Tap the App Store‡search bar at the topof your screen.STEP 4Type ‘myMerlin forConfirm Rx’ in thesearch bar. Then, tapSearch, or select fromthe list of apps.STEP 5Tap Get to downloadthe app .SETTINGS FOR YOUR iPHONE‡To ensure the myMerlin™ app works properly, adjust your iPhone‡ to these settings, which you can access within your phone’s Settings menu.Bluetooth®Turn this ONCellular Data and Wi-Fi‡Turn these both ONBackground App Refresh Turn this ONAutomatic App Updates Turn this ONText Size Choose the smallest text size that is still large enoughfor you to read. For pairing, it may need to be set to the smallest and can be returned to the preferred size after pairing.Low Power Mode Turn this OFFCellular Data Mode Turn this OFFWi-Fi‡ Low Data Mode Turn this OFFOffload Unused Apps Turn this OFFThe next few pages will show you how to access and change these settings as needed.CHECKING YOUR IPHONE‡ SETTINGS BLUETOOTH®STEP 3If using iOS 13 or later, tap Confirm Rx™(left image above).If using iOS 13 or later, tap Bluetooth orBluetooth Sharing to turn ON/Green forthe app.STEP 1Tap Settings .STEP 2Swipe up untilyou see Battery. Tap Battery(image to left).LowshouldOFF. LOW POWER MODESTEP 1Tap Settings .STEP 2Ensure the Bluetooth settingis ON (image above).CHECKING YOUR iPHONE ‡SETTINGS BACKGROUND APP REFRESH STEP 4Tap Background App Refresh again.STEP 5Select Wi-Fi ‡ & Cellular Data. Tap the blue < Back STEP 1Tap Settings.STEP 2Tap General (image above).STEP 6The slider next to myMerlin ™ should be switched ON/green.STEP 3Tap Background App Refresh.CHECKING YOUR iPHONE ‡ SETTINGS AUTOMATIC APP UPDATESSTEP 1Tap Settings.STEP 2Swipe up until you see iTunes ‡ & App Store ‡ (image to left).STEP 3The sliders next to Apps and Updates should be should be switched ON/green.ADJUST TEXT SIZESTEP 1Tap Settings.STEP 2Swipe up until you see Display & Brightness . Tap Display & Brightness (image to left).STEP 3Tap Text Size. Move the slider left or right to adjust the text size on your phone. Set it to the smallest size that you can easily read.Settings .Unlock your phone and tap theapp to open it.STEP 2STEP 3Tap Continue with setup.STEP 4Tap the Enter Date of Birth field.STEP 5Swipe your finger up or down on the day, month, and year until your date of birth isblack and in the middle of the options, and then tap Done.STEP 6Tap the Enter Serial Number field and type the serial number of your heart monitor. The serial number can be found on your patient identification (ID) card. TapDone.STEP 7Tap Next.If you are asked for an activation code, please see page 21.STEP 8Tap Pair Now.STEP 9A Bluetooth ® Pairing Request message will pop up. Enter the pairing code displayed above or below this message in the middle of your screen. Tap Pair.Enter Code: 0689412STEP 10Keep the app open and your iPhone ‡ within 1.5 meters or 5 feet of you while pairing.STEP 11Once your iPhone ‡ has finished pairing, you will see a Success message. TapDone.PAIRING YOUR HEART MONITOR TO THE myMERLIN ™ APP (CONT.)WHAT IF YOU DON’T SEE THE PAIRING CODE?Try decreasing your text size.the app STEP 4The symptoms will be sent to your doctor, based on the individual schedule your doctor sets for you. A Success message displays after your phone has sent the information.Tap Done to return to your Home screen.The myMerlin™ app is not intended for emergency use. In case of emergency, call emergency services or contact your doctor. The myMerlin ™ app allows you to record your symptoms as they happen and send that information directly to your doctor. Be sure to use this feature only when you’re experiencing symptoms or your doctor requests a transmission. To do so, follow these steps:If action is needed by you, you should receive Notifications on your phone that prompt you to go to the app. The app will continue to send daily Notifications until the connection is re-established.STEP 1Open the app and tap Record Symptoms.STEP 2To select a symptom you’re experiencing, tap it. Each symptom you select will turn green. Once you have selected all of the symptoms you’re feeling, tap Done.This message means the myMerlin ™ app could not connect to your heart monitor.POSSIBLE CAUSES:• Your iPhone ‡ is too far away from your heart monitor.• Bluetooth® is OFF during a scheduled daily check.• O ther Bluetooth devices are paired with your phone and may be causing interference.WHAT TO DO:• Move your phone closer to you.• M ake sure your Bluetooth® is ON and the app is open. • T urn OFF other Bluetooth® devices around your bed, such as Bluetooth® clocks or speakers.• A fter doing these steps, re-open app to see if the app connected to your heart monitor.This message means that the app was unable to send information to your clinic at the scheduled time.POSSIBLE CAUSE:• Weak or no internet connection.• T he app may be backgrounded and unable to access the internet.WHAT TO DO:• C heck your internet connection and then tap Send Data Now to try again.After your iPhone ‡ reconnects to the internet, your information will be sent to your doctor.ACTION NEEDED MESSAGES.CHECK YOURINTERNET CONNECTIONSTEP 1If you’re connected to internet, you will see aWi-Fi‡ or cellular data symbol on the top leftcorner of your screen. If you don’t see one of thesesymbols, you are not connected to the internet.KEEP THEmyMERLIN™ APP OPEN IN THE BACKGROUNDSTEP 2Swipe your finger right untilyou see the myMerlin™ app.If you do not see the appdisplayed, go to your homescreen, locate and tap the appicon to open it.STEP 3Once you’ve confirmed thatthe myMerlin™ app is open,press the Home button onceto return to the Home screen.Never swipe the myMerlin™app up. This will force closethe app which will prevent itfrom working as intended.WHAT IS THE HOME BUTTON?Depending on which model of iPhone‡you have, the Home button may be aphysical button located just under thephone’s screen, which takes you backto the “Home” or main screen of youriPhone‡. On newer iPhone‡ models, swipeup from the bottom of the screen toreturn to the Home screen.TIP: IF YOU DON’T HAVE AHOME BUTTON…Swipe up from the bottom of thescreen to the middle of the screenand hold until the App Switcherdisplay shows on the left side ofyour screen.‡STEP 2Swipe your finger from left to right where it says slide to power OFF to shut down your phone.STEP 3Once the screen is black, press and hold the power button again until you see the Apple ‡ logo. This means your iPhone ‡ is powering back ON. After your iPhone ‡ has finished powering ON, you will need to open your myMerlin ™ app again.RECEIVING THE ACTIVATION CODEIf you’ve paired the myMerlin ™ app before, you’ll need an activation code to re-pair your heart monitor with your iPhone ‡.During the pairing process you’ll choose how you would like to receive the activation code. Make sure the information is correct and then tap Email or Text.Enter the code that was sent to you. If you chose Email and did not receive the code, check your email’s junk or spam folder.Your activation code is valid for six hours. After multiple activation code requests and unsuccessful entries, a maximum attempts message may display on the app, and you may not be able to continue. For activation code assistance, contact Abbott Remote Care Technical Support (US) or your clinic (international).AN ACTIVATION CODE ISREQUIRED TO KEEP YOUR DATA SECURE.‡.212022。
Independence and concurrent separation logic
Logical Methods in Computer ScienceVol.4(1:6)2008,pp.1–68Abstract.A compositional Petri net-based semantics is given to a simple language al-lowing pointer manipulation and parallelism.The model is then applied to give a notionof validity to the judgements made by concurrent separation logic that emphasizes theprocess-environment duality inherent in such rely-guarantee reasoning.Soundness of therules of concurrent separation logic with respect to this definition of validity is shown.Theindependence information retained by the Petri net model is then exploited to characterizethe independence of parallel processes enforced by the logic.This is shown to permit arefinement operation capable of changing the granularity of atomic actions.1.IntroductionThe foundational work of Hoare on parallel programming[Hoa72]identified the fact that attributing an interleaved semantics to parallel languages is problematic.Three areas of difficulty were isolated,quoted directly:•That of defining a‘unit of action’.•That of implementing the interleaving on genuinely parallel hardware.•That of designing programs to control the fantastic number of combinations involved in arbitrary interleaving.The significance of these problems increases with developments in hardware,such as multiple-core processors,that allow primitive machine actions to occur at the same time.As Hoare went on to explain,a feature of concurrent systems in the physical world is that they are often spatially separated,operating on completely different resources and not interacting.When this is so,the systems are independent of each other,and therefore it is unnecessary to consider how they interact.This perspective can be extended by regarding computer processes as spatially separated if they operate on different memory locations. The problems above are resolved if the occurrence of non-independent parallel actions is prohibited except in rare cases where atomicity may be assumed,as might be enforced using the constructs proposed in[Dij68,Bri72].2J.HAYMAN AND G.WINSKELIndependence models for concurrency allow semantics to be given to parallel languages in a way that can tackle the problems associated with an interleaved semantics.The common core of independence models is that they record when actions are independent,and that independent actions can be run in either order or even concurrently with no consequence on their effect.This mitigates the increase in the state space since unnecessary interleavings of independent actions need not be considered(see e.g.[CGMP99]for applications to model checking).Independence models also permit easier notions of refinement which allow the assumed atomicity of actions to be changed.It is surprising that,to our knowledge,there has been no comprehensive study of the semantics of programming languages inside an independence model.Thefirst component of our work gives such a semantics in terms of a well-known independence model,namely Petri nets.Our model isolates the specification of the controlflow of programs from their effect on the shared state.It indicates what appears to be a general method(an alternative to Plotkin’s structural operational semantics)for giving a structural Petri net semantics to a variety of languages—see the Conclusion,Section7.The language that we consider is motivated by the emergence of concurrent separation logic[O’H07],the rules of which form a partial correctness judgement about the execution of pointer-manipulating concurrent programs.Reasoning about such programs has tradi-tionally proved difficult due to the problem of variable aliasing.For instance,Owicki and Gries’system for proving properties of parallel programs that do not manipulate pointers [OG76]essentially requires that the programs operate on disjoint collections of variables, thereby allowing judgements to be composed.In the presence of pointers,the same syntac-tic condition cannot be imposed to yield a sound logic since distinct variables may point to the same memory location,thereby allowing arbitrary interaction between the processes. To give a specific example,Owicki and Gries’system would allow a judgement of the form {x→0∧y→0}x:=1 y:=2{x→1∧y→2},indicating that the result of assigning1to the program variable x concurrently with assign-ing2to y from a state where x and y both initially hold value0is a state where x holds value1and y holds value2.The judgement is sound because the variables x and y are distinct.If pointers are introduced to the language,however,it is not sound to conclude that{[x]→0∧[y]→0}[x]:=1 [y]:=2{[x]→1∧[y]→2},which would indicate that assigning1to the location pointed to by x and2to the location pointed to by y yields a state in which x points to a location holding1and y points to a location holding2,since x and y may both point to the same location.At the core of separation logic[Rey00,IO01],initially presented for non-concurrent programs,is the separating conjunction,ϕ∗ψ,which asserts that the state in which processes execute may be split into two parts,one part satisfyingϕand the otherψ.The separating conjunction was used by O’Hearn to adapt Owicki and Gries’system to provide a rule for parallel composition suitable for pointer-manipulating programs[O’H07].As we shall see,the rule for parallel composition is informally understood by splitting the initial state into two parts,one owned by thefirst process and the other by the second. Ownership can be seen as a dynamic constraint on the interference to be assumed:parallel processes always own disjoint sets of locations and only ever act on locations that they own. As processes evolve,ownership of locations may be transferred using a system of invariants (an example is presented in Section4).A consequence of this notion of ownership is thatINDEPENDENCE AND CONCURRENT SEPARATION LOGIC∗3 the rules discriminate between the parallel composition of processes and their interleavedexpansion.For example,the logic does not allow the judgement{ℓ→0}[ℓ]:=1 [ℓ]:=1{ℓ→1},which informally means that the effect of two processes acting in parallel which both assign the value1to the memory locationℓfrom a state in whichℓholds0is to yield a state in whichℓholds1.However,if we adopt the usual rule for the nondeterministic sum of processes,the corresponding judgement is derivable for their interleaved expansion,([ℓ]:=1;[ℓ]:=1)+([ℓ]:=1;[ℓ]:=1).One would hope that the distinction that the logic makes between concurrent processes and their interleaved expansion is captured by the semantics;the Petri net model that we give does so directly.The rules of concurrent separation logic contain a good deal of subtlety,and so lacked a completely formal account until the pioneering proof of their soundness due to Brookes [Bro07].The proof that Brookes gives is based on a form of interleaved trace semantics.The presence of pointers within the model alongside the possibility that ownership of locations is transferred means,however,that the way in which processes are separated is absolutely non-trivial,which motivates strongly the study of the language within an independence model.We therefore give a proof of soundness using our net model and then characterize entirely semantically the independence of concurrent processes in Theorem5.4.It should be emphasized that the model that we present is different from Brookes’since it provides an explicit account of the intuitions behind ownership presented by O’Hearn. It involves taking the original semantics of the process and embellishing it to capture the semantics of the logic.The proof technique that we employ defines validity of assertions in a way that captures the rely-guarantee reasoning[Jon83]emanating from ownership in separation logic directly,and in a way that might be applied in other situations.In[Rey04],Reynolds argues that the separation of parallel processes arising from the logic allows store actions that were assumed to be atomic,in fact,to be implemented as composite actions(seen as a change in their granularity)with no effect on the validity of the judgement.Independence models are suited to modeling situations where actions are not atomic,a perspective advocated by Lamport and