E2FBP1 antagonizes the p16INK4A-Rb tumor suppressor machinery for growth suppression and cellula

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科幻小说推荐稿作文英语

When it comes to recommending science fiction novels,there are several classics and modern gems that are worth exploring.Here are some of the best science fiction novels that you might consider adding to your reading list:1.Dune by Frank Herbert:This epic novel is a mustread for any science fiction enthusiast. It tells the story of Paul Atreides,who navigates the treacherous world of politics and religion on the desert planet of Arrakis.2.Neuromancer by William Gibson:Often credited with popularizing the cyberpunk genre,this novel introduces readers to a world where artificial intelligence and virtual reality are integral parts of society.3.The Left Hand of Darkness by Ursula K.Le Guin:A thoughtprovoking exploration of gender and society,this novel follows an emissary on a mission to a planet where the inhabitants can change their gender at will.4.Snow Crash by Neal Stephenson:This novel combines elements of cyberpunk with a fastpaced narrative about a computer virus that affects both the virtual and real worlds.5.The Hitchhikers Guide to the Galaxy by Douglas Adams:A comedic take on the science fiction genre,this series follows the misadventures of an unwitting human and his alien friend as they travel through space.6.Enders Game by Orson Scott Card:A compelling story about a young boy who is trained to become a military leader in a future where Earth is at war with an alien race.7.1984by George Orwell:While not strictly science fiction,this dystopian novel is a seminal work that explores themes of totalitarianism,surveillance,and individual freedom.8.The Martian by Andy Weir:A more recent addition to the genre,this novel tells the story of an astronaut stranded on Mars,who must use his wits to survive.9.Brave New World by Aldous Huxley:Another dystopian classic,this novel presents a future society where happiness is valued above all else,often at the expense of truth and freedom.10.The ThreeBody Problem by Liu Cixin:A Chinese science fiction novel that explores the impact of contact with an alien civilization and the subsequent conflict it causes.11.Kindred by Octavia Butler:A unique blend of science fiction and historical fiction, this novel follows a black woman who is repeatedly pulled back in time to the antebellum South.12.Do Androids Dream of Electric Sheep?by Philip K.Dick:The novel that inspired the film Blade Runner,it delves into the nature of humanity and what it means to be alive in a world populated by androids.When recommending these novels,consider the readers preferences and interests.Each of these books offers a unique perspective on the future,technology,and humanitys place in the universe.Whether they prefer space operas,dystopian societies,or thoughtprovoking philosophical questions,theres a science fiction novel out there for everyone.。

细胞角蛋白与P16INK4a在宫颈癌前病变及宫颈癌中的研究进展

【键词】宫颈上皮内瘤样病变；宫颈肿瘤；角蛋白质类；Ｐ６＇关１ｒａ￣ＴｅＡｖｎｅｆｙｏｅａｉｓｎ１ｉｅｖｃｌｎｒｅｉｅａｏｌｉｎｒｉｌａｃｒＬＵＷｅ，ｈｄａｃｓｏｔｋｒｔｄＰ６ＣｎａｎＣｒｉａｔａｐｔｌｌＩｈｉＮｅｐａａａｄＣｅｖｃｎｅＩｉＱｓａＣ
一
个较长时间的过程，效的诊断和治疗ＣＮ是预防宫颈癌的最佳途径。研究认为，胞角蛋白ｌ（Ｋ１）官颈有Ｉ有细７Ｃ７是
干细胞的标记物，映了一种细胞化生由不成熟向成熟转化的现象。Ｃ８Ｃ７表达水平与宫颈上皮内瘤样病变程反Ｋ、Ｋ１
作者单位：０１２天津医科大学一中心临床学院３０９
胞骨架中间丝蛋白，今为止，迄在各种人上皮细胞中
已确定有２０种ＣＫ亚型表达。ＣＫ基因表达有很强
的规律性。细胞分化不同阶段及不同类型上皮细胞表达不同ＣＫ。在人正常宫颈上皮中存在Ｃｓ达，Ｋ表
的深入。发现ＣＮ并非是单向的病理生理学发展过Ｉ程，而是具有自然消退与发展为宫颈浸润癌的两种不同生物学行为。虽然ＣＮ有消退或逆转的可能，Ｉ但并不确定在什么样的情况下会消退或逆转。宫颈癌的形成一般要经历癌前病变的过程，因此，期诊早断ＣＮ并确定其预后转归是发现早期宫颈癌和减少Ｉ宫颈癌发生的关键。本文主要针对细胞角蛋白（ｖｃ．

JUMO 温度传感器说明书

Page 1/11Data Sheet 702040Blocks tructureFeature sk S tructured operating and programming layout k S elf-optimi s ation k Ramp functionk Timer functionk Digital input filter withprogrammable filter time con s tant k 1 limit comparator k limit s witchJUMO iTRON 04/08/16/32Compact microproce ss or controller sHou s ing for flu s h-panel mounting to DIN IEC 61554Brief de s criptionThe JUMO iTRON controller s erie s compri s e s univer s al and freely programmable com-pact in s trument s for a variety of control ta sks . It con s i s t s of five model s , with the bezel s ize s 96mm x 96mm, 96mm x 48mm in portrait and land s cape format, 48mm x 48mm and 48mm x 24mm.The controller s feature a clearly readable 7-s egment di s play which, depending on the ver-s ion, i s 10 or 20 mm high, for proce ss value and s etpoint indication or for dialog s . Only three k ey s are needed for configuration. Parameter s etting i s arranged dynamically, and after two operation-free s econd s the value i s accepted automatically. S elf-optimi s ation,which i s provided a s s tandard, e s tabli s he s the optimum controller parameter s by a k ey s tro k e. The ba s ic ver s ion al s o include s a ramp function with adju s table gradient s . A timer function ha s been integrated a s an extra.All controller s can be employed a s s ingle-s etpoint controller s with a limit comparator, or as double-s etpoint controller s . The lineari s ation s of the u s ual tran s ducer s are stored. Pro-tection i s IP66 at the front and IP20 at the bac k . The electrical connection i s by a plug-in connector with s crew terminal s .The input s and output s are s hown in the bloc k s tructure below.JUMO iTRON 08Type 702042JUMO iTRON 04Type 702044JUMO iTRON 08Type 702043JUMO iTRON 32Type 702040JUMO iTRON 16Type 702041Approval s /approval mark s (s ee "Technical data")Data Sheet 702040Page 2/11Technical dataThermocouple inputRe s i s tance thermometer inputStandard s ignal inputMea s urement circuit monitoring 1De s ignation Range 1Mea s urement accuracy Ambienttemperature error Fe-Con L Fe-Con J EN 60584Cu-Con U Cu-Con T EN 60584NiCr-Ni K EN 60584NiCr S i-Ni S i N EN 60584Pt10Rh-Pt S EN 60584Pt13Rh-Pt R EN 60584Pt30Rh-Pt6Rh BEN 60584-200to +900°C -200to +1200°C -200to +600°C -200to +400°C -200to +1372°C -100to +1300°C0— 1768°C 0—1768°C +300— 1820°C≤0.4%≤0.4%≤0.4%≤0.4%≤0.4%≤0.4%≤0.4%≤0.4%≤0.4%100 ppm/°C 100 ppm/°C 100 ppm/°C 100 ppm/°C 100 ppm/°C 100 ppm/°C 100 ppm/°C 100 ppm/°C 100 ppm/°CCold junctionPt 100 internal1. The s e range s refer to the ambient temperature of 20°CDe s ignation Connection type RangeMea s urement accuracy Ambienttemperature error Pt 100 EN 607512-/3-wire -200to +850°C ≤0.1%50 ppm/°C Pt 1000 EN 607512-/3-wire -200to +850°C ≤0.1%50 ppm/°C K TY11-62-wire-50to +150°C≤1.0%50 ppm/°CS en s or lead re s i s tance 20Ω max. per lead for 2- and 3-wire circuitMea s urement current 250µALead compen s ationNot required for 3-wire circuit. For 2-wire circuit, lead compen s ation can be implemented in s oftware through proce ss value correction.De s ignation RangeMea s urement accuracy Ambienttemperature error Voltage0—10V , input re s i s tance R E > 100k Ω2—10V , input re s i s tance R E > 100k Ω0—1V , input re s i s tance R E > 10M Ω10,2—1V , input re s i s tance R E > 10M Ω1≤0.1%≤0.1%≤0.1%≤0.1%100 ppm/°C 100 ppm/°C 100 ppm/°C 100 ppm/°C Current4—20mA, voltage drop 3V max.0—20mA, voltage drop 3V max.≤0.1%≤0.1%100 ppm/°C 100 ppm/°C1. for Type 702040/41 with 2 relay output s (option)Tran s ducer Overrange/underrangeProbe /lead s hort-circuit 1Probe/lead breakThermocouple•-•Re s i s tance thermometer •••Voltage 2—10V / 0.2—1V0—10V/ 0—1V •••-•-Current4—20mA 0—20mA•••-•-1. In the event of a fault, the output s move to a defined s tatu s (configurable).= factory s etting •recogni s ed-not recogni s edData Sheet 702040Page 3/11Output sControllerTimerElectrical dataHou s ingA ss ignment Type 702040/41Type 702042/43/44Output 1relayrelay Output 2logic 0/5V or logic input logic 0/5V Output 2 (option)logic 0/12V or logic input logic 0/12V Output 2 (option)relay not po ss ible Output 3not availablerelayTechnical data Relay ratingcontact life n.o. (ma k e) contact 3A at 250VAC re s i s tive load 150 000 operation s at rated loadLogiccurrent limiting load re s i s tance 0/5V 20mAR load 250Ω min .Logiccurrent limiting load re s i s tance 0/12V 20mAR load 600Ω min.= factory s ettingController types ingle-s etpoint controller with limit comparator, double-s etpoint controllerController s tructure s P/PD/PI/PIDA/D converter re s olution better than 15 bitS ampling time210m s ec/250m s ec with activated timer functionAccuracy0.7% ± 10ppm/°CS upply (s witch-mode power s upply)110—240V -15/+10%AC 48—63Hz, or 20—30V AC/DC 48—63Hz, or10—18V DC (Connection to S ELV or PELV)Te s t voltage s (type te s t)to EN 61010, Part 1, March 1994,overvoltage category II, pollution degree 2, for Type 702040/41overvoltage category III, pollution degree 2, for Type 702042/43/44Power con s umption max. 7VA Data bac k upEEPROMElectrical connectionat the rear, via plug-in s crew terminal s ,conductor cro ss -s ection up to 1.5mm 2 (1.0mm 2 for Type 702040/41) or2x 1.5mm 2 (1.0mm 2 for Type 702040/41) with ferrule sElectromagnetic compatibility interference emi ss ion interference immunity EN 61 326Cla ss Bto indu s trial requirement sS afety regulationto EN 61010-1In s tallation height maximum 2000 m above s ea levelCa s e typePla s tic ca s e for panel mounting acc to. IEC 61554 (indoor u s e)Dimen s ion s in mm (for Type)702040702041702042702043702044Bezel s ize48x 2448x 4848x 96(portrait)96x 48(land s cape)96x 96Depth behind panel100100707070Panel cut-out45+0.6x 22.2+0.345+0.6x 45+0.645+0.6x 92+0.892+0.8x 45+0.692+0.8x 92+0.8Ambient/s torage temperature range 0—55°C /-40 to +70°CData Sheet 702040Page 4/11Approval s /approval mark sDi s play and control sSelf-optimi s ation (SO)The s tandard s elf-optimi s ation facility produce s an automatic adju s tment of the controller to the proce ss .S elf-optimi s ation determine s the controller parameter s for PI and PID controller s (proportional band, re s et time, derivative time), a s well a s the cycle time and the filter time con s tant of the digital input filter.Ramp functionClimatic condition s not exceeding 75% rel. humidity, no conden s ationOperating po s ition unre s tricted Protection to EN 60529,IP66 at the front, IP20 at the bac kWeight75g approx.95g approx.145g approx.160g approx.200g approx.Approval mark Te s ting agencyCertificate/certification numberIn s pection ba s i sValid forUL Underwriter Laboratorie s E201387UL 61010-1all device s C S A C S A-Approval232831CAN/C S A-C22.2No. 61010.1-04all device sData Sheet 702040Page 5/11Limit comparatorLimit s witch (extra code)If the limit comparator function i s active, then the s witched s tate will have to be re s et by hand.Precondition: the condition that cau s ed the alarm i s no longer pre s ent (for l k 8: proce ss value < AL). The di s play s how s the alarm s tatu s .The alarm s tatu s will be retained after a power failure.Timer function (extra code)U s ing the timer function, the control action can be influenced by mean s of the adju s table time t i 0. After the timer ha s been s tarted by power ON, by pre ss ing the k ey or via the logic input, the timer s tart value t i 0 i s counted down to 0, either in s tantly or after the proce ss value ha s gone above or below a programmable tolerance limit. When the timer ha s run down, s everal event s are triggered, s uch a s control s witch-off (output 0%) and s etpoint s witching. Furthermore, it i s po ss ible to implement timer s ignalling during or after the timer count, via an output.The timer function can be u s ed in conjunction with the ramp function and s etpoint s witching.Table: Timer function s (u s ing the example of a rever s ed s ingle-s etpoint controller)Data Sheet 702040Page 6/11Tolerance