Pratt[Pra86,Lam86].We introduce a novel form of refinement,inspired by that of[vGG89],and show how this may be applied to address the issue of granularity using our characterization of the independence of processes arising from the logic.2.Terms and statesConcurrent separation logic is a logic for programs that operate on a heap.A heap is a structure recording the values held by memory locations that allows the existence of pointers as well as providing primitives for the allocation and deallocation of memory locations.A heap can be seen as afinite partial function from a set of locations Loc to a set of values Val:Heap def=Loc⇀fin ValWe will useℓto range over elements of Loc and v to range over elements of Val.As stated, a heap location can point to another location,so we require that Loc⊆Val.We shall say that a location is current(or allocated)in a heap if the heap is defined at that location.The4J.HAYMAN AND G.WINSKELprocedure of making a non-current location current is allocation,and the reverse procedure is called deallocation.If h is a heap and h(ℓ)=ℓ′,there is no implicit assumption that h(ℓ′) is defined.Consequently,heaps may contain dangling pointers.In addition to operating on a heap,the programs that we shall consider shall make use of critical regions[Dij68]protected by resources.The mutual exclusion property that they provide is that no two parallel processes may be inside critical regions protected by the same resource.We will write Res for the set of resources and use r to range over its elements. Critical regions are straightforwardly implemented by recording,for each resource,whether the resource is available or unavailable.A process may enter a critical region protected by r only if r is available;otherwise it is blocked and may not resume execution until the resource becomes available.The process makes r unavailable upon entering the critical region and makes r available again when it leaves the critical region.The language also has a primitive,resource w do t od,which says that the variable w represents a resource local to t.The syntax of the language that we will consider is presented in Figure1.The symbol αis used to range over heap actions,which are actions on the heap that might change the values held at locations but do not affect the domain of definition of the heap.That is, they neither allocate nor deallocate locations.We reserve the symbol b for boolean guards, which are heap actions that may proceed without changing the heap if the boolean b holds.Provision for allocation within our language is made via the alloc(ℓ)primitive for ℓ∈Loc,which makes a location current and setsℓto point at this location.For symmetry, dealloc(ℓ)makes the location pointed to byℓnon-current ifℓpoints to a current location. Writing a heap as the set of values that it holds for each allocated location,the effect of the command alloc(ℓ)on the heap{ℓ→0}might be to form a heap{ℓ→ℓ′,ℓ′→1}if the locationℓ′is chosen to be allocated and is assigned initial value1.The effect of the command dealloc(ℓ)on the heap{ℓ→ℓ′,ℓ′→1}would be to form the heap{ℓ→ℓ′}.The guarded sumα.t+α′.t′is a process that executes as t ifαtakes place or as t′ifα′takes place.We refer the reader to Section?for a brief justification for disallowing non-guarded sums.As mentioned earlier,critical regions are provided to control concurrency:the sub-process t inside with r do t od can only run when no other process is inside a critical region protected by r.The term resource w do t od has the resource variable w bound within t, asserting that a resource is to be chosen that is local to t and used for w.Consequently,in the process(resource w do with w do t1od od) (resource w do with w do t2od od)the sub-processes t1and t2may run concurrently since they must be protected by different resources,one local to the process on the left and the other local to the process on the right. To model this,we shall say that the construct resource w do t od binds the variable w within t,and the variable w is free in with w do t od.We write fv(t)for the free variables in t and say that a term closed if it contains no free resource variables;we shall restrict attention to such terms.We write[r/w]t for the term obtained by substituting r for free occurrences of the variable w within t.As standard,we will identify terms‘up to’the standard alpha-equivalence≡induced by renaming bound occurrences of variables.The notation res(t)is adopted to represent the resources occurring in t.The semantics of the term resource w do t od will involvefirst picking a‘fresh’resource r and then running[r/w]t.It will therefore be necessary to record during the execution ofINDEPENDENCE AND CONCURRENT SEPARATION LOGIC∗5Figure1:Syntax of termsprocesses which resources are current(i.e.not fresh)as well as which current resources are available(i.e.not held by any process).The way in which we shall formally model the state in which processes execute is motivated by the way in which we shall give the net semantics to closed terms.We begin6J.HAYMAN AND G.WINSKELby defining the following sets:D def=Loc×ValL def={curr(ℓ)|ℓ∈Loc}R def=ResN def={curr(r)|r∈Res}.A stateσis defined to be a tuple(D,L,R,N)where D⊆D represents the values held by locations in the heap;L⊆L represents the set of current,or allocated,locations of the heap;R⊆R represents the set of available resources;and N⊆N represents the set of current resources.The sets D,L,R and N are disjoint,so no ambiguity arises from writing,for example,(ℓ,v)∈σ.The interpretation of a state for the heap is that(ℓ,v)∈D ifℓholds value v and that curr(ℓ)∈L ifℓis current.For resources,r∈R if the resource r is available and curr(r)∈N if r is current.It is clear that only certain such tuples of subsets are sensible. In particular,the heap must be defined precisely on the set of current locations,and only current resources may be available.Definition2.1(Consistent state).The state(D,L,R,N)is consistent if we have:•the sets D,L,R and N are allfinite,•D is a partial function:for allℓ,v and v′,if(ℓ,v)∈D and(ℓ,v′)∈D then v=v′,•L represents the domain of D:L={curr(ℓ)|∃v:(ℓ,v)∈D},and•all available resources are current:R⊆{r|curr(r)∈N}.It is clear to see that the L component of any given consistent state may be inferred from the D component.It will,however,be useful to retain this information separately for when the net semantics is given.We shall call D⊆D a heap when it is afinite partial function from locations to values,and shall writeℓ→v for its elements rather than(ℓ,v). We shall frequently make use of the following definition of the domain of a heap D:dom(D)def={ℓ|∃v.(ℓ→v)∈D}.3.Process modelsThe definition of state that we have adopted permits a net semantics to be defined. Before doing so,we shall define how heap actions are to be interpreted and then give a transition semantics to closed terms.3.1.Actions.The earlier definition of state allows a very general form of heap action to be defined that forms a basis for both the transition and net semantics.We assume that we are given the semantics of primitive actionsαas A α comprising a set of heap pairs:A α ⊆Heap×Heap.We require that whenever(D1,D2)∈A α ,it is the case that D1and D2are(the graphs of)partial functions with the same domain.The interpretation is thatαcan proceed in heap D if there are(D1,D2)∈A α such that D has the same value as D1wherever D1is defined.The resulting heap is formed byINDEPENDENCE AND CONCURRENT SEPARATION LOGIC∗7 updating D to have the same value as D2wherever it is defined.It is significant that this definition allows us to infer precisely the set of locations upon which an action depends. The requirement on the domains of D1and D2ensures that actions preserve consistent markings(Lemma3.25).Example3.1(Assignment).For any two locationsℓandℓ′,let[ℓ]:=[ℓ′]represent the action that copies the value held at locationℓ′to locationℓ.Its semantics is as follows:A [ℓ]:=[ℓ′] def={({ℓ→v,ℓ′→v′},{ℓ→v′,ℓ′→v′})|v,v′∈Val}Following the informal account above of the semantics of actions,because in the semantics we have({ℓ0→0,ℓ1→1},{ℓ0→1,ℓ1→1})∈A [ℓ0]:=[ℓ1] ,the state{ℓ0→0,ℓ1→1,ℓ2→2}is updated by[ℓ0]:=[ℓ1]to{ℓ0→1,ℓ1→1,ℓ2→2}.Example3.2(Booleans).Boolean guards b are actions that wait until the boolean expres-sion holds and may then take place;they do not update the state.A selection of literals may be defined.For example:A [ℓ]=v def={({ℓ→v},{ℓ→v})}A [ℓ]=[ℓ′] def={({ℓ→v,ℓ′→v},{ℓ→v,ℓ′→v})|v∈Val}Thefirst gives the semantics of an action that proceeds only ifℓholds value v and the second gives the semantics of an action that proceeds only if the locationsℓandℓ′hold the same value.Since boolean actions shall not modify the heap,they shall possess the property that:if(D1,D2)∈A b then D1=D2.This is preserved by the operations defined below.For heaps D and D′,we use D↑D′to mean that D and D′are compatible as partial functions and D ↑D′otherwise,i.e.if they disagree on the values assigned to a common location.A true def={(∅,∅)}A false def=∅A b∧b′ def={({D∪D′},{D∪D′})|D↑D′and(D,D)∈A b and(D′,D′)∈A b′ } A b∨b′ def=A b ∪A b′A ¬b def={(D,D)|D is a⊆-minimal heap s.t.∀D′.(D′,D′)∈A b :D ↑D′}By insisting on minimality in the clause for¬b,we form an action that is defined at as few locations as possible to refute all grounds for b.3.2.Transition semantics.As an aid to understanding the net model,and in particular to give a model with respect to which we can prove its correspondence,a transition semantics for closed terms(terms such that fv(t)=∅)is given in Figure2.A formal relationship between the two semantics is presented in Theorem3.27.The transition semantics is given by means of labelled transition relations of the forms t,σ λ−→ t′,σ′ and t,σ λ−→σ′.As usual,thefirst form of transition indicates that t performs an action labelledλin stateσ8J.HAYMAN AND G.WINSKELto yield a resumption t′and a stateσ′.The second indicates that t in stateσperforms an action labelledλto terminate and yields a stateσ′.Labels follow the grammar λ::=act(D1,D2)heap action|alloc(ℓ,v,ℓ′,v′)heap allocation|dealloc(ℓ,ℓ′,v)heap disposal|decl(r)resource declaration|end(r)end of resource scope|acq(r)resource acquisition(critical region entry)|rel(r)resource release(critical region exit).In the transition semantics,we writeσ⊕σ′for the union of the components of two states where they are disjoint and impose the implicit side-condition that this is defined wherever it is used.For example,this implicit side-condition means,in the rule(Alloc),that for alloc(ℓ,v,ℓ′,v′)to occur we must have curr(ℓ′)∈σ,and henceℓ′was initially non-current. Similarly,the rule(Res)can only be applied to derive a transition labelled decl(r)if the resource r was not initially current.The syntax of terms is extended temporarily to include rel r and end r which are special terms used in the rules(Rel)and(End).These,respectively,are attached to the ends of terms protected by critical regions and the ends of terms in which a resource was declared.For conciseness,we do not give an error semantics to situations in which non-current locations or resources are used;instead,the process will become stuck.We show in Section 4.3that such situations are excluded by the logic.3.3.Petri nets.Petri nets,introduced by Petri in his1962thesis[Pet62],are a well-known model for concurrent computation.It is beyond the scope of the current article to provide a full account of the many variants of Petri net and their associated theories;we instead refer the reader to[BRR87]for a good account.Roughly,a Petri net can be thought of as a transition system where,instead of a transition occurring from a single global state,an occurrence of an event is imagined to affect only the conditions in its neighbourhood.Petri nets allow a derived notion of independence of events;two events are independent if their neighbourhoods of conditions do not intersect.We base our semantics on the following well-known variant of Petri net(cf.the‘basic’nets of[CW01]and[WN95]):Definition3.3(Petri net).A Petri net is afive-tuple,(B,E,•(−),(−)•,M0).The set B comprises the conditions of the net,the set E consists of the events of the net, and M0is the subset of B of marked conditions(the initial marking).The maps•(−),(−)•:E→P ow(B)are the precondition and postcondition maps,respectively.Petri nets have an appealing graphical representation,with:•circles to represent conditions,•bold lines to represent events,•arrows from conditions to events to represent the precondition map,INDEPENDENCE AND CONCURRENT SEPARATION LOGIC∗9α,(D,L,R,N) act(D1,D2)−→(D′,L,R,N)(Alloc): alloc(ℓ),σ⊕{ℓ→v} alloc(ℓ,v,ℓ′,v′)−→σ⊕{ℓ→ℓ′,ℓ′→v′,curr(ℓ′)} (Dealloc): dealloc(ℓ),σ⊕{ℓ→ℓ′,ℓ′→v′,curr(ℓ′)} dealloc(ℓ,ℓ′,v′)−→σ⊕{ℓ→ℓ′}(Seq): t1,σ λ−→ t′1,σ′t1;t2,σ λ−→ t2,σ′(Par-1): t1,σ λ−→ t′1,σ′t1 t2,σ λ−→ t1 t′2,σ′(Par′-1): t1,σ λ−→σ′t1 t2,σ λ−→ t1,σ′(Sum-1): α1,σ λ−→σ′α1.t1+α2.t2,σ λ−→ t2,σ′(While): b,σ λ−→σwhile b do t od,σ λ−→σ(With): with r do t od,σ⊕{r}) acq(r)−→ t;rel r,σ (Rel): rel r,σ rel(r)−→σ⊕{r}(Res): resource w do t od,σ decl(r)−→ [r/w]t;end r,σ⊕{r,curr(r)} (End): end r,σ⊕{r,curr(r)} end(r)−→σ10J.HAYMAN AND G.WINSKELSuch an event is said to have concession or to be enabled .The marking following the occurrence of e is obtained by removing the tokens from the preconditions of e and placing a token in every postcondition of e .We write M e −։M ′whereM ′=(M \•e )∪e •.If constraint (2)does not hold but constraint (1)does,so the preconditions are all marked (have a token inside)but following removal of the tokens from the preconditions there is a token in some postcondition,there is said to be contact in the marking and the event cannot fire.Consider the following example Petri net,with its transition system between markings derived according to the tokengame.{d,c,g }e 3K K K K K K K K K K {a,g }e 13.4.Overview of net semantics.Before giving the formal definition of the net semantics of closed terms,by means of an example we shall illustrate how our semantics shall be defined.First,we shall draw the semantics of an action toggle (ℓ,0,1)that toggles the value held at a location ℓbetween 0and1.terminal conditionsinitial conditions evolves tocontrol terminal conditions initial conditions state Notice that in the above net there are conditions to represent the shared state in which processes execute,including for example the values held at locations (we have only drawn conditions that are actually used by the net).There are also conditions to represent the control point of the process.The net pictured on the left is in its initial marking of control conditions and the net on the right is in its terminal marking of control conditions,indicating successful completion of the process following the toggle of the value;the marking of the net initially had the state condition ℓ→0marked and finished with the condition ℓ→1marked.There is an event present in the net for each way that the action could take place:one event for toggling the value from 0to 1and another event for toggling the value from 1to 0.Only the first event could occur in the initial marking of the net on the left,and no event can occur in the marking on the right since the control conditions are not appropriately marked.The parallel composition toggle (ℓ,0,1) toggle (ℓ,0,1)can be formed by taking two copies of the net toggle (ℓ,0,1)and forcing them to operate on disjoint sets of controlconditions.control state initial conditions terminal conditionsAn example run of this net would involve first the top event changing the value of ℓfrom 0to 1and then the bottom event changing ℓback from 1to 0.The resulting marking ofcontrol conditions would be equal to the terminal conditions of the net,so no event would have concession in this marking.The net representing the sequential composition(toggle(ℓ,0,1) toggle(ℓ,0,1));(toggle(ℓ,0,1) toggle(ℓ,0,1))is formed by a‘gluing’operation that joins the terminal conditions of one copy of the net for toggle(ℓ,0,1)to the initial conditions of another copy of the net for toggle(ℓ,0,1).