limitThe po s ition of the tolerance limit depend s on the controller type:- S ingle-s etpoint controller (rever s ed, heating): Tolerance limit i s below the s etpoint - S ingle-s etpoint controller (direct, cooling): Tolerance limit i s above the s etpoint - Double-s etpoint controller: Tolerance limit i s below the s etpointIf, during the control proce ss , the proce ss value goe s above/below the tolerance limit, then the timer will be s topped for the duration of the infringement.Di s play and operationThe timer value i s di s played at the operating level and remain s s o permanently (no time-out).Operation i s from the k eypad, when the timer value i s vi s ible in the di s play, or via the logic input. The operating option s compri s e s tart,s top, continue and cancel timer function, and are s hown differently in the di s play.The current timer value and the timer s tart value are acce ss ible and adju s table at any time at a s eparate timer level.Data Sheet 702040Page 7/11Parameter and configurationOperating levelParameter levelConfiguration levelDe s ignation Di s play Factory s ettingValue range S etpointSP /SP1/SP20S PL—S PH Ramp s etpointSPr 0S PL—S PH Timer value/timer s tart valuet i /t i 00 —999.9hDe s ignation Di s play Factory s ettingValue range S etpoint 1SP 10S PL—S PH S etpoint 2SP 20S PL—S PH Limit value for limit comparator AL 0-1999to +9999digit Proportional band 1Pb:100—9999digit Proportional band 2Pb:200—9999digit Derivative time dt 80s ec 0—9999s ec Re s et time rt 350s ec 0—9999s ec Cycle time 1CY 120.0s ec 1.0—999.9s ec Cycle time 2CY 220.0s ec1.0—999.9s ec Contact s pacingdb 00—1000digit Differential (hy s tere s i s ) 1HYS.110—9999digit Differential (hy s tere s i s ) 2HYS.210—9999digit Wor k ing point Y:00%-100to +100%Maximum output Y:1100%0to 100%Minimum output Y:2-100%-100to +100%Filter time con s tant dF 0.6s ec 0.0—100.0s ec Ramp s loperASd—999digitDe s ignation Di s play Factory s etting Value range/s electionTran s ducerC111Pt100Pt100, Pt1000, K TY11-6, T, J, U, L, K , S ,R, B, N, 0 (4)—20mA, 0 (2)—10VDecimal place/unitC112none/°C none, one, two/°C, FController type/output s C113s ee table on next pageLimit comparator function C114no function no function, l k 1—8Ramp functionC115no function no function, °C/min, °C/h Output s ignal on overrange/ underrange C1160% output limit comparator off 0%, 100%, -100% limit comparator on/offLogic inputC117no function k ey / level inhibit,ramp s top, s etpoint s witchingOutput s 1, 2 and 3(only Type 702042/43/44)C118function s a s defined under C113freely configurable(s ee table on next page)Timer functionC120no function s ee de s cription “Timer function”S tart condition for timerC121from k eypad/logic input - power ON - k eypad/logic input- tolerance limitTimer s ignalling C122no function - timer s tart to timer run-down- after run-down for 10s ec - after run-down for 1 min.- after run-down until ac k nowledgementUnit of time (timer)C123mm.ss - mm.ss- hh.mm - hhh.hS tart value of value range SCL0-1999 to +9999 digitData Sheet 702040Page 8/11Controller type/output s (C 113)Expanded configuration option s for the output s on Type 702043/44 (C118)End value of value range SCH 100-1999 to +9999 digit Lower s etpoint limit SPL -200-1999 to +9999 digit Upper s epoint limitSPH 850-1999 to +9999 digit Proce ss value correction OFFS 0-1999 to +9999 digit Differential (hy s tere s i s )HySt 1 0—9999 digitController typeOutput 1Output 2 + 3S ingle s etpoint rever s ed controller limit comparator/timer s ignalling S ingle s etpoint direct controllerlimit comparator/timer s ignallingDouble s etpointcontroller rever s edcontroller direct S ingle s etpoint rever s ed limit comparator/timer s ignalling controller S ingle s etpoint direct limit comparator/timer s ignallingcontrollerDouble s etpoint controller directcontroller rever s ed= factory s ettingOutput 1: Relay (K1)Output 2: Logic (K2)Output 3: Relay 1-s e t p o i n t c o n t r o l l e rFunction s of the output s a s defined under C 113controller output limit comparator timer s ignalling controller output timer s ignalling limit comparator limit comparator controller output timer s ignalling limit comparator timer s ignalling controller output timer s ignalling controller output limit comparator timer s ignalling limit comparator controller output 2-s e t p t .c o n t r o l l e rcontroller output 1controller output 2limit comparator/timer controller output 1limit comparator/timer controller output 2controller output 2controller output 1limit comparator/timer controller output 2limit comparator/timer controller output 1limit comparator/timer controller output 1controller output 2limit comparator/timercontroller output 2controller output 1Data Sheet 702040Page 9/11Dimen s ion sType 702040 / …Type 702043/...Type 702041 / …Type 702044/...Type 702042 / …Typehorizontal vertical 70.2040/418mm min.8mm min.70.2042/43/4410mm min.10mm min.Edge-to-edge mounting(minimum s pacing s of the panel cut-out s)Data Sheet 702040Page 10/11Connection diagram sJUMO iTRON 32, Type 702040, 48mm x 24mm format JUMO iTRON 16, Type 702041, 48mm x 48mm formatJUMO iTRON 08, Type 702042, 48mm x 96mm format (portrait)JUMO iTRON 08, Type 702043. 96mm x 48mm format (land s cape)JUMO iTRON 04, Type 702044, 96mm x 96mm formatStandard ver s ion / Ver s ion with 12V logic outputVer s ion with 2 relay outputs2014-09-01/00357838Data Sheet 702040Page 11/11Order detail sExtra order code s for cu s tomized configuration(2)Ba s ic type exten s ion(3)Input s(1)(2)(3)(4)(5)(6)Type de s ignation 7020../..-...-...-../...,...** Li s t extra code s in s equence, s eparated by comma s(1)Ba s ic type(bezel s ize in mm)40=48x 24, 41 = 48x 48, 42 = 48x 96 (portrait), 43 = 96x 48 (land s cape), 44 = 96x 96(2)Ba s ic typeexten s ion 8899==controller type configurable 1controller type configured to cu s tomer s pecification 2(3)Input s 888999==input s configurable 1input s configured to cu s tomer s pecification 2(4)Output s000=S tandardType 702040/41Type 702042/43/44Output 1relay (n.o. ma k e)relay (n.o. ma k e)Output 2logic 0/5V , optionally configurable a s logic input logic 0/5V Output 3not available relay (n.o. ma k e)Option sType 702040/41Type 702042/43/44113=Output 2(output s 1+3 a s for S tandard)logic 0/12V , optionally configurable a s logic input logic 0/12V 101=Output 2(output 1 a s for S tandard)relay (n.o. ma k e)(logic input i s alway s available)not po ss ible(5)Supply162523===10—18V DC20—30V AC/DC 48—63Hz110—240V AC -15/+10% 48—63Hz (6)Extra code069=UL and C S A approval 210=Timer function220=Timer function + limit s witch 3Delivery package ex-factory for Type 702040/41Type 702042/43/441 mounting frame2 mounting brac k et s1 s eal, 1 Operating In s truction s 70.20401. s ingle-s etpoint with limit comparator, s ee factory s etting s under configuration and parameter level2. s ee extra order code s (below) or factory s etting s under configuration and parameter level3. The linearization s for K TY11-6 and thermocouple B have been deletedController typeOutput 1Output 2 and 310=s ingle s etpoint rever s ed 1controller limit comparator/timer s ignalling 11=s ingle s etpoint direct 2controllerlimit comparator/timer s ignalling 30=double s etpoint controller rever s edcontroller direct 20=s ingle s etpoint rever s ed 1limit comparator/timer s ignalling controller 21=s ingle s etpoint direct 2limit comparator/timer s ignalling controller33=double s etpointcontroller directcontroller rever s ed1. controller output i s active when proce ss value i s below s etpoint, e. g. heating2. controller output i s active when proce ss value i s above s etpoint, e. g. cooling001=Pt1003-wire 040=Fe-Con J 045=Pt13 Rh-Pt R 063=0—10V 003=Pt1002-wire041=Cu-Con U 046=Pt30 Rh-PtRh B 071=2—10V 005=Pt1000 2-wire 042=Fe-Con L 048=NiCr S i-Ni S i N601=K TY11-6 (PTC)006=Pt1000 3-wire 043=NiCr-Ni K 052=0—20mA 039=Cu-Con T044=Pt10Rh-PtS053=4—20mA= factory-s et。

人乳头状瘤病毒、p16 INK4A在宫颈鳞状上皮病变中的意义

ＰｅｋｉｎｇＵｎｉｖｅｒｓｉｔｙＨｅａｌｔｈＳｃｉｅｎｃｅＣｅｎｔｅｒ，Ｂｅｉｊｉｎｇ１０００８０，Ｃｈｉｎａ）
Ａｂｓｔｒａｃｔ：ＯｂｊｅｃｔｉｖｅＴｏｅｘｐｌｏｒｅｔｈｅｃｌｉｎｉｃｏｐａｔｈｏｌｏｇｉｃｓｉｇｎｉｆｉｃａｎｃｅｏｆｔｈｅｄｉｆｅｒｅｎｔｓｕｂｔｙｐｅｏｆＨＰＶ，ｐ１６，ｐ５３，Ｋｉ一６７ａｎｄ
６４．６７％（１１９１１８４）；ＨＰＶ１６／１８ｗａｓｍｏｓｔｌｙｄｅｔｅｃｔｅｄｉｎｔｈｅｇｒｏｕｐｓｏｆｃｅｒｖｉｃａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａａｎｄＣＩＮ，ｅｓｐｅｃｉａｌｌｙｉｎＣＩＮ１１ＩａｎｄＣＩＮⅡ ｓｕｂｇｒｏｕｐｓ；ＨＰＶ３１／３３ＷａｓｄｅｔｅｃｔｅｄｄｏｍｉｎａｎｔｌｙｉｎｇｒｏｕｐＣＩＮｌ：ＴｈｅｐｏｓｉｔｉｖｅｒａｔｅｏｆＨＰＶ６／ｌ１ｗａｓｈｉｇｈｅｓｔｉｎｔｈｅ
（１．海淀 Ⅸ妇幼保健院病理科，北京１０００８０；２北京大学医学部病理学系，北京１０００８０）
［摘要］目的探讨人乳头状瘤病毒的不同亚型及ｐ１６ｐ５３、Ｋｉ一６７、ＥＲ在不同程度宫颈鳞状上皮病变中的表达及临床病理意义。方法采用原位杂交及免疫组化方法，检测人乳头状瘤病毒的不同亚型，ｐ１６、ｐ５３、Ｋｉ一６７及ＥＲ在２０４例不同程度宫颈病变组织中的表达情况。结果ＨＰＶ在不同程度宫颈病变中总检出率为６４．６７％（１１９／１８４）；在宫颈鳞癌、ＣＩＮ组中检出最多的感染类型为ＨＰＶ１６／１８，尤其在ＣＩＮＨＩ、ＣＩＮⅡ组中阳性表达率较高；ＨＰＶ３１／３３主要在ＣＩＮＩ病变中表达；而ＨＰＶ６／１１在尖锐湿疣组检出率最高。随着宫颈病变严重程度的增加，ｐ１６、ｐ５３和

心理发展的主要理论和流派

器官缺陷、被娇纵、被忽略。当个人面对他无法适当应付的问题时，他表示他绝对无法解决这个问题时，便是自卑情结。
13
3 父母对人格发展的影响与弗洛伊德一样，阿德勒也认为出生后的头几
年对人成年后人格的形成非常重要，但是其还强调父母在这一过程中的作用。（1）过多的关注，造成溺爱危险，缺乏独立性，引起更强的自卑。 (2)忽视，会造成儿童长大后变得冷漠多疑。
phallic stage:小突起，性蕾期开始产生恋母（男孩）恋父（女孩）情结→自居作
用→“超我”开始发展
自居作用：儿童克服俄底浦斯情结的三种心理机制之一，原指幼童由于惧怕双亲中与自己同性的一方，而努力使自己成为双亲中同性的那样，以他们自居，从而获得替代性满足的现象。
④潜伏期（6－11、12岁）latent stage 机体发展进入相当恬静时期，快乐来自外界
二、新精神分析学派
代表人物：埃里克森（Eric Erikson,1902-1994）
（一）基本观点
人格发展渐成说
1、既强调生物学的影响，同时也强调文化、社会因素
2、强调自我的主导和整合作用 3、每个人的成长都体验着一定顺序的生物、
心理和社会事件，所以人格发展也是按一定的成熟程度分阶段向前发展。由于这个发展过程是以自我为主导、将个人内心生活与社会任务结合起来的过程，所以又称为心理－社会发展理论（Psychosocial Development）。
小阿尔伯特实验
4、具有丰富的儿童教育思想（教育万能论） ①反对统一标准，提倡个别对待 ②反对体罚儿童 ③要求注意在教育中培养儿童的各种习惯 ④强调对幼儿进行正确的护理 ⑤提倡对儿童青少年施行正确的性教育
二、新行为主义
代表人物: 斯金纳（B.F.Skinner， 1904-1990）

保修说明书英文

‎‎‎‎保修说明书‎英文‎ Th‎e fol‎l owin‎g exc‎e rpt ‎f rom ‎t he o‎r igin‎a l ra‎n dom,‎and ‎c onve‎r ted ‎t o pl‎a in t‎e xt, ‎d o no‎trep‎r esen‎t the‎full‎cont‎e nt, ‎f or r‎e fere‎n ce o‎n ly. ‎售后服务承‎诺书 Af‎t er s‎a le s‎e rvic‎eund‎e rtak‎i ng 浙‎江新天地家‎私秉持“全‎方位、高品‎质、快速度‎”的服务标‎准，以客户‎满意为目标‎，谨此公开‎承诺。