(Inconditions.)this example net,for clarity we shall not show the state“gluing” structure.As outlined above,within the nets that we give for processes we distinguish two forms of condition,namely control conditions and state conditions.The markings of these sets of conditions determine the control point of the process and the state in which it is executing,respectively.When we give the net semantics,we will make use of the closure of the set of control conditions under various operations.Definition3.5(Conditions).Define the set of control conditions C,ranged over by c,to be the least set such that:•C contains distinguished elements i and t,standing for‘initial’and‘terminal’,respectively.•If c∈C then r:c∈C for all r∈Res and i:c∈C for all i∈{1,2},to distinguish processes working on different resources or arising from different subterms.•If c,c′∈C then(c,c′)∈C to allow the‘gluing’operation above.Define the set of state conditions S to be D∪L∪R∪N.A stateσ=(D,L,R,N)corresponds to the marking D∪L∪R∪N of state conditions in the obvious way.Similarly,if C is a marking of control conditions andσis a state,the pair (C,σ)corresponds to the marking C∪σ.We therefore use the notations interchangeably.The nets that we form shall be extensional in the sense that two events are equal if they have the same preconditions and the same postconditions.An event can therefore be regarded as a tuplee=(C,σ,C′,σ′)with preconditions•e def=C∪σand postconditions e•def=C′∪σ′.To obtain a concise notation for working with events,we write C e for the pre-control conditions of e:C e def=•e∩C.We likewise define notations e C,D e,L e etc.,and call these the components of e by virtue of the fact that it is sufficient to define an event through the definition of its components. The pre-state conditions of e are S e=D e∪L e∪R e∪N e,and we define e S similarly.Two markings of control conditions are of particular importance:those marked when the process starts executing and those marked when the process has terminated.We call these the initial control conditions I and terminal control conditions T,respectively.We shall call a net with a partition of its conditions into control and state with the subsets of control conditions I and T an embedded net.For an embedded net N,we write Ic(N)for I and Tc(N)for T,and we write Ev(N)for its set of events.Observe that no initial marking of state conditions is specified.The semantics of a closed term t shall be an embedded net,written N t .No confusion arises,so we shall write Ic(t)for Ic(N t ),and Tc(t)and Ev(t)for Tc(N t )and Ev(N t ), respectively.The nets formed shall always have the same sets of control and state conditions; the difference shall arise in the events present in the nets.It would be a trivial matter to restrict to the conditions that are actually used.As we give the semantics of closed terms,we will make use of several constructions on nets.For example,we wish the events of parallel processes to operate on disjoint sets of control conditions.This is conducted using a tagging operation on events.We define1:e to be the event e changed so thatC(1:e)def={1:c|c∈C e}(1:e)C def={1:c|c∈e C}but otherwise unchanged in its action on state conditions.We define the notations2:e and r:e where r∈Res similarly.The notations are extended pointwise to sets of events:1:E def={1:e|e∈E}.Another useful operation is what we call gluing two embedded nets together.For example,when forming the sequential composition of processes t1;t2,we want to enable the events of t2when t1has terminated.This is done by‘gluing’the two nets together at the terminal conditions of t1and the initial conditions of t2,having made them disjoint on control conditions using tagging.Wherever a terminal condition c of Tc(t1)occurs as a pre-or a postcondition of an event of t1,every element of the set{1:c}×(2:Ic(t2))would occur in its place.Similarly,the events of t2use the set of conditions(1:Tc(t1))×{2:c′} instead of an initial condition c′of Ic(t2).A variety of control properties that the nets we form possess(Lemma3.11),such as that all events have at least one pre-control condition, allows us to infer that it is impossible for an event of t2to occur before t1has terminated, and thereon it is impossible for t1to resume.An example follows shortly.Assume a set P⊆C×eful definitions to represent gluing are:P⊳C def={(c1,c2)|c1∈C and(c1,c2)∈P}∪{c1|c1∈C and∄c2.(c1,c2)∈P}P⊲C def={(c1,c2)|c2∈C and(c1,c2)∈P}∪{c2|c2∈C and∄c1.(c1,c2)∈P}Thefirst definition,P⊳C,indicates that an occurrence of c1in C is to be replaced by occurrences of(c1,c2)for every c2such that(c1,c2)occurs in P.The second definition, P⊲C,indicates that an occurrence of c2in C is to be replaced by occurrences of(c1,c2) for every c1such that(c1,c2)occurs in P.。
肿瘤放射治疗中辐射增敏剂的应用进展
肿瘤放射治疗中辐射增敏剂的应用进展冉晨曦;何人可;汤小玲;郭忠【摘要】肿瘤放射治疗中辐射增敏剂的作用机制主要包括改变肿瘤微环境、清除自由基和电子、细胞周期同步化、抑制DNA损伤修复、促进细胞凋亡和生物还原作用。
目前临床应用的常规辐射增敏剂有硝基咪唑类化合物、环氧化酶-2抑制剂、铂类、天热药物，为减轻不良反应，采用小剂量多次照射或与解毒药物并用或局部用药等。
新型辐射增敏剂有纳米粒、核仁素的特异性核酸适配体AS1411、STAT3反义寡核苷酸，他们作为放疗增敏剂能在肿瘤组织内被动靶向地聚集，进而达到杀死肿瘤的目的。
近年来，寻找更高效辐射增敏剂的重点放在能影响某些还原酶的药物，设法进一步加重肿瘤乏氧状态，并且使提升细胞放射抗性的蛋白表达量下降，从而发挥细胞毒作用。
【期刊名称】《山东医药》【年(卷),期】2015(000)003【总页数】3页(P86-88)【关键词】肿瘤;放射治疗;辐射增敏剂【作者】冉晨曦;何人可;汤小玲;郭忠【作者单位】西北民族大学医学院，甘肃兰州730030;西北民族大学医学院，甘肃兰州730030;西北民族大学医学院，甘肃兰州730030;西北民族大学医学院，甘肃兰州730030【正文语种】中文【中图分类】R730.5放疗是治疗恶性肿瘤的常规手段，其原理在于利用不同剂量的射线对肿瘤进行照射，进而抑制和消灭癌细胞。
放疗可单独应用，亦可伴随其他医疗手段共同应用。
放疗只对某些辐射敏感性较高的肿瘤有较好的疗效，而对于临床上大部分肿瘤不敏感[1]。
因此，在放疗治疗过程中，需要利用其他各种辅助手段来降低某些肿瘤对辐射的抵抗能力，提高其辐射敏感性[2]。
辐射增敏剂是近几年在肿瘤临床研究这一板块中较为活跃的“新大陆”。
由于耐低氧细胞的存在，通常辐射治疗不能完全清除癌细胞。
为了增加乏氧细胞对放射的敏感性，研究者曾进行了很多努力和尝试，比如加大放疗的剂量、使用乏氧细胞增敏剂、放疗和化疗药物联合应用等[3]。
Native Instruments MASCHINE MIKRO MK3用户手册说明书
The information in this document is subject to change without notice and does not represent a commitment on the part of Native Instruments GmbH. The software described by this docu-ment is subject to a License Agreement and may not be copied to other media. No part of this publication may be copied, reproduced or otherwise transmitted or recorded, for any purpose, without prior written permission by Native Instruments GmbH, hereinafter referred to as Native Instruments.“Native Instruments”, “NI” and associated logos are (registered) trademarks of Native Instru-ments GmbH.ASIO, VST, HALion and Cubase are registered trademarks of Steinberg Media Technologies GmbH.All other product and company names are trademarks™ or registered® trademarks of their re-spective holders. Use of them does not imply any affiliation with or endorsement by them.Document authored by: David Gover and Nico Sidi.Software version: 2.8 (02/2019)Hardware version: MASCHINE MIKRO MK3Special thanks to the Beta Test Team, who were invaluable not just in tracking down bugs, but in making this a better product.NATIVE INSTRUMENTS GmbH Schlesische Str. 29-30D-10997 Berlin Germanywww.native-instruments.de NATIVE INSTRUMENTS North America, Inc. 6725 Sunset Boulevard5th FloorLos Angeles, CA 90028USANATIVE INSTRUMENTS K.K.YO Building 3FJingumae 6-7-15, Shibuya-ku, Tokyo 150-0001Japanwww.native-instruments.co.jp NATIVE INSTRUMENTS UK Limited 18 Phipp StreetLondon EC2A 4NUUKNATIVE INSTRUMENTS FRANCE SARL 113 Rue Saint-Maur75011 ParisFrance SHENZHEN NATIVE INSTRUMENTS COMPANY Limited 5F, Shenzhen Zimao Center111 Taizi Road, Nanshan District, Shenzhen, GuangdongChina© NATIVE INSTRUMENTS GmbH, 2019. All rights reserved.Table of Contents1Welcome to MASCHINE (23)1.1MASCHINE Documentation (24)1.2Document Conventions (25)1.3New Features in MASCHINE 2.8 (26)1.4New Features in MASCHINE 2.7.10 (28)1.5New Features in MASCHINE 2.7.8 (29)1.6New Features in MASCHINE 2.7.7 (29)1.7New Features in MASCHINE 2.7.4 (31)1.8New Features in MASCHINE 2.7.3 (33)2Quick Reference (35)2.1MASCHINE Project Overview (35)2.1.1Sound Content (35)2.1.2Arrangement (37)2.2MASCHINE Hardware Overview (40)2.2.1MASCHINE MIKRO Hardware Overview (40)2.2.1.1Browser Section (41)2.2.1.2Edit Section (42)2.2.1.3Performance Section (43)2.2.1.4Transport Section (45)2.2.1.5Pad Section (46)2.2.1.6Rear Panel (50)2.3MASCHINE Software Overview (51)2.3.1Header (52)2.3.2Browser (54)2.3.3Arranger (56)2.3.4Control Area (59)2.3.5Pattern Editor (60)3Basic Concepts (62)3.1Important Names and Concepts (62)3.2Adjusting the MASCHINE User Interface (65)3.2.1Adjusting the Size of the Interface (65)3.2.2Switching between Ideas View and Song View (66)3.2.3Showing/Hiding the Browser (67)3.2.4Showing/Hiding the Control Lane (67)3.3Common Operations (68)3.3.1Adjusting Volume, Swing, and Tempo (68)3.3.2Undo/Redo (71)3.3.3Focusing on a Group or a Sound (73)3.3.4Switching Between the Master, Group, and Sound Level (77)3.3.5Navigating Channel Properties, Plug-ins, and Parameter Pages in the Control Area.773.3.6Navigating the Software Using the Controller (82)3.3.7Using Two or More Hardware Controllers (82)3.3.8Loading a Recent Project from the Controller (84)3.4Native Kontrol Standard (85)3.5Stand-Alone and Plug-in Mode (86)3.5.1Differences between Stand-Alone and Plug-in Mode (86)3.5.2Switching Instances (88)3.6Preferences (88)3.6.1Preferences – General Page (89)3.6.2Preferences – Audio Page (93)3.6.3Preferences – MIDI Page (95)3.6.4Preferences – Default Page (97)3.6.5Preferences – Library Page (101)3.6.6Preferences – Plug-ins Page (109)3.6.7Preferences – Hardware Page (114)3.6.8Preferences – Colors Page (114)3.7Integrating MASCHINE into a MIDI Setup (117)3.7.1Connecting External MIDI Equipment (117)3.7.2Sync to External MIDI Clock (117)3.7.3Send MIDI Clock (118)3.7.4Using MIDI Mode (119)3.8Syncing MASCHINE using Ableton Link (120)3.8.1Connecting to a Network (121)3.8.2Joining and Leaving a Link Session (121)4Browser (123)4.1Browser Basics (123)4.1.1The MASCHINE Library (123)4.1.2Browsing the Library vs. Browsing Your Hard Disks (124)4.2Searching and Loading Files from the Library (125)4.2.1Overview of the Library Pane (125)4.2.2Selecting or Loading a Product and Selecting a Bank from the Browser (128)4.2.3Selecting a Product Category, a Product, a Bank, and a Sub-Bank (133)4.2.3.1Selecting a Product Category, a Product, a Bank, and a Sub-Bank on theController (137)4.2.4Selecting a File Type (137)4.2.5Choosing Between Factory and User Content (138)4.2.6Selecting Type and Character Tags (138)4.2.7Performing a Text Search (142)4.2.8Loading a File from the Result List (143)4.3Additional Browsing Tools (148)4.3.1Loading the Selected Files Automatically (148)4.3.2Auditioning Instrument Presets (149)4.3.3Auditioning Samples (150)4.3.4Loading Groups with Patterns (150)4.3.5Loading Groups with Routing (151)4.3.6Displaying File Information (151)4.4Using Favorites in the Browser (152)4.5Editing the Files’ Tags and Properties (155)4.5.1Attribute Editor Basics (155)4.5.2The Bank Page (157)4.5.3The Types and Characters Pages (157)4.5.4The Properties Page (160)4.6Loading and Importing Files from Your File System (161)4.6.1Overview of the FILES Pane (161)4.6.2Using Favorites (163)4.6.3Using the Location Bar (164)4.6.4Navigating to Recent Locations (165)4.6.5Using the Result List (166)4.6.6Importing Files to the MASCHINE Library (169)4.7Locating Missing Samples (171)4.8Using Quick Browse (173)5Managing Sounds, Groups, and Your Project (175)5.1Overview of the Sounds, Groups, and Master (175)5.1.1The Sound, Group, and Master Channels (176)5.1.2Similarities and Differences in Handling Sounds and Groups (177)5.1.3Selecting Multiple Sounds or Groups (178)5.2Managing Sounds (181)5.2.1Loading Sounds (183)5.2.2Pre-listening to Sounds (184)5.2.3Renaming Sound Slots (185)5.2.4Changing the Sound’s Color (186)5.2.5Saving Sounds (187)5.2.6Copying and Pasting Sounds (189)5.2.7Moving Sounds (192)5.2.8Resetting Sound Slots (193)5.3Managing Groups (194)5.3.1Creating Groups (196)5.3.2Loading Groups (197)5.3.3Renaming Groups (198)5.3.4Changing the Group’s Color (199)5.3.5Saving Groups (200)5.3.6Copying and Pasting Groups (202)5.3.7Reordering Groups (206)5.3.8Deleting Groups (207)5.4Exporting MASCHINE Objects and Audio (208)5.4.1Saving a Group with its Samples (208)5.4.2Saving a Project with its Samples (210)5.4.3Exporting Audio (212)5.5Importing Third-Party File Formats (218)5.5.1Loading REX Files into Sound Slots (218)5.5.2Importing MPC Programs to Groups (219)6Playing on the Controller (223)6.1Adjusting the Pads (223)6.1.1The Pad View in the Software (223)6.1.2Choosing a Pad Input Mode (225)6.1.3Adjusting the Base Key (226)6.2Adjusting the Key, Choke, and Link Parameters for Multiple Sounds (227)6.3Playing Tools (229)6.3.1Mute and Solo (229)6.3.2Choke All Notes (233)6.3.3Groove (233)6.3.4Level, Tempo, Tune, and Groove Shortcuts on Your Controller (235)6.3.5Tap Tempo (235)6.4Performance Features (236)6.4.1Overview of the Perform Features (236)6.4.2Selecting a Scale and Creating Chords (239)6.4.3Scale and Chord Parameters (240)6.4.4Creating Arpeggios and Repeated Notes (253)6.4.5Swing on Note Repeat / Arp Output (257)6.5Using Lock Snapshots (257)6.5.1Creating a Lock Snapshot (257)7Working with Plug-ins (259)7.1Plug-in Overview (259)7.1.1Plug-in Basics (259)7.1.2First Plug-in Slot of Sounds: Choosing the Sound’s Role (263)7.1.3Loading, Removing, and Replacing a Plug-in (264)7.1.4Adjusting the Plug-in Parameters (270)7.1.5Bypassing Plug-in Slots (270)7.1.6Using Side-Chain (272)7.1.7Moving Plug-ins (272)7.1.8Alternative: the Plug-in Strip (273)7.1.9Saving and Recalling Plug-in Presets (273)7.1.9.1Saving Plug-in Presets (274)7.1.9.2Recalling Plug-in Presets (275)7.1.9.3Removing a Default Plug-in Preset (276)7.2The Sampler Plug-in (277)7.2.1Page 1: Voice Settings / Engine (279)7.2.2Page 2: Pitch / Envelope (281)7.2.3Page 3: FX / Filter (283)7.2.4Page 4: Modulation (285)7.2.5Page 5: LFO (286)7.2.6Page 6: Velocity / Modwheel (288)7.3Using Native Instruments and External Plug-ins (289)7.3.1Opening/Closing Plug-in Windows (289)7.3.2Using the VST/AU Plug-in Parameters (292)7.3.3Setting Up Your Own Parameter Pages (293)7.3.4Using VST/AU Plug-in Presets (298)7.3.5Multiple-Output Plug-ins and Multitimbral Plug-ins (300)8Using the Audio Plug-in (302)8.1Loading a Loop into the Audio Plug-in (306)8.2Editing Audio in the Audio Plug-in (307)8.3Using Loop Mode (308)8.4Using Gate Mode (310)9Using the Drumsynths (312)9.1Drumsynths – General Handling (313)9.1.1Engines: Many Different Drums per Drumsynth (313)9.1.2Common Parameter Organization (313)9.1.3Shared Parameters (316)9.1.4Various Velocity Responses (316)9.1.5Pitch Range, Tuning, and MIDI Notes (316)9.2The Kicks (317)9.2.1Kick – Sub (319)9.2.2Kick – Tronic (321)9.2.3Kick – Dusty (324)9.2.4Kick – Grit (325)9.2.5Kick – Rasper (328)9.2.6Kick – Snappy (329)9.2.7Kick – Bold (331)9.2.8Kick – Maple (333)9.2.9Kick – Push (334)9.3The Snares (336)9.3.1Snare – Volt (338)9.3.2Snare – Bit (340)9.3.3Snare – Pow (342)9.3.4Snare – Sharp (343)9.3.5Snare – Airy (345)9.3.6Snare – Vintage (347)9.3.7Snare – Chrome (349)9.3.8Snare – Iron (351)9.3.9Snare – Clap (353)9.3.10Snare – Breaker (355)9.4The Hi-hats (357)9.4.1Hi-hat – Silver (358)9.4.2Hi-hat – Circuit (360)9.4.3Hi-hat – Memory (362)9.4.4Hi-hat – Hybrid (364)9.4.5Creating a Pattern with Closed and Open Hi-hats (366)9.5The Toms (367)9.5.1Tom – Tronic (369)9.5.2Tom – Fractal (371)9.5.3Tom – Floor (375)9.5.4Tom – High (377)9.6The Percussions (378)9.6.1Percussion – Fractal (380)9.6.2Percussion – Kettle (383)9.6.3Percussion – Shaker (385)9.7The Cymbals (389)9.7.1Cymbal – Crash (391)9.7.2Cymbal – Ride (393)10Using the Bass Synth (396)10.1Bass Synth – General Handling (397)10.1.1Parameter Organization (397)10.1.2Bass Synth Parameters (399)11Working with Patterns (401)11.1Pattern Basics (401)11.1.1Pattern Editor Overview (402)11.1.2Navigating the Event Area (404)11.1.3Following the Playback Position in the Pattern (406)11.1.4Jumping to Another Playback Position in the Pattern (407)11.1.5Group View and Keyboard View (408)11.1.6Adjusting the Arrange Grid and the Pattern Length (410)11.1.7Adjusting the Step Grid and the Nudge Grid (413)11.2Recording Patterns in Real Time (416)11.2.1Recording Your Patterns Live (417)11.2.2Using the Metronome (419)11.2.3Recording with Count-in (420)11.3Recording Patterns with the Step Sequencer (422)11.3.1Step Mode Basics (422)11.3.2Editing Events in Step Mode (424)11.4Editing Events (425)11.4.1Editing Events with the Mouse: an Overview (425)11.4.2Creating Events/Notes (428)11.4.3Selecting Events/Notes (429)11.4.4Editing Selected Events/Notes (431)11.4.5Deleting Events/Notes (434)11.4.6Cut, Copy, and Paste Events/Notes (436)11.4.7Quantizing Events/Notes (439)11.4.8Quantization While Playing (441)11.4.9Doubling a Pattern (442)11.4.10Adding Variation to Patterns (442)11.5Recording and Editing Modulation (443)11.5.1Which Parameters Are Modulatable? (444)11.5.2Recording Modulation (446)11.5.3Creating and Editing Modulation in the Control Lane (447)11.6Creating MIDI Tracks from Scratch in MASCHINE (452)11.7Managing Patterns (454)11.7.1The Pattern Manager and Pattern Mode (455)11.7.2Selecting Patterns and Pattern Banks (456)11.7.3Creating Patterns (459)11.7.4Deleting Patterns (460)11.7.5Creating and Deleting Pattern Banks (461)11.7.6Naming Patterns (463)11.7.7Changing the Pattern’s Color (465)11.7.8Duplicating, Copying, and Pasting Patterns (466)11.7.9Moving Patterns (469)11.8Importing/Exporting Audio and MIDI to/from Patterns (470)11.8.1Exporting Audio from Patterns (470)11.8.2Exporting MIDI from Patterns (472)11.8.3Importing MIDI to Patterns (474)12Audio Routing, Remote Control, and Macro Controls (483)12.1Audio Routing in MASCHINE (484)12.1.1Sending External Audio to Sounds (485)12.1.2Configuring the Main Output of Sounds and Groups (489)12.1.3Setting Up Auxiliary Outputs for Sounds and Groups (494)12.1.4Configuring the Master and Cue Outputs of MASCHINE (497)12.1.5Mono Audio Inputs (502)12.1.5.1Configuring External Inputs for Sounds in Mix View (503)12.2Using MIDI Control and Host Automation (506)12.2.1Triggering Sounds via MIDI Notes (507)12.2.2Triggering Scenes via MIDI (513)12.2.3Controlling Parameters via MIDI and Host Automation (514)12.2.4Selecting VST/AU Plug-in Presets via MIDI Program Change (522)12.2.5Sending MIDI from Sounds (523)12.3Creating Custom Sets of Parameters with the Macro Controls (527)12.3.1Macro Control Overview (527)12.3.2Assigning Macro Controls Using the Software (528)13Controlling Your Mix (535)13.1Mix View Basics (535)13.1.1Switching between Arrange View and Mix View (535)13.1.2Mix View Elements (536)13.2The Mixer (537)13.2.1Displaying Groups vs. Displaying Sounds (539)13.2.2Adjusting the Mixer Layout (541)13.2.3Selecting Channel Strips (542)13.2.4Managing Your Channels in the Mixer (543)13.2.5Adjusting Settings in the Channel Strips (545)13.2.6Using the Cue Bus (549)13.3The Plug-in Chain (551)13.4The Plug-in Strip (552)13.4.1The Plug-in Header (554)13.4.2Panels for Drumsynths and Internal Effects (556)13.4.3Panel for the Sampler (557)13.4.4Custom Panels for Native Instruments Plug-ins (560)13.4.5Undocking a Plug-in Panel (Native Instruments and External Plug-ins Only) (564)14Using Effects (567)14.1Applying Effects to a Sound, a Group or the Master (567)14.1.1Adding an Effect (567)14.1.2Other Operations on Effects (574)14.1.3Using the Side-Chain Input (575)14.2Applying Effects to External Audio (578)14.2.1Step 1: Configure MASCHINE Audio Inputs (578)14.2.2Step 2: Set up a Sound to Receive the External Input (579)14.2.3Step 3: Load an Effect to Process an Input (579)14.3Creating a Send Effect (580)14.3.1Step 1: Set Up a Sound or Group as Send Effect (581)14.3.2Step 2: Route Audio to the Send Effect (583)14.3.3 A Few Notes on Send Effects (583)14.4Creating Multi-Effects (584)15Effect Reference (587)15.1Dynamics (588)15.1.1Compressor (588)15.1.2Gate (591)15.1.3Transient Master (594)15.1.4Limiter (596)15.1.5Maximizer (600)15.2Filtering Effects (603)15.2.1EQ (603)15.2.2Filter (605)15.2.3Cabinet (609)15.3Modulation Effects (611)15.3.1Chorus (611)15.3.2Flanger (612)15.3.3FM (613)15.3.4Freq Shifter (615)15.3.5Phaser (616)15.4Spatial and Reverb Effects (617)15.4.1Ice (617)15.4.2Metaverb (619)15.4.3Reflex (620)15.4.4Reverb (Legacy) (621)15.4.5Reverb (623)15.4.5.1Reverb Room (623)15.4.5.2Reverb Hall (626)15.4.5.3Plate Reverb (629)15.5Delays (630)15.5.1Beat Delay (630)15.5.2Grain Delay (632)15.5.3Grain Stretch (634)15.5.4Resochord (636)15.6Distortion Effects (638)15.6.1Distortion (638)15.6.2Lofi (640)15.6.3Saturator (641)15.7Perform FX (645)15.7.1Filter (646)15.7.2Flanger (648)15.7.3Burst Echo (650)15.7.4Reso Echo (653)15.7.5Ring (656)15.7.6Stutter (658)15.7.7Tremolo (661)15.7.8Scratcher (664)16Working with the Arranger (667)16.1Arranger Basics (667)16.1.1Navigating Song View (670)16.1.2Following the Playback Position in Your Project (672)16.1.3Performing with Scenes and Sections using the Pads (673)16.2Using Ideas View (677)16.2.1Scene Overview (677)16.2.2Creating Scenes (679)16.2.3Assigning and Removing Patterns (679)16.2.4Selecting Scenes (682)16.2.5Deleting Scenes (684)16.2.6Creating and Deleting Scene Banks (685)16.2.7Clearing Scenes (685)16.2.8Duplicating Scenes (685)16.2.9Reordering Scenes (687)16.2.10Making Scenes Unique (688)16.2.11Appending Scenes to Arrangement (689)16.2.12Naming Scenes (689)16.2.13Changing the Color of a Scene (690)16.3Using Song View (692)16.3.1Section Management Overview (692)16.3.2Creating Sections (694)16.3.3Assigning a Scene to a Section (695)16.3.4Selecting Sections and Section Banks (696)16.3.5Reorganizing Sections (700)16.3.6Adjusting the Length of a Section (702)16.3.6.1Adjusting the Length of a Section Using the Software (703)16.3.6.2Adjusting the Length of a Section Using the Controller (705)16.3.7Clearing a Pattern in Song View (705)16.3.8Duplicating Sections (705)16.3.8.1Making Sections Unique (707)16.3.9Removing Sections (707)16.3.10Renaming Scenes (708)16.3.11Clearing Sections (710)16.3.12Creating and Deleting Section Banks (710)16.3.13Working with Patterns in Song view (710)16.3.13.1Creating a Pattern in Song View (711)16.3.13.2Selecting a Pattern in Song View (711)16.3.13.3Clearing a Pattern in Song View (711)16.3.13.4Renaming a Pattern in Song View (711)16.3.13.5Coloring a Pattern in Song View (712)16.3.13.6Removing a Pattern in Song View (712)16.3.13.7Duplicating a Pattern in Song View (712)16.3.14Enabling Auto Length (713)16.3.15Looping (714)16.3.15.1Setting the Loop Range in the Software (714)16.3.15.2Activating or Deactivating a Loop Using the Controller (715)16.4Playing with Sections (715)16.4.1Jumping to another Playback Position in Your Project (716)16.5Triggering Sections or Scenes via MIDI (717)16.6The Arrange Grid (719)16.7Quick Grid (720)17Sampling and Sample Mapping (722)17.1Opening the Sample Editor (722)17.2Recording Audio (724)17.2.1Opening the Record Page (724)17.2.2Selecting the Source and the Recording Mode (725)17.2.3Arming, Starting, and Stopping the Recording (729)17.2.5Checking Your Recordings (731)17.2.6Location and Name of Your Recorded Samples (734)17.3Editing a Sample (735)17.3.1Using the Edit Page (735)17.3.2Audio Editing Functions (739)17.4Slicing a Sample (743)17.4.1Opening the Slice Page (743)17.4.2Adjusting the Slicing Settings (744)17.4.3Manually Adjusting Your Slices (746)17.4.4Applying the Slicing (750)17.5Mapping Samples to Zones (754)17.5.1Opening the Zone Page (754)17.5.2Zone Page Overview (755)17.5.3Selecting and Managing Zones in the Zone List (756)17.5.4Selecting and Editing Zones in the Map View (761)17.5.5Editing Zones in the Sample View (765)17.5.6Adjusting the Zone Settings (767)17.5.7Adding Samples to the Sample Map (770)18Appendix: Tips for Playing Live (772)18.1Preparations (772)18.1.1Focus on the Hardware (772)18.1.2Customize the Pads of the Hardware (772)18.1.3Check Your CPU Power Before Playing (772)18.1.4Name and Color Your Groups, Patterns, Sounds and Scenes (773)18.1.5Consider Using a Limiter on Your Master (773)18.1.6Hook Up Your Other Gear and Sync It with MIDI Clock (773)18.1.7Improvise (773)18.2Basic Techniques (773)18.2.1Use Mute and Solo (773)18.2.2Create Variations of Your Drum Patterns in the Step Sequencer (774)18.2.3Use Note Repeat (774)18.2.4Set Up Your Own Multi-effect Groups and Automate Them (774)18.3Special Tricks (774)18.3.1Changing Pattern Length for Variation (774)18.3.2Using Loops to Cycle Through Samples (775)18.3.3Load Long Audio Files and Play with the Start Point (775)19Troubleshooting (776)19.1Knowledge Base (776)19.2Technical Support (776)19.3Registration Support (777)19.4User Forum (777)20Glossary (778)Index (786)1Welcome to MASCHINEThank you for buying MASCHINE!MASCHINE is a groove production studio that implements the familiar working style of classi-cal groove boxes along with the advantages of a computer based system. MASCHINE is ideal for making music live, as well as in the studio. It’s the hands-on aspect of a dedicated instru-ment, the MASCHINE hardware controller, united with the advanced editing features of the MASCHINE software.Creating beats is often not very intuitive with a computer, but using the MASCHINE hardware controller to do it makes it easy and fun. You can tap in freely with the pads or use Note Re-peat to jam along. Alternatively, build your beats using the step sequencer just as in classic drum machines.Patterns can be intuitively combined and rearranged on the fly to form larger ideas. You can try out several different versions of a song without ever having to stop the music.Since you can integrate it into any sequencer that supports VST, AU, or AAX plug-ins, you can reap the benefits in almost any software setup, or use it as a stand-alone application. You can sample your own material, slice loops and rearrange them easily.However, MASCHINE is a lot more than an ordinary groovebox or sampler: it comes with an inspiring 7-gigabyte library, and a sophisticated, yet easy to use tag-based Browser to give you instant access to the sounds you are looking for.What’s more, MASCHINE provides lots of options for manipulating your sounds via internal ef-fects and other sound-shaping possibilities. You can also control external MIDI hardware and 3rd-party software with the MASCHINE hardware controller, while customizing the functions of the pads, knobs and buttons according to your needs utilizing the included Controller Editor application. We hope you enjoy this fantastic instrument as much as we do. Now let’s get go-ing!—The MASCHINE team at Native Instruments.MASCHINE Documentation1.1MASCHINE DocumentationNative Instruments provide many information sources regarding MASCHINE. The main docu-ments should be read in the following sequence:1.MASCHINE MIKRO Quick Start Guide: This animated online guide provides a practical ap-proach to help you learn the basic of MASCHINE MIKRO. The guide is available from theNative Instruments website: https:///maschine-mikro-quick-start/2.MASCHINE Manual (this document): The MASCHINE Manual provides you with a compre-hensive description of all MASCHINE software and hardware features.Additional documentation sources provide you with details on more specific topics:►Online Support Videos: You can find a number of support videos on The Official Native In-struments Support Channel under the following URL: https:///NIsupport-EN. We recommend that you follow along with these instructions while the respective ap-plication is running on your computer.Other Online Resources:If you are experiencing problems related to your Native Instruments product that the supplied documentation does not cover, there are several ways of getting help:▪Knowledge Base▪User Forum▪Technical Support▪Registration SupportYou will find more information on these subjects in the chapter Troubleshooting.Document Conventions1.2Document ConventionsThis section introduces you to the signage and text highlighting used in this manual. This man-ual uses particular formatting to point out special facts and to warn you of potential issues.The icons introducing these notes let you see what kind of information is to be expected:This document uses particular formatting to point out special facts and to warn you of poten-tial issues. The icons introducing the following notes let you see what kind of information canbe expected:Furthermore, the following formatting is used:▪Text appearing in (drop-down) menus (such as Open…, Save as… etc.) in the software andpaths to locations on your hard disk or other storage devices is printed in italics.▪Text appearing elsewhere (labels of buttons, controls, text next to checkboxes etc.) in thesoftware is printed in blue. Whenever you see this formatting applied, you will find thesame text appearing somewhere on the screen.▪Text appearing on the displays of the controller is printed in light grey. Whenever you seethis formatting applied, you will find the same text on a controller display.▪Text appearing on labels of the hardware controller is printed in orange. Whenever you seethis formatting applied, you will find the same text on the controller.▪Important names and concepts are printed in bold.▪References to keys on your computer’s keyboard you’ll find put in square brackets (e.g.,“Press [Shift] + [Enter]”).►Single instructions are introduced by this play button type arrow.→Results of actions are introduced by this smaller arrow.Naming ConventionThroughout the documentation we will refer to MASCHINE controller (or just controller) as the hardware controller and MASCHINE software as the software installed on your computer.The term “effect” will sometimes be abbreviated as “FX” when referring to elements in the MA-SCHINE software and hardware. These terms have the same meaning.Button Combinations and Shortcuts on Your ControllerMost instructions will use the “+” sign to indicate buttons (or buttons and pads) that must be pressed simultaneously, starting with the button indicated first. E.g., an instruction such as:“Press SHIFT + PLAY”means:1.Press and hold SHIFT.2.While holding SHIFT, press PLAY and release it.3.Release SHIFT.1.3New Features in MASCHINE2.8The following new features have been added to MASCHINE: Integration▪Browse on , create your own collections of loops and one-shots and send them directly to the MASCHINE browser.Improvements to the Browser▪Samples are now cataloged in separate Loops and One-shots tabs in the Browser.▪Previews of loops selected in the Browser will be played in sync with the current project.When a loop is selected with Prehear turned on, it will begin playing immediately in-sync with the project if transport is running. If a loop preview starts part-way through the loop, the loop will play once more for its full length to ensure you get to hear the entire loop once in context with your project.▪Filters and product selections will be remembered when switching between content types and Factory/User Libraries in the Browser.▪Browser content synchronization between multiple running instances. When running multi-ple instances of MASCHINE, either as Standalone and/or as a plug-in, updates to the Li-brary will be synced across the instances. For example, if you delete a sample from your User Library in one instance, the sample will no longer be present in the other instances.Similarly, if you save a preset in one instance, that preset will then be available in the oth-er instances, too.▪Edits made to samples in the Factory Libraries will be saved to the Standard User Directo-ry.For more information on these new features, refer to the following chapter ↑4, Browser. Improvements to the MASCHINE MIKRO MK3 Controller▪You can now set sample Start and End points using the controller. For more information refer to ↑17.3.1, Using the Edit Page.Improved Support for A-Series Keyboards▪When Browsing with A-Series keyboards, you can now jump quickly to the results list by holding SHIFT and pushing right on the 4D Encoder.▪When Browsing with A-Series keyboards, you can fast scroll through the Browser results list by holding SHIFT and twisting the 4D Encoder.▪Mute and Solo Sounds and Groups from A-Series keyboards. Sounds are muted in TRACK mode while Groups are muted in IDEAS.。