‎ Zh‎e jian‎g new‎worl‎d fur‎n itur‎e uph‎o ld t‎h e pr‎i ncip‎l e of‎a fu‎l l ra‎n ge, ‎h igh ‎q uali‎t y, f‎a sts‎e rvic‎e sta‎n dard‎s, cu‎s tome‎r sat‎i sfac‎t ion ‎a s th‎e goa‎l, to‎the ‎p ubli‎c mit‎m ent.‎‎一、服‎务承诺 O‎n e, s‎e rvic‎e mit‎m ent ‎1．我公司‎组建了一批‎强硬的应急‎维修服务队‎，有经验丰‎富的现场工‎程师和高级‎技师，对出‎现的任何问‎题都能在最‎快的时间内‎赶到现场，‎进行维修和‎更换。

‎ 1,‎our ‎p any ‎h as s‎e t up‎a nu‎m ber ‎o f to‎u gh e‎m erge‎n cy s‎e rvic‎e tea‎m, on‎-site‎expe‎r ienc‎e d en‎g inee‎r s an‎d sen‎i or t‎e chni‎c ians‎, arr‎i ved ‎o n th‎e sce‎n e in‎the ‎f aste‎s t ti‎m e fo‎r any‎prob‎l ems,‎main‎t enan‎c e an‎d rep‎l acem‎e nt. ‎2．产品交‎付一周内，‎我公司售后‎服务部的工‎作人员会根‎据客户的联‎系方式，进‎行电话跟踪‎咨询，直到‎客户满意为‎止。

p16 INK4a在宫颈细胞学鳞状上皮内瘤变中的意义

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意颈细胞学鳞状上皮内瘤变在宫
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PANDO 家用电器产品说明书

Modelo E-237PANDOOPTIMIZA SUS PROCESOS GRACIAS A SU APUESTA POR LAFABRICACIÓN INTELIGENTE CON SOLIDWORKSSituada en Argentona (Barcelona) con casi 40 años de experiencia, INOXPAN es reconocida en el mercado bajo la marca PANDO por su extensa experiencia en el diseño, fabricación y comercialización de campanas extractoras de cocina , hornos, placas de gas e inducción y vinotecas, para uso doméstico.niciaron su andadura en España en el año 1979, siempre como artesanos especialistas en la transformación del acero inoxidable. Al poco tiempo, se implantaron en mercados exteriores, como Francia y Portugal, donde su presencia está consolidada desde hace ya muchos años como el referente en productos de marca premium del sector y también en otros países de Europa como I nglaterra, Alemania, Bélgica y Holanda. Recientemente han conseguido posicionarse en el mercado latinoamericano y ahora se encuentran en la conquista de Estados Unidos.INNOVACIÓN CONSTANTEEl trabajo continuo, con fabricación propia y con un amplio departamento de I+D+i, llevaron a PANDO a convertirse en líder absoluto en el mercado español en el canal “Tienda estudio de cocina”; siendo éste su cliente principal, junto con arquitectos, decoradores-interioristas y diseñadores, que ven en PANDO como el único fabricante capaz de dar solución a todas sus necesidades.Una marca con un fuerte compromiso con sus orígenes y con la necesidad de aumentar el prestigio que ha conseguido gracias al trabajo de todo el equipo que la impulsa.Se esfuerzan cada día para ser mejores y para que sus campanas de cocina sean las más eficientes a nivel de extracción, ruido, tratamiento de los humos y consumo energético. Integran los mejores motores ECO del mercado y los sistemas de iluminación LED en prácticamente la totalidad de las campanas que fabrican para seguir siendo líderes en calidad frente a las empresas de su competencia en el sector. “Nuestro amplio portfolio y la posibilidad de ofrecer soluciones a medida a nuestros clientes, sumado a la calidad de todos los componentes, son nuestros principales puntos fuertes y han hecho que nos convirtamos en el N.º 1 en proveedores de campanas extractoras” comenta Sergio Seña, Director de compras de PANDO.SOLIDWORKS COMO SOLUCIÓN DEFINITIVAEn su búsqueda permanente de eficiencia e i nnovación, PANDO necesitó reestructurar sus procesos y ser competitivo en el sector, por ello en 2008 decidió incorporar las soluciones de diseño de SOLI DWORKS. Tras unos años trabajando en un entorno 3D más productivo, resolvieron en 2015 ampliar su eficacia e i mplantaron S OL DWORKS P DM P rofessional y SOL I DWORKS Composer con el objetivo de agilizar el desarrollo de sus productos, enriquecer la comunicación con sus proveedores, quienes disponían de la tecnología SOLIDWORKS para sus desarrollos, y mejorar la presentación de sus productos previos a la fabricación.Durante este proceso, CIMWORKS cómo su distribuidor oficial, apoyó la evaluación de las soluciones y brindó la formación y asesoramiento necesario, que hicieron determinante la toma de decisión y llevar a cabo la ampliación de la tecnología SOLI DWORKS en PANDO. Además, tras la implantación de las herramientas, contaron con una formación especializada que ha permitido una mejora constante de los procesos productivos dentro de la organización.LA IMPORTANCIA DEL CONTROL DE DATOSCon SOLI DWORKS PDM Professional, han logrado tener un mayor control de la información de los proyectos, permitiendo reutilizar los diseños gestionar todo el proceso de desarrollo de sus productos en un menor tiempo, optimizando los flujos de trabajo y mejorando notablemente la gestión de la documentación técnica. Ahora en PANDO el control de la información de cada documento agiliza la creación de nuevos proyectos, permitiendo la estandarización de productos de serie nuevos. También han conseguido ahorrar tiempo, ya queReto:Desarrollar productos de forma ágil y condatos precisos, gestionar y controlar los datosde los proyectos y mejorar su presencia en la presentación de productosSolución:Implantar el software de diseño SOLIDWORKS, de gestión de datos de producto SOLIDWORKS PDM Professional y de desarrollo de documentación gráfica SOLIDWORKS Composer.Beneficios:•Se ganó control en los datos, mejorando la optimización de los recursos y aumentando la agilidad para realizar cambios y personalizar productos.•Se agilizó la búsqueda de datos y archivos relacionados con otros proyectos•Se agilizó en un 30% la producción de documentación técnica, reduciendo el tiempo de salida al mercado de sus productos•Se mejoró estéticamente la presentación desus productos ganando presencia frente a susclientes potenciales“D esd e qu e h e mose ntrado e n e l mundoSOLIDWORKS si e mpr eque re mos ir ampliandolas herramientas de la suite. El mercadote re quie re cada ve z más datos, máspre se ncia y con e stas solucione s lohe mos conse guido.”antes la gestión de las referencias y de todas las versiones se realizaba de forma manual.El fácil acceso a archivos ordenados les proporciona una idea fiable y sólida para trabajar en cualquier proyecto. La trazabilidad de los datos y la adecuada estructura de éstos, les han ayudado a reducir al mínimo el número de errores y a agilizar el proceso de fabricación de sus productos. Así mismo, la comunicación fluye entre departamentos y se potencia la visibilidad de los datos, lo que repercute directamente en el aumento de agilidad para responder a las demandas de los clientes.DOCUMENTACIÓN TÉCNICA DE CALIDADLa creación de la documentación solía ser un paso por separado que tenía lugar después del diseño de productos, provocando retrasos y trabajo extra, mientras que ahora gracias a SOL DWORKS Composer, es un proceso que se realiza simultáneamente, lo que ha permitido que PANDO reduzca hasta en un 30% el tiempo de salida al mercado de sus productos y ha mejorado la estética de sus documentos técnicos, consiguiendo la presencia que requerían.“Ahora tenemos la documentación más rápido y bien organizada, pudiendo implicar no solo a la oficina técnica sino a otros departamentos. Hoy en día presentar a un cliente un plano en 2D se considera obsoleto”remarca Sergio Señ seguridad que proporcionan las herramientas de SOL I DWORKS ha hecho que se agilicen los procesos permitiendo a PANDO tener la oportunidad de innovar en sus productos y desarrollar nuevas líneas de negocio con el propósito de alcanzar sus objetivos de mercado. Actualmente, utilizan las herramientas SOLIDWORKS un total de 5 personas: 2 en el área de diseño, 1 persona para la gestión de datos en el área de calidad, el responsable técnico y el director de producción.El siguiente paso es potenciar la oficina técnica, tanto para desarrollo de producto nuevo, como producto especial, utilizando el potencial de SOL DWORKS para el desarrollo de los proyectos. También impulsar en más departamentos, el uso de la documentación gráfica como vídeos o manuales interactivos, utilizando los diseños 3D para la presentación de producto y además tener la posibilidad de validar los diseños y poder disponer de los datos de simulación del comportamiento de las campanas a nivel de fluodinámica, aspiración, etc.La documentación técnica de calidad generada con SOLIDWORKS Composer ha cobrado un importante papel en el posicionamiento de PANDO como líder indiscutible del sectorCampanas extractoras de cocina , hornos, placas de 50Argentona (Bancelona) - España www.pando.es CIMWORKSLa plataforma 3DEXPERIENCE impulsa nue stras aplicacione s y ofre ce un e xte nso portfolio de experiencias que dan solución a 12 industrias diferentes.Dassault Systèmes, la compañía de 3DEXPERIENCE®, suministra a empresas y usuarios universos virtuales en los que pueden dar rienda suelta a su imaginación para crear diseños innovadores y sostenibles. Sus soluciones, líderes mundiales, transforman las fases de diseño, producción y asistencia de todo tipo de productos. Las soluciones de colaboración de Dassault Systèmes fomentan la innovación social, lo que amplía las posibilidades de que el mundo virtual mejore el mundo real. El grupo aporta un gran valor a más de 220 000 clientes de todos los tamaños y sectores en más de 140 países. Si desea obtener más información, visite /es.Europe/Middle East/Africa Dassault Systèmes10, rue Marcel Dassault CS 4050178946 Vélizy-Villacoublay Cedex France AmericasDassault Systèmes 175 Wyman StreetWaltham, Massachusetts 02451-1223USA Asia-PacificDassault Systèmes K.K.ThinkPark Tower2-1-1 Osaki, Shinagawa-ku,Tokyo 141-6020Japan。

IDEXX 4Dx

Screening for vector-borne disease IDEXX 4Dx® Plus Test clinical reference guideWith the IDEXX 4Dx ® Plus T est, a positive result can also be an indication of ticks and and the pathogens they carry. Know more with every resultdetect antibodies to these pathogens When you use the IDEXX 4Dx Plus T est as a screening tool, you maycarried by these ticks Anaplasmaphagocytophilum Borrelia burgdorferi (Lyme disease)Ehrlichia ewingiiEhrlichia canis Anaplasma platysBabesia spp.Rocky Mountain spotted feverEhrlichia chaffeensis TularemiaRocky Mountain spotted fever STARIBartonella spp.Babesia spp.Ehrlichia canis Brown dog tickRhipicephalus sanguineusAmerican dog tickDermacentor variabilisBlack-legged tick (deer tick)Ixodes scapularis Ixodes pacificusLone star tickAmblyomma americanumRocky Mountain spotted fever TularemiaGeographic tickdistribution as of 20213that may also transmit other pathogens and infections to dogs and peopleLyme diseasebacterium Borrelia burgdorferi cases that have mild to severe disease.* S erology is typically used to diagnose Lyme disease. B. burgdorferi Did you know?•D ogs testing positive for antibodies to the C 6 peptide had 43% increased risk of having chronic kidney disease (CKD) compared to seronegative dogs.4• T he C 6 peptide used in the IDEXX 4Dx ® Plus Test and Lyme Quant C 6® Antibody Test does not cross-react with the antibody response to commercially available Lyme vaccines.5 • D ogs with seroreactivity to both B. burgdorferi and Anaplasma phagocytophilum may have two times the risk of developing clinical illness than singularly infected dogs.2Borrelia burgdorferiPrimary vectorsIxodes scapularis or Ixodes pacificus Black-legged tick (deer tick)Pathology• Localizes in tissues of infected dogs • Synovitis (may be subclinical) • Lyme nephritisClinical presentationChronic infection with clinical signs that may present acutely:• Fever, anorexia• Polyarthritis, lameness• Rapidly progressive renal failure • Neurologic syndromesLaboratory abnormalities• Elevated C 6 antibody level ≥ 30 U/mL • May have proteinuria• M ay have IDEXX SDMA ® T est result > 14 µg/dLCKD monitoring• Chemistry panel with SDMA – R ecommended to evaluate forthe development of protein-losing kidney disease• Urinalysis with Reflex UPC – R ecommended to evaluate forproteinuria • CBC with blood film evaluation – R ecommended as part of aminimum databaseHeartworm diseaseDirofilaria immitis, the causative agent of heartworm disease, is transmitted when mosquitoes infected with D. immitis larvae feed on (or bite) a healthy dog. Heartworm disease has subtle or mild clinical signs in the early stages, making preventive measures so much more important—especially as advanced infection may result in death.Did you know?•D espite availability of monthly preventives, prevalence rates of canine heartworm have remained consistent nationwide.7•T he American Heartworm Society (AHS) and the Companion Animal Parasite Council (CAPC) recommend testing all dogs for both antigen and microfilariae annually.7,8•F or more information and current recommendations on treating canine heartworm disease, goto or . Dirofilaria immitisPrimary vectorMosquitoPathologyInfective larvae (L3) mature to adult worms in the heart and pulmonary arteriesClinical presentation Asymptomatic at first, later developing:• Mild, persistent cough• Lethargy• Exercise intolerance• Reduced appetite• Weight lossLaboratory abnormalities that may be seen • Eosinophilia• Azotemia• Increased liver enzymes• ProteinuriaAnaplasmaphagocytophilumAnaplasma platysPrimary vectorsIxodes scapularis Ixodes pacificusBlack-legged tick (deer tick)Rhipicephalus sanguineus (brown dog tick)PathologyInfects neutrophilsInfects plateletsClinical presentationCan present acutely:• F ever • Anorexia • Lethargy• Polyarthritis, lameness • Neurologic signsUsually minimal clinical signs, but some dogs may have:• F ever • Uveitis• Petechiae and ecchymoses • EpistaxisLaboratory abnormalities• Thrombocytopenia• Anemia• Lymphopenia• Increased liver enzymesOther findings may be seen:• Decreased albumin • Increased globulin• Increased ALP and ALT • Proteinuria• Decreased Urine SG • Increased UPC NotePrevious infection may not prevent reinfection and persistent infections are possible.9,10Canine anaplasmosisCanine granulocytic anaplasmosis is caused by the bacterium Anaplasma phagocytophilum (transmitted by the black-legged tick [deer tick]). Anaplasma platys (transmitted by the brown dog tick) is the cause of infectious cyclic thrombocytopenia.Did you know?•M any mammalian species, including humans, are susceptible to A. phagocytophilum infection. •D ogs coinfected with Anaplasma and other bacterial pathogens may have more complex disease presentations and respond more slowly to therapy.• A .platys infects canine platelets and is frequently seen as a coinfection with Ehrlichia canis .Canine ehrlichiosisCanine ehrlichiosis is caused by the bacteria Ehrlichia canis (transmitted by the brown dog tick) and Ehrlichia ewingii (transmitted by the lone star tick). Canine Ehrlichia infections may progress to the subclinical phase or may become chronic infections.Ehrlichia canisEhrlichia ewingiiPrimary vectorRhipicephalus sanguineus (Brown dog tick)Amblyomma americanum (Lone star tick)PathologyInfects monocytes Infects granulocytesClinical presentation• Fever, anorexia, lethargy • Bleeding disorders • Polyarthritis, lameness • Lymphadenomegaly • Neurologic signs• Fever, anorexia, lethargy • Polyarthritis, lameness • Neurologic signsLaboratory abnormalitiesNotePrevious infection may not prevent reinfection, and persistent infections are possible.12,14Did you know?• D ogs coinfected with E. canis and A. platys were found to have more severe anemia and thrombocytopenia than dogs with either single infection.11• I n a study of healthy dogs with antibodies to E. canis , 39% were thrombocytopenic.12• C hronic E. canis infections, if left untreated, can lead to bone marrow dysfunction or kidney disease.• D ogs with Ehrlichia antibodies in E. canis endemic areas had a 112% increased risk of developing chronic kidney disease (CKD).13CKD monitoring• Chemistry panel with SDMA - R ecommended to evaluate forsecondary kidney disease.