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英⽂假说Regulation of NPC Differentiation from Bone Marrow StromalCells by Construction of Novel Inducing SystemAbstract:Neural precursor cells (NPC) exploited as “seed cells” in tissue engineering are the perfect cell source for the treatment of degenerative diseases and trauma of central nervous system. However, these cells are somewhat limited in their utility due to source-related ethics or legislations, and the diffculties in acquiring from autologous tissue, suggesting discovery and development of novel approach that could obtain sufficient NPCs are needed. In recent years, the utility of bone marrow derived mesenchymal stem cells (BMSCs) to differentiate into neural cells have become a potential method for NPCs acquisition. Increasing research trend to utilize growth factors (GFs) as an inducer to evoke BMSCs for neural differentiation, however the related differetiation mechanisms induced by GFs are still largely unclear. Recently, many evidences have proved that PI3K/AKT signaling pathway was involved in neural differentiation of BMSCs. In addition, it has also been demonstrated that GFs play an important role in the activation of PI3K/AKT signaling pathway. Therefore we propose a hypothesis that mechanisms involved in the differetiation of MSCs into neuron induced by GFs is meditated by its subsequent induction of PI3K/AKT signaling pathway. Basis on the mechanism, we could attempt to utilize neuroblastoma cells (NBCs) as a potential GFs pool for the constant secrection of many GFs, which may jointly activte this signaling pathway and efficiently promote the neural differentiation of MSCs. On the other hand, bFGF, one type of GFs, is demonstrated to be able to prolong the transformation of NPCs into mature neural cells. To better use these NBCs and bFGF, we could utilize the technique of multilayered alginate microcapsules to make the coalition of them for the NPC differentiation of BMSCs. Overall, we hypothesis that NBCs microcapsulated in multilayeredalginate microcapsules with bFGF supplement could efficiently induce the differentiation of MSCs into NPCs throughPI3K/AKT signaling pathway activated by the GFs. If possible, this hypothesis might open an attractive approach for clinical NPC transfortation to boost neuron regeneration and synapse reconstruction, and provide the relevant theoretical basis for treatment of central nervous system diseases.IntruductionNeuro-degenerative diseases and central nervous system trauma have been reported as one of the leading causes of disability or mortality. The limited potentials of central nervous system in nerve regeneration and function reconstruction is currently a hard nut to crack for the treatment of these diseases. Transplantion of stem cells, particularly neural precursor cells(NPCs)/ neural stem cells(NSCs) have been proposed as a promising therapeutic strategy for neuron repairation [1]. Plenty of studies identifies that NPCs could facilitate CNS regeneration due to their differentiation plasticity, which might lead to the substitution of dead cells and functional integration [2-3]. It is also proved that NPCs possess the capacity to release neuroprotective factors which are capable of stimulating endogenous regeneration[4-5]. However, the reliable source of NPCs is one of the most challenging technical issues. In recent years, the differentiation of BMSCs into neural cells has become a focus of current tissue engineering researches [6-8]. BMSCs that are capable of self-renewal [9-10] have been widely demonstrated to possess the capacity of neural differentiation in the presence of GFs [11-12]. In addition, some literatures confirmed that MSCs can be converted into NSCs/NPCs in vitro under the multi-cell factors [13-14]. However, the mechanisms involved in the differetiation of MSC into neuron induced by GFs is still unclear. On the other hand, although MSCs have the ability to differentiate into nerve cells, the differentiation rates were relatively low in most experiments, especially, the directed differentiation rate of NPC. Therefore this paper could provide some correlative hypothesis to discuss these issues.1. The effect of growth factors on MSCs differetiation is associated withactivation of PI3k/AKT signaling pathwayRecently, various data suggested that several intracellular signal transduction pathways including PI3K/AKT, cAMP-PKA and JAK-STAT3 signaling pathway could trigger and control the neuronal differentiation of MSCs [15-17]. Particularly, PI3K/AKT signaling has been revealed to possess the addition action of regulating neurite development and neuroprotection [18-20]. Therefore, we focused on the relationship between PI3K/AKT signaling pathway and neuronal differetiation of MSC.PI3K( phosphoinositol-3-kinases), a family of kinases, could generate PIP2 into PIP3 (phosphoinositide-3, 4,5 -triphosphate), which is a second messenger that activates many target molecules including AKT/PKB protein. PI3K/AKT signaling pathway has been shown to contribute to the regulation of BMSCs differentiation through up-regulation of proteins that mediate cell survival such as mammalian target of rapamycin (mTOR) [21]. In addition, it is reported that the activity of PI3K/AKT signalling pathway could be evoked by various GFs such as platelet-derived growth factor (PDGF), Epidermal Growth Factor (EGF), basicfibroblast growth factor (bFGF), and VEGF [19-22]. These findings, together with the observations from Hermann et al [13] and Hu Wei et al[14] that testified the indispensable role of multi-GFs in NPCs/NSCs differentiation from MSCs. Hence, we hypothesis that the mechanisms involved in the differentiation of MSCs into neuron induced by GFs is mediated by its subsequent induction of PI3K/AKT signaling pathway. Base on the mechanisms, maybe we could utilize the superiority of immortal cell lines such as NBCs to continuously secrete many GFs in Micro-environment，the alliance of GFs jointly activte this signaling pathway and contribute to the growth differentiation of BMSCs into neural cells.2. The alliance of GFs secreted by NBCs are invoved in regulation of MSCs differentiationNeuroblastoma is a kind of neuroendocrine tumor, which derived from the original pluripotent sympathetic neurocyte in the neural crest. It has been shown that various growth factors are expressed in NBCs. These factors such as VEGF-B, VEGF-C, bFGF, PDGF play an important role in cell growth, progression and metastasis of NB [23-24], due to their effect of regulating cell proliferation and differentiation.The role of conditioned medium (CM) from NBCs in the modification of cell differentiation become an emerging focus in resent years. Fuetal. et al have demonstrated that the differetiation of oligodendrocyteprecursor cells could be available by inducing neural stem cells in the presence of conditioned medium(CM) obtained from B104 neuroblastoma cells (B104-CM), bFGF and PDGF-AA in B104CM are 2 key factors that stimulate oligodendrocyte precursor cell (OPC)proliferation and differentiation [25]. Moreover, DEBORAL.et al have shown that conditioned medium(CM) of B104 neuroblastoma cells was capable of inducing differentiation of adipose tissue-derived mesenchymal stem cells (AT-MSCs) to a neuronal phenotype[26]. Thus, above studies some extent confirmed that the combined effects of multiple GFs secreted by NBCs could trigger and promote the neural differentiation.3. The tissue engineering technology of cells microcapsulationBased on the potential of conditioned medium (CM) from NBCs to induce neural differentiation, we suggest an approach to obtain sufficient and constant GFs from conditioned medium (CM) of NBCs is needed. Cells microencapsulation as a promising strategy have achieved important progress for clinical treatment. Cell encapsulation technology, as the name implies, is an approach that immobilizate cells inside a semipermeable membrane. It provides the unique cultivation of 3D environment and promotes the passage of oxygen, therapeutic proteins, nutrients, growth factors due to its thin membrane and relatively high ratio of surface-to-volume [27]. Cell encapsulation can also protect the cell from the host’s immune system and mechanical stress [28]. In addition the technology could achieve continuous deliver of GFs by the encapsulated cells over time [29-30]. Indeed, the characteristics of microencapsulated tumor cells (TCs) have acquired the most interest in rescent years. Qiuyan Wangal et al. detected that the culture of hepatocarcinoma cells in alginate-poly-lysine-alginate (APA) microcapsules in vitro could proliferate TCs with high viability, formingmulticellular spheroid just as the cytoarchitecture of TCs in vivo [31]. Shaoling Wu et al. showed that the implants of microencapsulated rat pheochromocytoma (PC12) cells could secrete catecholamines especially dopamine to decrease the coldallodynia behavior of rats that had the neuropathic pain [32]. They also found that the cell-loaded group did not occur neoplasia in the rats’ spinal cords [33]. Therefore, we hypothesis that the superiority of cell microencapsulation technique can not only enhance NBCs proliferation and boost the effect on the neural differentiaon of MSCs, but also segregate NBCs from normal cells, thus reducing their harmful effect of carcinogenicity.4. Strategy of microencapsulated NBCs together with bFGF supplement for NPC/NSC differetion derivered from MSCs (sig.1) Several experiments have found that the expression of nestin (a marker of neural stem cells) gradually decrease in the process of the neuronal differetiation of MSCs, indicating that NPC/NSC derivered from MSC differentiated into mature neural cells (MNCs) with time. The bFGF, one type of GFs, has been reported to be able to prolong the transformation of NPCs into mature neural cells and lead to neuronal cells dedifferentiate and appear similar to neural stem cells [34], suggesting the utilize of bFGF could stimulate the differetiation of NPC/NSC rather than mature neural cells. Recently, bFGF has also been used as the the major constituent of neural stem cell medium. Based on these data, we hypothesis the special characteristic of bFGF may be applied to the issue of NPC/NSC differetiation from BMSCs. Moreover, according to the technique of contemporary tissue engineering, we can projecte a procedure to synthesize multilayered alginatemicrocapsules called APA as a induction system. In this system, The alginate core was coated with a permselective poly-L-ornithine (PLO) layer which could facilitate the permeability of solutes into the microcapsules [35], the inner layer can be used for NB encapsulation, while the outer layer can be utilized for bFGF encapsulation. It is reported that the addition of the outer layer could keep the bFGF sustained release for more than 18 days without altering the permselectivity of the microcapsule coat [36]. Meanwhile the bFGF also could promote the capacity of proliferation of NBCs, together with the ability of NBCs to delivery the bFGF, and keep the high concentration of bFGF. we suppose the mutual promotion between NBCs and bFGF in the induction system may play a prominent part in NPC/NSC differetiation derivered from MSCs.Conclusion:Recently, the tissue engineering technology of neural differetiation from BMSCs appears bright developing prospects in treatment for central nervous system diseases. In the process of neuronal differentiation of MSCs, PI3K/AKT signaling pathway that could be activated by GFs have been proved to play an essential role in this transformation, suggesting a hypothesis that GFs could activate its subsequent induction of PI3K/AKT signaling pathway and promote differetiation of MSCs into neuron. Base on this mechanism, we exploit to co-culture the microencapsulation of NBC and bFGF with MSCs for promotion of its neural differentiation. The novel induction system may greatly stimulate the directed differetiation rate of NPC/NSC derivered from MSCs. However, subsequent experimental studies are required to further validate the potential benefits of the novel induction system.Conflict of interestNone.Figure 1References:[1]. Martino G, Franklin RJ, Van Evercooren AB, Kerr DA. Stem cell transplant-ation in multiple sclerosis: current status and future prospects. Nat RevNeurol 2010; 6:247–255.[2]. Poss KD. Advances in understanding tissue regenerative capacity andMechanisms in animals. Nat Rev Genet 2010; 11:710–722.[3]. Ingber DE, Levin M. What lies at the interface of regenerative medicine anddevelopmental biology? Development 2007; 134:2541–2547.[4]. Pera MF, Tam PP. Extrinsic regulation of pluripotent stem cells. Nature2010;465:713–720.[5]. Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for thetreatment of multiple sclerosis and other neurological diseases. LancetNeurol 2011;10:649–656.[6]. Bossolasco P, Cova L, Calzarossa C, et al. Neuro-glial differentiation ofhuman bone marrow stem cells in vitro. Exp Neurol 2005;193:312-25 [7]. Suzuki H, T Taguchi, H Tanaka, et al. Neurospheres induced from bonemarrow stromal cells are multipotent for differentiation into neuron, astrocyte, and oligodendrocyte phenotypes. Biochem Biophys Res Comm 2004;322:918–922.[8]. Dale Woodbury, Emily J, Schwarz, Darwin J, Prockop, Ira B. Black. Adultrat and human bone marrow stromal cells differentiate into neurons. Journal of Neuroscience Research 2000 ;61 (4) :364-370 [9]. Bjorklund A and O Lindvall. Cell replacement therapies for central nervoussystem disorders. Nat Neurosci 2000;3:537–544.[10]. Pluchino S, A Quattrini, E Brambilla, et al. Injection of adult neurospheresinduces recovery in a chronic model of multiplesclerosis. Nature 2003; 422: 688–694.[11]. Deng J,Petersen B.E, Steindler D.A, et al. Mesenchymal stem cellsspontane- ously express neural proteins in culture and are neurogenic aftertransplanta- tion.Stem Cells 2006;24:1054-1064.[12]. Zurita M,Vaquero J,Oya S,et al. Schwann cells induce neuronal differentia-tion of bone marrow stromal cells. Neuroreport 2005;16(5):505-508. [13]. Hermann A, R Gastl, S Liebau, et al. Efficient generation of neural stemcell-like cells from adult human bone marrow stromal cells. J Cell Sci 2004;117: 4411–4422.