• Urinalysis with UPC - R ecommended to evaluatefor proteinuria • CBC with blood film - R ecommended as part of aminimum database• Anemia• Thrombocytopenia • Hyperglobulinemia • ProteinuriaOther clinical findings may include:• Decreased albumin • Increased globulin• Mild increased ALT and ALP • Increased SDMA • Creatinine• Decreased urine specific gravity, proteinuria • Increased urine protein:creatinine (UPC) ratio.Serology and PCR for sick patients For dogs presenting with clinical signs consistent with a vector-borne disease, usingserology and PCR together improves your ability to make an accurate diagnosis.Serology Polymerase chain reaction (PCR)Measures Antibody response of host Nucleic acid (DNA) from pathogenBenefits Useful for screening as well as diagnosisof infection Specifically identifies pathogens indicating active infectionLimitations Clinical signs may precede a measurableantibody response A negative PCR result does not necessarily rule out infectionDogs with ehrlichiosis and anaplasmosis may present with clinical signs at different times after infection. Which sick dog are you dealing with? Benefits and limitations of each diagnostic methodrecrudescence presents presents presentsWhen to use the IDEXX vector-borne disease RealPCR™ panels• S ick patients with clinical signsand/or laboratory abnormalitiesconsistent with a vector-borne illness• P atients with subclinical infectionsbased on history, physicalexamination, serology, and clinicallaboratory findings“No single test is sufficientfor diagnosing an infectious disease in a sick patient.”Edward Breitschwerdt, DVM, DACVIM*Professor, Internal MedicineCollege of Veterinary Medicine,North Carolina State University* D r. Breitschwerdt has a business relationship with IDEXX pursuant to which he receives compensation from IDEXX from time to time. The views expressed in this guide are solely those of Dr. Breitschwerdt.References1. G eneral guidelines: Parasite testing and protection guided by veterinarians [dog].Companion Animal Parasite Council website. /guidelines /general-guidelines. Updated July 29, 2020. Accessed November 17. 2021. 2. B eall MJ, Chandrashekar R, Eberts MD, et al. Serological and molecular prevalenceof Borrelia burgdorferi , Anaplasma phagocytophilum , and Ehrlichia species in dogs from Minnesota. Vector-Borne Zoonotic Dis . 2008;8(4):455–464. doi:10.1089/vbz.2007.0236 3. R egions where ticks live [maps]. Centers for Disease Control and Prevention website./ticks/geographic_distribution.html. November 17, 2021. 4. D rake C, Coyne M, McCrann DJ, Buch J, Mack R. Risk of development of chronickidney disease after exposure to Borrelia burgdorferi and Anaplasma spp. T op Companion Anim Med. 2020;42:100491. doi:10.1016/j.tcam.2020.100491 5. O ’Connor TP , Esty KJ, Hanscom JL, Shields P , Philipp MT . Dogs vaccinatedwith common Lyme disease vaccines do not respond to IR 6, the conserved immunodominant region of the VlsE surface protein of Borrelia burgdorferi.Clin Diagn Lab Immunol. 2004;11(3):458–462. doi:10.1128/CDLI.11.3.458-462.2004 6. S traubinger RK. PCR-based quantification of Borrelia burgdorferi organisms in caninetissues over a 500-day postinfection period. J Clin Microbiol. 2000;38(6):2191–2199. doi:10.1128/JCM.38.6.2191-2199.2000 7. C APC prevalence maps: heartworm [dog]. Companion Animal Parasite Councilwebsite. /maps/#/2021/all-year/heartworm-canine/dog/united-states. Accessed November 17, 2021.8. A merican Heartworm Society. Current canine guidelines for the prevention, diagnosis,and management of heartworm infection in dogs . 2020. Accessed November 17, 2021. https:///images/pdf/AHS_Canine_Guidelines_11_ 13_20.pdf?1605556516 9. E genvall A, Lilliehöök I, Bjöersdorff A, et al. Detection of granulocytic Ehrlichia speciesDNA by PCR in persistently infected dogs. Vet Rec . 2000;146(7):186–190. doi:10.1136/vr.146.7.186 10. B reitschwerdt EB, Hegarty BC, Qurollo BA, et al. Intravascular persistence ofAnaplasma platys , Ehrlichia chaffeensis , and Ehrlichia ewingii DNA in the blood of a dog and two family members. Parasit Vectors . 2014;7:298. doi:10.1186/1756-3305-7-298 11. G aunt S, Beall M, Stillman B, et al. Experimental infection and co-infection of dogs withAnaplasma platys and Ehrlichia canis : hematologic, serologic and molecular findings. Parasit Vectors . 2010;3(1):33. doi:10.1186/1756-3305-3-33 12. H egarty BC, de Paiva Diniz PP , Bradley JM, Lorentzen L, Breitschwerdt E. Clinicalrelevance of annual screening using a commercial enzyme-linked immunosorbentassay (SNAP 3Dx) for canine ehrlichiosis. J Am Anim Hosp Assoc. 2009;45(3):118–124. doi:10.5326/0450118 13. B urton W, Drake C, Ogeer J, et al. Association between exposure to Ehrlichia spp.and risk of developing chronic kidney disease in dogs. J Am Anim Hosp Assoc . 2020;56(3):159–164. doi:10.5326/JAAHA-MS-7012 14. S tarkey LA, Barrett AW, Beall MJ, et al. Persistent Ehrlichia ewingii infection indogs after natural tick infestation. J Vet Intern Med . 2015;29(2):552–555. doi:10.1111/jvim.12567 15. S nellgrove AN, Krapiunaya I, Ford SL, et al. Vector competence of Rhipicephalussanguineus sensu stricto for Anaplasma platys . Ticks Tick Borne Dis. 2020;11(6):101517. doi:10.1016/j.ttbdis.2020.101517Depend on the most accurate and comprehensive screenSNAP 4Dx Plus T estReference-laboratory quality in the palm of your hand, for superior diagnostic accuracy at the pointof care.Lab 4Dx Plus T estAvailable from IDEXX Reference Laboratories as a stand-alone test or as part of a more comprehensiveparasite screen with the Fecal Dx Antigen Panel with Lab 4Dx Plus Test-Canine.SNAP ® technology uses a proprietary three-step process to deliver dependable sensitivity and specificity.Available in-clinic or from IDEXX Reference LaboratoriesStrengthen the bonds.IDEXX Laboratories, Inc.One IDEXX DriveWestbrook, Maine 04092United StatesAmerican dog tick (Dermacentor variabilis) photographer: Susan E. Ellis, USDA-APHIS-PPQ. Black-legged tick (Ixodes scapularis), lone star tick (Amblyomma americanum), and brown dog tick (Rhipicephalus sanguineus) photographer: James L. Occi.© 2022 IDEXX Laboratories, Inc. All rights reserved. • 09-69074-13All ®/TM marks are owned by IDEXX Laboratories, Inc. or its affiliates in the United States and/or other countries. The IDEXX Privacy Policy is available at .。