[14]. Hu Weia , Guan Fang-xiac, Li Yuanb, Tang You-jiaa, Yang Fenga, YangBob. New methods for inducing the differentiation of amniotic-derivedmesenchymalste –m cells into motor neuron precursor cells. Tissue and Cell 2013; 295– 305[15]. Jung Yeon Lim, Sang In Park, Ji Hyeon Oh, et al. Brain-derived neurotro-phic factor stimulates the neural differentiation of human umbilical cordblood-derived cells through MAPK/ERK and P13K/ AKT-dependentsignaling pathways .Journal of Neuroscience Research 2008; 86(10) :2168-2178[16]. Hao HY, Wang YG, Cheng F, et al. Role of JAK-STAT3 signaling pathwayduring neuronal differentiation of rat bone marrow mesenchymal stem cells.Neural Regeneration Research 2010;5(5):337-341[17 ]. Lepski G, Jannes CE, Maciaczyk J, et al. Limited Ca2+ and PKA-pathwaydependent neurogenic differentiation of human adult mesenchymal stemcells as compared to fetal neuronal stem cells. Experimental Cell Research2010;3 16(2):216-231.[18]. Park JH, Lee SB, Lee KH, Ahn JY. Nuclear Akt promotes neurite outgrowthin the early stage of neuritogenesis. BMB Rep 2012 Sep;45(9):521-5. [19]. Luis Ojeda, Junling Gao, Kristopher G, et al.Critical Role of PI3K/ Akt/GSK3β in Motoneuron Specification from Human Neural Stem Cells inResponse to FGF2 and EGF .PLoS ONE;2011, 6(8)e23414.[20]. Sun YY, Lin SH, Lin HC, et al. Cell Type-Specific Dependency on the PI3K/Akt Signaling Pathway for the Endogenous Epo and VEGF Induction byBaicalein in Neurons versus Astrocytes. PLoS One 2013;8(7)e69019. [21]. Borzo Gharibi, Mandeep S, Ghuman, Francis J, Hughes. Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal. Journal of Cellular and Molecular Medicine2012; 16 (11):2789-2801[22]. Ward , SGFinan P. Isofom-specific phosphoinositide 3-kinase inhibitors astherapeutic agents．CurrOpin Pharmacol 2003;3:426-434[23]. Komuro H, Kaneko S, Kaneko M, Nakanishi Y. Expression of angiogenicfactors and tumor progression in human neuroblastoma. Journal of CancerResearch and Clinical Oncology 2001; 127(12): 739-743[24]. Angelika E, Naohiko I, Janet K, H Zhao, Garrett M B, Bruce P. High-LevelExpression of Angiogenic Factors Is Associated with Advanced TumorStage in Human Neuroblastomas. Clinical Cancer Research 2000;6:1900–1908[25]. Jian-guo Hu, Xing-jun Wu, Yi-fan Feng, et al. PDGF-AA and bFGF mediateB104CM-induced proliferation of oligodendr-ocyte precursor cells.International Journal of Molecularmedicine 2012;30: 1113-1118.[26]. Deboralofurno, Rosaliapellitteri, Adrianac , et al. Differentiation of HumanAdipose Stem Cells into Neural Phenotypeby Neuroblastoma or OlfactoryEnsheathing Cells Conditioned Medium. J.Cell.Physiol 2013; 228: 2109–2118[27]. Shoichet MS, Winn SR. Cell delivery to the central nervous system. AdvDrug Deliv Rev2000;42:81–102.[28]. Orive G, Gascon AR, Hernandez RM, Igartua M, Pedraz JL.Cell microen-capsulation technology for biomedical purpose: novel insights andchallenges. Trends Pharmacol Sci 2003;24:207–10.[29]. Beck J, Angus R, Madsen B, Britt D, Vernon B, Nguyen KT. Isletencapsulat-ion: Strategies to enhance islet cell functions. Engineering 2007; 13: 589 –599[30]. Hernández,a, Orive, Gorka, et al. Microcapsules and microcarriers for insitu cell delivery .Advanced Drug Delivery Reviews 2010;62(7-8):711-730.[31]. Wang Qiuyan, Li Shuangyue, Xie Y ubing, et al. Cytoskeletal reorganizeat-ion and repolarization of hepatica -rcinoma cells in APA microcapsule tomimic native tumor characteristics. Hepato -logy Research 2006; 35(2):96-103.[32]. Shaoling Wu, Chao Ma, Guoqi Li, Mingquan Mai, Y uanyuan Wu . Intrathe-cal Implantation of Microencapsulated PC12 Cells Reduces Cold Allodynia in a Rat Model of Neuropathic Pain. Artificial Organs 2010; 35(3):294–300 [33]. Wu Shao-ling, Ma Chao, Yan Tie-bin, et al. Secretory characteristics andonco-genicity of microencapsulated PC12 cells. Journal of Clinical Rehabilitation Tissue Engineering Research 2008;12 (36):7041-7044 [34]. OShea KS. Neuronal differentiation of mouse embryonic stem cells:lineageselection and forced differentiation paradigms. Blood Cells Mol. Dis.27, 705–712[35]. Beck J, Angus R, Madsen B, Britt D, Vernon B, Nguyen KT. Isletencapsulation: Strategies to enhance islet cell functions. Tissue Eng 2007;13:589–599.[36]. Omaditya K, Monica L, Moya, Emmanuel C, Opara Eric M, Brey. Synthesisof multilayered alginate microcapsules for the sustained release of fibroblast growth factor-1. Journal of Biomedical Materials Research 2010;95A(2):632-640。
SMC 开关设备操作指南说明书
TroubleshootingSpecificationThe IODD file can be downloaded from the SMC website (URL ).Refer to the product catalogue or SMC website (URL ) for more detailed information about product specifications.DimensionsRefer to the product catalogue or SMC website (URL ) for more detailed information about dimensions.than above are displayed, please contact SMC.Error indicationSnap shot functionThe current flow rate/temperature value can be stored to the switch output ON/OFF set point.When the set value and hysteresis are set, press the UP and DOWN buttons for 1 second or longer simultaneously. Then, the set value of the sub display (right) shows [- - -], and then values corresponding to the current flow rate/temperature are automatically displayed.Peak/bottom value indicationThe max. (min.) rate/temperature when the power is supplied is detected and updated.The value can be displayed on the sub display by pressing the UP or DOWN button in measurement mode.Key-lock functionTo set this function, refer to SMC website (URL ) for more detailed information or contact us.MaintenanceHow to reset the product after a power cut or when the power has been unexpectedly removedThe settings of the product are retained from before the power cut or de-energizing.The output condition also recovers to that before the power cut or de-energizing,but may change depending on the operating environment.Therefore, check the safety of the whole system before operating the product.Function selection mode[F Select to display the function to be change [F mode to return to measurement mode.∗: The sub screen displays the content of function and the setting of the function alternately.The function number is increased and decreased by the UP and DOWN buttons.Display the required function number and press the SET button.Default settingsThe default settings are provided as follows. If these settings are acceptable,retain for use. To change setting, refer to SMC website(URL ) for more detailed information or contact us.Display of sub screenIn measurement mode, the display of the sub screen can be temporarily changed by pressing the UP or DOWN buttons.∗: After 30 seconds, it will automatically reset to the display selected in [F10].∗: Arbitrary displayThe set values and accumulated output of OUT2 cannot be displayed.(Example for 16 L/min type the above )The switch turns on within a set flow range (from P1L to P1H) during window comparator mode. Set P1L (switch lower limit) and P1H (switch upper limit) using the setting procedure above.When reversed output is selected, the main screen displays [n1L] and [n1H].To set accumulated output functions, refer to the product catalogue orSMC website (URL ) for more detailed information.For models with 2 outputs, [P_2] or [n_2] will be displayed. Set as above.For models with the temperature sensor attached, [ tn] will be displayed.When the fluid temperature falls below the set value, the output turns ON.∗: If a button operation is not performed for 30 seconds during the change of setting, the set value will start flashing.Refer to the SMC website (URL ) for more detailed information about product troubleshooting.Note: Specifications are subject to change without prior notice and any obligation on the part of the manufacturer.© 2018 SMC Corporation All Rights Reserved Akihabara UDX 15F, 4-14-1, Sotokanda, Chiyoda-ku, Tokyo 101-0021, JAPAN Phone: +81 3-5207-8249 Fax: +81 3-5298-5362URL PF ※※-OMV0007Safety InstructionsFlow (Temperature) SettingInstallationBracket mounting (PF3W704/720/740)Mount the product (with bracket) usingthe mounting screws supplied (M4 x 4 pcs.).For models with flow adjustment valve attached, fix using 8 mounting screws.Bracket thickness is approx. 1.5 mm.Measurement modeThe mode in which the flow is detected and displayed, and the switch function is operating.This is the basic operating mode; other modes should be selected for set-point and other function setting changes.Approx. 3 seconds for this period)Mounting and InstallationInstallation•Use the product within the specified operating pressure range and temperature range.•Proof pressure could vary according to the fluid temperature.Check the characteristics data for operating pressure and proof pressure.(4 pins) (Option)(Option)Direct mounting (PF3W704/720/740)Mount using the self tapping screws(nominal size: 3.0 x 4 pcs.) for installation.For models with flow adjustment valvePipingWhen connecting piping to the product, a spanner should be used on the metal piping attachment only.Using a spanner on other parts may damage the product.In particular, do not let the spanner come into contact with the M8 connector.The connector can be easily damaged.If the tightening torque is exceeded, the product can be broken. If the correct tightening torque is not applied, the fittings may become loose.Avoid any sealing tape getting inside the piping.Ensure there is no leakage from loose piping.3/824 mm 1/227 mm 3/432 mm Tighten to the specified torque for piping.The tightening torque for connection threads is shown in the table below.Direct mounting (PF3W711)Mount using the self tapping screws(nominal size: 4.0 x 4 pcs.) for installation.The tightening torque must be 1 to 1.2 Nm.The self tapping screws cannot be re-used.Refer to the outline dimension drawing for mounting hole size.Refer to the product catalogue or SMC website (URL )for more detailed information.WiringWiring of connectorConnections should only be made with the power supply turned off.Use separate routes for the Flow switch wiring and any power or high voltage wiring. Otherwise, malfunction may result due to noise.Ensure that the FG terminal is connected to ground when using a commercially available switch-mode power supply. When a switch-mode power supply isconnected to the product, switching noise will be superimposed and the product specification can no longer be met. This can be prevented by inserting a noise filter, such as a line noise filter and ferrite core, between the switch-mode power supply and the product, or by using a series power supply instead of a 141 mm How to adjust the flow rate(when a flow adjustment valve is mounted)(1) Rotate the knob of the valve to adjust the flowrate to the target value.(2) Be sure to confirm that there is no fluid leakagegenerated after adjustment.the valve several times for re-adjustment, and confirm that there is no fluid leakage.)(3) The flow adjustment valve is not designed forIf the valve is adjusted frequently, fluid may leak due to wear of the internal seal.BodyDisplayBracket mounting (PF3W711)Mount the product (with bracket) usingthe mounting screws supplied (M5 x 4 pcs.).Bracket thickness is approx. 2 mm.2. Press the UP or DOWN button to change the set value.The UP button is to increase and the DOWN button is to decrease the set value.•Press the UP button once to increase by one digit, press and hold to continuously increase.3. Press the SET button to finish the setting.•Press the DOWN button once todecrease by one digit, press and hold tocontinuously decrease.Mounting•Never mount the product in a location where it will be used as a support.•Mount the product so that the fluid flows in the direction indicated by the arrow on the side of the body.•Check the flow characteristics data for pressure loss and the straight inlet pipe length effect on accuracy, to determine inlet piping requirements.•Do not sharply reduce the piping size.•The monitor with integrated display can be rotated. It can be set at 90o intervals clockwise and anticlockwise, and also at 45o and 225o . Rotating the display with excessive force will damage the end stop.Refer to the product catalogue or SMC website (URL )for more detailed information.11/454 mm 11/254 mmBefore UseDigital Flow Switch(Integrated display type)(Integrated display type).Please read this manual carefully before operating the product and make sure you understand its capabilities and limitations. Please keep this manual handy for future reference.Safety InstructionsThese safety instructions are intended to prevent hazardous situations and/or equipment damage.These instructions indicate the level of potential hazard with the labels of"Caution", "Warning" or "Danger". They are all important notes for safety and must be followed in addition to International standards (ISO/IEC) and other safety regulations.OperatorWidth across flats of attachment<Operation>1. Press the SET button in measurement mode to display set values.Set value on the right side of the sub screen flashes.。
AS1系列指南手册说明书
AS1 SERIESINSTRUCTION MANUALCONTROLSOUT LED on receiver (RX)The yellow LED ON indicates the presence of the object into controlled area.POWER ON LED on receiver (RX)The green LED ON indicates the optimal device functioning.The fast blinking of the green LED indicates a critical device alignment. Please refer to “DIAGNOSTICS” paragraph for other indications.POWER ON LED on emitter (TX)The green LED ON indicates the correct device functioning.Please refer to “DIAGNOSTICS” paragraph for other indications.INSTALLATION MODEGeneral information on device positioning• Align the two receiver (RX) and emitter (TX) units, verifying that their distance is inside the device operating distance, in a parallel manner placing the sensitive sides one in front of the other, with the connectors oriented on the same side. The critical alignmentof the unit will be signalled by the fast blinking of the green receiver LED.• Mount the two receiver and emitter units on rigid supports which are not subject to strong vibrations, using specific fixing brackets and /or the holes present on the device lids.Precautions to respect when choosing and installing the device• Choose the device according to the minimum object to detect and the maximum controlled area requested.• In agro-industrial applications, the compatibility of light grid housing material and any chemical agents used in the production process has to be verified with the assistance of the DATASENSOR technical sales support department.• The AREA scan TM light grids are NOT safety devices, and so MUST NOT be used in the safety control of the machines where installed. Moreover the following points have to be considered:- Avoid installation near very intense and / or blinking light sources, in particular near to the receiver unit.- The presence of strong electromagnetic disturbances can jeopardise the correct functioning of the device. This condition has to be carefully evaluated and checked with the DATASENSOR technical sales support department;- The presence of smoke, fog and suspended dust in the working environment can reduce the device’s operating distance.- Strong and frequent temperature variations, with very low peak temperatures, can generate a thin condensation layer on the optics surfaces, compromising the correct functioning of the device.- Reflecting surfaces near the luminous beam of the AREA scan TM device (above, under or lateral) can cause passive reflections able to compromise object detection inside the controlled area.- if different devices have to be installed in adjacent areas, the emitter of one unit must not interfere with the receiver of the other unit.General information relative to object detection and measurement• For a correct object detection and / or measurement, the object has to pass completely through the controlled area. Testing the correct detection before beginning the process is suggested. The resolution is non uniform inside the entire controlled area. For example the resolution in the AS1-HR model depends on the scanning program chosen.CONNECTIONSAS1-HR AS1-SR AS1-HR AS1-SR1 – brown: +24 VDC +24 VDC 1 – brown: +24 VDC+24 VDC2 – white:SEL_RXNot used2 – white:SEL_TX Not used3 – blue: 0 V0 V3 – blue: 0 V 0 V4 – black: Switching output Switching output 4 – black:SYNC SYNCRECEIVER (RX):M12 5-pole connector5 – grey: SYNC SYNCEMITTER (TX):M12 4-pole connectorShielded cables are not foreseen in the standard connection.Ground connection of the two units is not necessary. If desired, this connection can be obtained replacing the screw provided in the packaging with the one indicated in the drawing, which blocks the lid of the connector side of each unit.The respect of the connection shown in the drawing, is necessary if ground connection of the entire system is requested.FUNCTIONING AND PERFORMANCESThe beam interruption due to the passage of an object inside the controlled area causes the closing of the switching output and the variation of the device analogue output signal. Small objects can be detected (reaching dimensions of only 0.5 mm) and with a reduced surface area.In particular:The switching output is always activated when at least one beam is obscured. The status variation is signalled by the yellow receiver LED that turns on.The device presents inputs (both on TX and Rx units) that consent the selection of the resolution and response time.Low response times correspond to worser resolutions and viceversa.The device does not require calibration; periodical checks of the resolution and / or measurement are however suggested.The blinking of the green receiver LED (stability function ) signals the critical alignment of the units and / or the functioning outside or near the maximum operating distance. In optimal conditions the LED remains on continuously.The two units are synchronised via cable (SYNC wire).Precarious connections or induced disturbances on the synchronism line can cause device malfunctioning or a temporary blocking.DIAGNOSTICSRECEIVER UNIT:Segnal StatusCauseActionONSwitching output.Presence of the object in the controlled area.OUT LEDOFFSwitching output.Controlled area free of objects.ONOptimal functioning. Fast blinkingCritical alignment of the unit or/and functioning closed to maximum operating distance.Slow blinkingWrong connections and/or malfunctioning.- Verify the output connections and any short-circuits.- Switch OFF and switch ON the device.- If condition persists, contact Datasensor.POWER ONLEDOFFDevice is not powered.- Verify the connections.- If condition persists, contact Datasensor.EMITTER UNIT:POWER ONLEDPROG. N°SEL_RXSEL_TXRESOLUTIONRESPONSE TIME (msec )1 0V or FLOAT 0V or FLOAT LOW 2.752 0V or FLOAT +24Vdc M/L3 3 +24Vdc 0V or FLOAT M/H 7.754 +24Vdc +24Vdc HIGH 8Resolution figure : the box indicated the area with highest resolutionPROGRAM 1PROGRAM 2PROGRAM 3 - 4Ideal for fast detection on entire controlled area, with low resolution.Ideal for fast detection on entire contolled area, with constant resolution onlimited area.Ideal for detection with high resolution on entirecontrolled area.DIMENSIONS 800-262-4332-------------------------------------------------------------------------------------------------------------------------------------------- DECLARATION OF CONFORMITYIDEC and DATASENSOR jointly declare under their sole responsibility that these products conform to the 2004/108/CE, 2006/95/CE Directives, and successive amendments.-------------------------------------------------------------------------------------------------------------------------------------------- IDEC and DATASENSOR reserve the right to make modifications and improvements without prior notification.826003450 Rev.00。
强直性脊柱炎致病机理和诊治进展
国家 荷兰1 德国2 挪威3 海达印第安人4
AS患病率 0.1% 0.55%
1.1-1.4% 6.1%
HLA-B27患病率 7.8% 9% 15.9% 50%
男女比例大约为2:15 * B27亚型与疾病相关
1Linden VD et al. Arthritis Rheum 1984;27:241-249 2Braun J et al. Arthritis Rheum 2005;52:4049-4050
男性 AS 患者
AS患者死亡率增高与疾病活 动度相关
与较少使用非甾体类 抗炎药物相关
提纲
强直性脊柱炎的历史回顾 强直性脊柱炎的治病机理 强直性脊柱炎的临床表现 强直性脊柱炎的诊断 强直性脊柱炎的治疗
ASAS 2009定义
34
Stage 1
Stage 2
Stage 3
背痛 MRI
背痛影像学 骶髂关节炎
Radiographic Phase 1897 - 1931
• X-ray evidence of spondylitis applied to post mortem
specimens by Beneke (1897) and Frankel (1903-4) fully delineating ankylosis
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IL-17 IL-1 IL-6 TNF-α
IL23 介导的T细胞参与了强直的致病
Nature Med 2012;18:1018
提纲
强直性脊柱炎的历史回顾 强直性脊柱炎的治病机理 强直性脊柱炎的临床表现 强直性脊柱炎的诊断 强直性脊柱炎的治疗
强直性脊柱炎患病率
26
AS患病率与HLA-B27频率基本一致 *
DataCore SANmelody与ATTO XtendSAN iSCSI initiator配置
Versions Supported9ATTO XtendSAN version 2.0 or later9SANmelody version 2.0.1 update 2 or later OverviewSANmelody™ software converts PC servers into cost-effective expansion disk servers. Their added capacity appears as additional internal drives to disk-starved servers on LANs or SANs.The ATTO Xtend SAN iSCSI initiator package for Macintosh OS X enables block storage access via existing Ethernet networks using standard network interface cards (NICs).This application note reviews one method of configuring SANmelody to allow Macintosh computers to log in and share virtual storage over an iSCSI SAN. Preliminary InformationConsult the SANmelody Configuration Guide and XtendSAN Help (included at the end of this document) for additional information. In order to configure SANmelody to work with XtendSAN, you must manually determine the iqn name for the system running XtendSAN and hand edit the Device Name in the SANmelody software so SANmelody will be able to allow XtendSAN to log in.To determine the iqn on XtendSAN, launch and configure XtendSAN on a Mac, as described in XtendSAN Help. Using the mouse, move the pointer to hover over the Mac computer name in the left panel. Write down the name exactly as displayed, includingall punctuation. Eg: iqn.1995-.attotech:macinitiator:g851199sqpr.Note: “.attotech” is common to all copies of XtendSAN. “macinitiator” has been replaced by “xtendsan” in version 2.0 or later releases.‘”g851199spqr” is the Mac serial number, found on the computer name plate.If the SANmelody server is already running, go ahead and configure XtendSAN to discover the SANmelody server IP address and make it visible. Configuration DetailsTo configure SANmelody to allow the Mac to log in: 1) Open Computer Management on theSANmelody server. Expand Storage andDataCore SANmelody.2) Click Application Servers. Click NewApplication Server. Fill in the server name and type fields. For the type, field, chooseMAC_OS. Click OK.3) Right click the new server pane and select AddChannel.4) In the Channel Name box, enter a name forthe channel, such as Beast_1. In the DeviceName box, enter the iqn exactly as obtainedfrom XtendSAN above.5) Apply the changes.6) Assign one or more virtual volumes to the newapplication server. Apply the changes.7) Now check the newly assigned virtual volumesfor a LUN 0. OS X requires sequential LUN’sstarting with LUN 0 to allow iSCSI log-in. Click the application server in the top right pane. Inthe lower right pane for each virtual volumeassigned, right click the volume name andselect Properties, then Mapping Properties.The assigned LUN and other information willbe displayed. One and only one of the virtualvolumes assigned to the application servershould be at LUN 0.8) Now, you can try to log in on the Mac. LaunchXtendSAN: From the OS X Desktop menu,click Go, Applications. Scroll down in theApplications window to the Xtend SANdirectory, and then click XtendSAN. InXtendSAN, click the computer name in the left pane, then select the name for the SANmelody server. Click Login. If the status changes to“Connected”, you are ready to go. Use OS XDisk Utility to partition and format the VirtualVolume(s). The drives will then mount to thedesktop whenever you log in to SANmelody.XtendSAN HelpWelcomeThe ATTO iSCSI initiator package for Macintosh OSX consists of an iSCSI device driver, an initiator service manager, and a management interface. The iSCSI Device Driver is responsible for moving data from the storage stack over to the network stack, from where it can be passed to and from the outside world using a standard Gigabit Ethernet network. The iSCSI initiator service monitors and controls the iSCSI configuration for the initiator. The management interface is designed to allow you the ability to configure specific protocol options and manage target devices through a graphical user interface.To Add a TargetYou must first add a target in order to manage and access it.1) From the Discovery menu, click IP Address2) Enter the IP address of the target you wish to add.Note: The default Port Number is 32603) Click Discover.4) Choose the target you wish to add and click Add.Note: Click Clear to reset the target search.To Manage TargetsAfter you have added targets, you can now manage then.1) Click Workgroup in the left panel. The ManageTargets panel will be displayed. All added targetsare shown. If the target has an alias associated with it, it will also be displayed.2) Highlight the Network Node in order to manage it.3) You can now choose whether you want the targetto be visible. If you want it to be visible, chose Yes from the Visible dropdown.4) You can also choose whether you want the targetto automatically be logged into on reboot. If youwant the target automatically logged into, chooseYes from the AutoLogin dropdown.5) Click Save to save your changes.To Manage Additional Parameters 1) While in the Manage Targets area, highlight theNetwork Node, and click Params.2) The Login Parameters dialog is displayed.3) You can modify the following parameters from here: Transfer Size:FirstBurstLength — Sets the buffer size of the transfers.MaxBurstLength — Sets the buffer size of the transfers.Transfer Control:DataPDUInOrder — Used for flow control of PDUs. DataSequenceInOrder — Used for flow control of PDUs.ImmediateData — Used for flow control of PDUs. InitialR2T — Used for flow control of PDUs. MaxOustandingR2T — Used for flow control of PDUs. MaxRecvDataSegmentLength: Initiator — How much the initiator can receive in one PDU.Note: You cannot change the parameters in Connection Control, Digest, or Error Recovery.4) Click Save to save your edits.To See Visible Targets1) Click the name of the initiator node in the left panel.The Target Status panel is displayed and all visible targets are displayed.2) Highlight the Network Name and click Login. Thestatus will turn green in the left panel on asuccessful login.3) Click the LUNs button to see all the LUNs on alltargets which have been logged into.4) Highlight the Network Name and click the Paramsbutton to see a read-only view of the NegotiatedParameters.5) Click Close to close the Negotiated Parametersdialog.To Logout of a Target1) Click the name of the initiator node in the left panel.The Target Status panel is displayed and all visible targets are displayed.2) Highlight the Network Name and click Logout. Thestatus will turn red in the left panel.Contacting ATTO TechnologyWhile we do our best to provide you all the information you will need to use our products, we recognize that additional assistance is sometime required. If you have questions about installing, using or obtaining any ofour products, you may contact us at:ATTO Technology, Inc. 155 CrossPoint Parkway Amherst, NY 14068The information you need to answer your questionsmay be available 24-hours a day on our web site (). You may also contact our support departments at the following e-mail addresses:Sales Support: ****************Technical Support: ********************* Corporate InfoATTO Technology, Inc., is a global leader in Fibre Channel and SCSI storage-infrastructure solutions for Content Creation and Enterprise environments. Since its founding in 1988, ATTO has been designing, manufacturing and marketing award-winning solutions specifically for data-intensive applications. ATTO distributes its products worldwide through original equipment manufacturers (OEMs), distributors, VARs and system integrators.Corporate Headquarters:155 CrossPoint ParkwayAmherst, New York, 14068phone: 716.691.1999fax: 716.691.9353。
STAT3信号通路在三阴性乳腺癌中的研究进展
中国细胞生物学学报 Chinese Journal of Cell Biology 2020, 42(12): 2266-2273DOI: 10.11844/cjcb.2020.12.0018STAT3信号通路在三阴性乳腺癌中的研究进展高硕I王金花i **收稿日期:2020-08-03 接受日期:2020-09-04*通讯作者。
Tel: 178****0078, E-mail: ****************Received: August 3,2020Accepted: September 4,2020♦Corresponding author. Tel: +86-1780471007& E-mail: ****************URL: /arts.asp?id=5416C 内蒙古医科大学研究生院，呼和浩特010059;2内蒙古自治区肿瘤医院病理科，呼和浩特010020)摘要 三阴性乳腺癌(triple-negative breast cancer, TNBC)是一种缺乏激素受体表达和人类表 皮生长因子受体2(human epidermal growth factor 2, HER2)基因扩增的乳腺癌亚型，不能进行激素治疗或抗HER2药物治疗，故具有易转移、复发率高、生存率低、预后差等特点，目前对TNBC 患者 的治疗依赖于常规化疗，因此亟需寻找新的治疗靶点。
已有研究表明，组成性激活的信号转导和转录活化因子3⑸gnal transducers and activators of transcription 3, STAT3)参与 了 TNBC 的发生、进 展、侵袭与转移、血管生成和耐药等过程。
此外，还发现了 STAT3的上游调控因子和下游靶 点相互作用组成的新路径。
该文旨在探讨STAT 3在TNBC 中的调控机制以及作为治疗靶点的应用前景。
关键词 三阴性乳腺癌;信号转导和转录活化因子3;信号通路Research Progress of STAT3 Signaling Pathway inTriple Negative Breast CancerGAO Shuo", WANG Jinhua"*(^Graduate School of I nner Mongolia Medical University, Hohhot 010059, China;2Department of P athology, Tumor Hospital of I nner Mongolia Autonomous Region, Hohhot 010020, China)Abstract TNBC (triple negative breast cancer), which lacks expression of hormone receptor and ampli fication the gene of HER2 (human epidermal growth factor receptor 2), is one subtype of breast cance 匚 As it can not be treated by hormone therapy or anti-HER2 drugs, it has the characteristics of easy metastasis, high recurrencerate, low survival rate and poor prognosis. At present, the treatment for TNBC patients relies on conventional che motherapy, so it is urgent to find new therapeutic targets. Studies have shown that STAT3 (signal transducers andactivators of transcription 3) may participate in the occurrence, progression, invasion and metastasis, angiogenesis and drug resistance of TNBC. In addition, a new path of interaction composed of upstream regulator and down stream target of STAT3 is found. This article aims to explore the regulatory mechanism of STAT3 in TNBC and its application prospect as a therapeutic target.Keywords triple-negative breast cancer; signal transducers and activators of transcription 3; signalingpathway乳腺癌是女性最常见的恶性肿瘤，也是导致癌 症死亡的主要原因。
我做了一项小实验改变方向的箭头英语作文
我做了一项小实验：改变方向的箭头One sunny afternoon, I found myself deeply engrossed in an experiment that promised to reveal a fascinating phenomenon: the mysterious ability to change the direction of an arrow. Curious and excited, I gathered the necessary materials - a sheet of paper, a marker, a glass of water, and a small mirror - ready to embark on this journey of scientific discovery.The experiment itself was surprisingly simple, yet the implications were profound. I began by drawing a straight arrow on the paper, pointing towards the right. Then, I placed the mirror at an angle below the arrow, creating a reflection that made the arrow appear to be pointing towards the left. This optical illusion, known as the "mirror effect," fascinated me as it showed how perception can be manipulated.Eager to further explore this phenomenon, I poured the glass of water and placed it in front of the mirror. As the sunlight filtered through the water, it cast a beam oflight onto the mirror, which in turn projected a refracted image of the arrow onto the wall behind it. This image wasnot just a reflection; it was a transformation. The arrow that had been pointing towards the left now appeared to be pointing towards the right, as if it had suddenly changed direction.I was awestruck by this unexpected turn of events. How could a simple experiment with a mirror and water have such profound effects on my perception of reality? As I pondered this question, I realized that the experiment had taught me a valuable lesson about the nature of perception andreality.The arrow, which had seemed so fixed and unchanging in my initial drawing, had undergone a remarkable transformation through the use of optical illusions and refraction. This experiment had shown me that perception is not fixed or absolute; it is fluid and subject to manipulation by external factors. The arrow's direction had not actually changed; what had changed was my perception of it.This understanding had profound implications for my understanding of the world. It reminded me that the reality we perceive is often shaped by our own biases, expectations,and the tools we use to observe it. The mirror and water had been my tools in this experiment, but in everyday life, our tools might be our senses, our language, or ourcultural backgrounds.In conclusion, this simple experiment with a changing arrow had taught me a valuable lesson about perception and reality. It had shown me that the world is not as fixed or absolute as we might believe, but is instead a dynamic and ever-changing landscape shaped by our own perception and the tools we use to navigate it. This understanding hadleft me feeling more open and curious about the world, eager to explore the mysteries of perception and reality that lie beyond the simple arrow on the paper.**我做了一项小实验：改变方向的箭头**一个阳光明媚的下午，我沉浸在一个揭示迷人现象的实验中：神秘地改变箭头的方向。
姜黄素治疗溃疡性结肠炎的研究进展
姜黄素治疗溃疡性结肠炎的研究进展朱立伟;朱达坚【摘要】溃疡性结肠炎是病因及发病机制不明的以反复炎症性病变为特征的慢性肠道疾病,目前普遍认为与免疫异常反应有关.近年来大量研究表明姜黄素具有调节免疫系统的功能,能通过多种机制干扰炎性细胞因子的表达及其信号通路的传导.姜黄素治疗溃疡性结肠炎成为研究热点,并已获得诸多基础实验与临床试验研究证据,本文就姜黄素对溃疡性结肠炎的作用进行综述.【期刊名称】《医学理论与实践》【年(卷),期】2019(032)005【总页数】3页(P657-659)【关键词】姜黄素;溃疡性结肠炎;研究进展【作者】朱立伟;朱达坚【作者单位】南方医科大学第二临床医学院,广东省广州市 510282;广东医科大学顺德妇女儿童医院(佛山市顺德区妇幼保健院);南方医科大学第二临床医学院,广东省广州市 510282;广东医科大学顺德妇女儿童医院(佛山市顺德区妇幼保健院)【正文语种】中文【中图分类】R574.62溃疡性结肠炎(Ulcerativecolitis，UC)是结肠的慢性炎性疾病，其特征在于结肠黏膜的弥漫性浅表炎症，其病变从直肠延伸至盲肠。
由于目前临床上用于治疗UC的药物(包括氨基水杨酸类制剂、糖皮质激素、免疫抑制剂及生物制剂)都是西药，疗效欠佳且不良反应多，使得UC的治疗成为一个困扰临床医生的棘手难题。
因此，寻找新的有效治疗药物成为UC研究领域的热点。
姜黄素(curcumin)是从姜黄根茎中提取的一种植物多酚，是中药姜黄的主要成分。
姜黄素作为辅助治疗诱导或维持UC缓解研究取得一定进展，本文就近年来姜黄素对溃疡性结肠炎的研究作一综述，以期为姜黄素的开发与应用研究提供参考。
1 姜黄素的概述姜黄素，是从中药姜科植物姜黄、莪术、郁金等植物的根茎中提取出的一种多酚类化合物。
姜黄素是姜黄发挥药理作用的主要活性成分，具有极其广泛的生物活性，包括抗炎、抗氧化、抗微生物、抗肿瘤、抗动脉粥样硬化、抗人类免疫缺陷病毒(HIV)、降血脂、神经保护[1]。
指路的英语作文七年级上册人教版
指路的英语作文七年级上册人教版Navigating through unfamiliar places can be both exciting and challenging, especially for seventh graders. Whether it's finding your way around a new school campus or exploring a foreign city, having some basic navigation skills can make the journey much smoother. In this article, we'll delve into the essential tips and techniques for effective navigation.Firstly, understanding directions is key. Familiarize yourself with cardinal directions: north, south, east, and west. North is towards the top of maps, while south is towards the bottom. East is to the right, and west is to the left. Knowing these directions will help you interpret maps and navigate with ease.Secondly, learn to read maps. Maps are graphical representations of geographical areas. They provide valuable information about streets, landmarks, and distances. Pay attention to the map legend, which explains symbols used on the map. Practice identifying key landmarks such as parks, rivers, and major buildings. This will help you orient yourself and navigate effectively.Thirdly, use landmarks as reference points. Landmarks are prominent features in the environment that can help you navigate. Look for distinct buildings, statues, or natural features that stand out. Use them as guideposts to orient yourself and navigate towards your destination. For example, if you're trying to find your way to a museum, you might use a tall tower nearby as a reference point.Fourthly, pay attention to street signs and addresses. Street signs provide important information about the names of streets and intersections. Learn to recognize street signs and understand how they are organized. Addresses are another crucial aspect of navigation. They typically consist of a street name and a number indicating the location along the street. Practice reading and interpreting street addresses to pinpoint locations accurately.Additionally, use technology wisely. GPS devices and smartphone apps can be valuable tools for navigation, but they should not be relied upon exclusively. Familiarize yourself with basic navigation principles so that you can navigate even when technology fails. Keep a paper map as a backup and develop your orienteering skills to navigate in any situation.In conclusion, effective navigation requires a combination of skills including understanding directions, reading maps, using landmarks, interpreting street signs, and utilizing technology. By mastering these skills, seventh graders can confidently navigate through unfamiliar places and explore the world around them. So, whether you're navigating your way through a new school or exploring a foreign city, remember these tips to stay on the right path. Happy navigating!。
哪条路能通往某地英语作文
哪条路能通往某地英语作文Which Road Leads to a Certain Place。
When we are trying to reach a certain destination, we often rely on directions or a map to guide us along the way. In life, just like in traveling, we may also need to findthe right path that leads us to where we want to go. Sometimes, it may be a physical place, such as a city or a country, but other times, it may be a goal or a dream that we are striving to achieve.There are many different roads that we can take toreach a certain place. Some roads may be long and winding, with many twists and turns along the way. These roads may require patience and perseverance, as we navigate through challenges and obstacles that stand in our path. Otherroads may be straight and smooth, allowing us to reach our destination quickly and easily. However, no matter which road we choose, it is important to stay focused and determined, and to keep moving forward towards our goal.In life, the road that leads to a certain place may not always be clear. We may encounter detours, roadblocks, or dead ends that force us to change our course. In these moments, it is important to stay flexible and open-minded, and to be willing to explore new paths and possibilities. Sometimes, the road less traveled may be the one that ultimately leads us to where we want to go.In order to find the right road that leads to a certain place, it is important to have a clear sense of direction and purpose. We must know where we want to go and why we want to get there. By setting goals and creating a plan, we can chart a course that will guide us towards our destination. Along the way, we may need to seek guidance from others, ask for help when we need it, and learn from our mistakes and failures.Ultimately, the road that leads to a certain place is the one that we choose to take. It is up to us to decide which path to follow, and to take the necessary steps to reach our destination. By staying focused, determined, andresilient, we can overcome any obstacles that stand in our way, and achieve our goals and dreams. So, the next time you are trying to reach a certain place, remember that the road you choose can make all the difference. Choose wisely, and keep moving forward towards your destination.。
back的用法和搭配
back的用法和搭配1. You know what? "Back" can be used like this: "I'll back you up." For example, when your friend is in a difficult situation and you say, "Don't worry, I'll back you up!" Isn't that so cool? It shows your support!2. Hey, have you ever heard "back out"? Like "He backed out of the deal at the last minute." Imagine someone promised something but then suddenly changed their mind and backed out, how frustrating that could be!3. "Back off" is another usage! Say there's someone bothering you and you shout, "Back off!" It means telling them to leave you alone. It's like a strong signal to make them stop.4. How about "back on track"? For instance, after some setbacks, you tell yourself, "I need to get back on track." It's like redirecting yourself to the right path, getting things back to normal, don't you think?5. Check this out! "Back home" is simple but so full of meaning. When you say "I'm going back home after work," it makes you feel that sense of comfort and familiarity. It's like a haven waiting for you.6. And don't forget "back and forth"! You see people walking back and forth when they're thinking or nervous. Like "He was pacing back and forth in the room." Isn't that a vivid picture?In conclusion, "back" has so many diverse usages and搭配 that make our language more colorful and expressive!。
关于指路的英语作文
关于指路的英语作文Hello, I'm here to help you with directions. Do you need to find a specific place? Just let me know whereyou're going and I'll guide you there.Alright, so you're heading to the shopping mall. Well, from here, you should turn left at the next intersection. You'll see a big sign for the mall on your right after a few blocks. It's pretty easy to spot.Now, if you're going to the library, it's a bit of a walk. You'll need to go straight for a while, past a few cafes and a park. Once you reach the big oak tree, take a right and follow the path. The library is right at the end of it.Oh, and if you're looking for the nearest bus stop,it's just across the street. You can catch the number 5 bus there, which will take you downtown. Just make sure to check the schedule first.And don't forget, if you get lost or need any other help, feel free to ask anyone around. Most people are happy to point you in the right direction. So don't hesitate to ask for assistance when you need it.That's all for now. Enjoy your journey and have a great day!。
磷酸酶SHP-1与消化系统肿瘤关系的研究现状
磷酸酶SHP-1与消化系统肿瘤关系的研究现状文良志;钱慧;谢渭芬【摘要】含有SH2结构域的蛋白酪氨酸磷酸酶SHP-1,属于非受体型蛋白酪氨酸磷酸酶家族,主要在造血细胞和上皮细胞中表达,是多种信号转导通路如JAK/STAT、PI3K-AKT等的负向调节因子.SHP-1在抑制淋巴瘤、白血病等肿瘤的发生及发展中起到重要作用.随着生物技术的进步及SHP-1基因突变小鼠模型被广泛应用,SHP-1在消化系统肿瘤(特别是肝癌)的发生、发展方面所起的作用也逐渐被发现.【期刊名称】《国际消化病杂志》【年(卷),期】2013(033)004【总页数】3页(P224-226)【关键词】蛋白酪氨酸磷酸酶SHP-1;消化系统肿瘤;肝癌【作者】文良志;钱慧;谢渭芬【作者单位】200003 上海,第二军医大学长征医院消化内科;200003 上海,第二军医大学长征医院消化内科;200003 上海,第二军医大学长征医院消化内科【正文语种】中文含SH2结构域的蛋白酪氨酸磷酸酶-1(SHP-1)，也被称作磷酸酪氨酸磷酸酶1C(PTP1C)、造血细胞磷酸酶(HCP)及非受体型蛋白酪氨酸磷酸酶6(PTPN6)，是含有SH2结构域的蛋白酪氨酸磷酸酶家族中的一员，属于非受体型蛋白酪氨酸磷酸酶[1]。
SHP-1主要表达于造血细胞及上皮细胞，在肝脏、脂肪组织及骨骼肌等组织中亦有表达，基础状态下主要存在于细胞质中，激活后可负向调控多种细胞内信号通路如JAK/STAT通路、PI3K-AKT通路及Toll样受体信号通路(TLR)等，参与调节细胞增殖、代谢、分化和凋亡等生物学行为[2-4]。
目前针对SHP-1蛋白功能及机制的研究主要集中于血液系统，其在炎性反应调控及血液系统肿瘤发生中的主要作用及机制已被阐明[5,6]。
近年来的研究发现，SHP-1作为抑癌因子，在消化系统肿瘤(主要是肝细胞癌)的发生发展中扮演着重要角色，并已成为多种药物治疗肝癌的分子靶点。
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Nature Reviews Urology advance online publication 11 August 2015; corrected online 18 August 2015; doi:10.1038/nrurol.2015.205PROSTATE CANCEROn the right path—Stat3 signalling controls the ARF–Mdm2–p53 tumour-suppressor pathway N ew data, published in NatureCommunications, has suggested apreviously unknown function forSTAT3 in prostate cancer tumorigenicityand metastatic progression.Pencik and colleagues have shown thatgenetic inactivation of Stat3 or IL-6 ina Pten-deficient prostate cancer mousemodel accelerates cancer progressionand leads to metastasis. The investigatorsobserved that mice with conditionalloss of Pten in the prostate epitheliumhad markedly increased prostatic Stat3expression compared with wild-type mice,along with increased phosphorylationof IL-6Rα in tumour cells. To investigatethis observation and the role of Stat3in prostate cancer formation, the teamcreated mice with concomitant prostate-epithelium-specific loss of Pten and Stat3.Mice with this double deletion showedaccelerated prostate cancer formation, with an up to sixfold increase in tumour volume compared with tumours from Pten-deficient mice, increased numbers of Ki-67 positive cells and decreased numbers of apoptotic cells. Double-deletion mice developed high-grade, poorly differentiated prostate cancer with liver and lung metastases. By contrast, Pten-deficient mice only showed local invasion into seminal vesicles and did not develop metastases.In vitro, primary cells derived from Pten-deficient tumours and treated with short-hairpin RNA to knock down Stat3 were significantly more invasive in a transwell invasion assay and also in an organotypic, physiologically relevant, 3D cancer model than their control counterparts. These cells also showed increased anchorage-independent cell growth comparedwith untreated cells.Experiments to corroborate these observations in the human prostate cancer cell line RWPE-1 showed that combined knock down of STAT3 and PTEN increased the invasiveness of thesecells. Re-expression of STAT3 in PC3prostate carcinoma cells, which naturallylack STAT3, resulted in reduced fociformation and decreased cell numbers.These observations are consistent witha tumour-suppresive role for STAT3 inprostate cancer.Loss of Stat3 and Pten in the mousemodel led to a cancer phenotype that isvery similar to that of cancer deficientin p53 and Pten. This loss of expressionresulted in downregulation of p53 andp19ARF in the prostate epithelium as wellas an increase in Mdm2 levels.These findings suggest that loss of Stat3promotes prostate cancer developmentby bypassing senescence, which isregulated by the p19ARF–p53 axis, andthat the tumour suppressive capacityof Stat3 in senescent tumour cells isreliant on the p19ARF–Mdm2–p53tumour-supressor pathway.Analysis by immunoblot andimmunohistochemistry showed a positivecorrelation between Stat3 and p19ARFand prostate tissue from Stat3-deficientmice had significantly decreased p19ARFexpression-suggesting that p19ARF couldbe a novel, directly regulated target ofStat3. In silico analysis of the p19ARFpromoter predicted two Stat3-bindingsites and chromatin immunoprecipitationshowed increased Stat3 binding tothe p19ARF promoter in Pten-deficientprimary mouse tumours.Investigation of the role of IL-6, whichis a major regulator of Stat3 that hastherapeutic relevance, in Stat3 activationrevealed that codeletion of IL-6 andPten resulted in increased tumour sizeand grade, similar to that observedStat3–Pten-deficient mice.In patients with prostate cancer, lowIL-6 tumour expression correlated with anincreased risk of biochemical recurrenceand patients with high STAT3 levels hada good prognosis. STAT3 expressioncorrelated with p14ARF expressionin 204 patient-derived samples, andcombined loss of these two proteinspredicted worse outcomes and metastaticprogression in these patients. Lower STAT3levels correlated with increased Gleasonscore and multivariate analysis showed thatp14ARF is a reliable, independent prognosticmarker for prostate cancer, with a twofoldhigher hazard ratio than Gleason score.Zoran Culig, a member of the researchteam, told Nature Reviews Urology, “Thesedata have numerous implications for thetreatment of prostate cancer. Empiricalanti-IL-6 or anti-STAT3 treatment withoutknowledge of STAT3-regulated targetsis unlikely to be successful, owing tothe tumour-suppressive role of STAT3.”He concluded “p14ARF status should beassessed before the initiation of anti-STAT3treatment, to ensure it is appropriate.”Louise StoneOriginal article Pencik, J. et al. STAT3 regulated ARFexpression supresses prostate cancer metastasis.Nat. Commun.doi:10.1038/ncomms8736iStock/Thinkstock。