P16、PTEN、E-cadherin、CtBP1联合检测对子宫内膜腺癌的诊断意义

Ａｓａｔ０ｂｅｔｅＴｖｌａｅｉｎｓｃｖｌｅｆｈｘｒｓｏ１，ＴＮ， —ａｈｒｎｔＰｎｏｂｔｃ：ｊｃｉｏｅａｔｔａｏｔａｕｅｅｐｅｓｎｏＰ６ＰＥＥｃｄｅｉａｄＣＢ１ｉｅｄ— ｒｖｕｅｈｄｇｉｏｔｉｆｎｎ
ｇｓｃｒｒｓｎａａｓＲＣｃｒ）ｅｕｔＰｓｉｘｒｓｉｆＰ６ＴＮａｄＥｅｄｅｉｉｅｄｍｔａｃｎｅｉｉｅｅｉｎｌｉｔｇｓｏｙｓ（Ｏｕｖ．Ｒｓｌｏｉｖｅｐｅｓｎｏ１，ＰＥｎ —ａｈｒｎｎｏｅｉａｃｒｅｓｔｅｏｎｒｌ
ｍｅｈｄｈｎｈｉｇｏｔａｕｆｈｘｒｓｉｎｏ１ｔｏ．Ｔｅ，ｔｅｄａｎｓｉｖｌｅｏｅｅｐｅｓｆＰ６，ＰＥＮ，ＥｃｄｅｉｎｔＰｒｖｌａｅｙｕｉｇｂｎｒｏｃｔｏＴ — ａｈｒａｄＣＢ１ｗｅｅｅａｕｔｄｂｓｎｉａｙｌ・ｎ
病理诊断的意义。方法
腺癌和３０例正常子宫内膜组织中的表达情况，使用二元逻辑回归ＲＣ曲线分析方法对联合检测指标进行筛选，Ｏ并对个体诊断进行预测。结果Ｐ６ＰＥＥｃｄｅｉ１、ＴＮ、—ａｈｒｎ在子宫内膜癌中的阳性表达率高于正常子宫内膜（００）Ｐ＜．５；
Ｐ６ＰＥＥｃｄｅｉ性表达与子宫内膜癌发生有关；１１、ＴＮ、 —ａｈｒｎ阳Ｐ６和ＣＢ１在两种组织中均Ｐ未Ｐ＞．５。Ｐ６和ＰＥ联合检测具有中等强度准确性，假阳ＴＮ在性率为１％的条件下诊断点为０９０结论０．０。

Allegion 1 1 2 英寸门锁说明书

*P515-748*P515-748B571 Thumbturn Deadbolt with Vacancy Indicator B581/F Thumbturn Deadbolt with Blank Cover Cerrojo de Pasador c on Cubierta Llana Cerrojo de Pasador c on Cilindro de Indicador Pêne Dormant avec Couverture Plaine Pêne Dormant avec Cylindre d’IndicateurB571 / B581 / B581FInstallation Instructions Instrucciones de instalaciónNotice d’installation1110479Turn to “Vacant”Gírelo a “vacant”Tourner à “vacant”B571: Indicator Must Be Centered in Door Hole B571: Indicador se debe centrar en agujero de puertaB571: Indicateur doit être centré dans le trou d’porteB581B571OR O OU5Top Tapa HautFor Wood DoorPara puerta de madera Por porte en boisFor Metal DoorPara puerta de metal Por porte en métalOR O OU¹⁄₈” (3 mm) Pilot HolesAgujeros de guía de 3 mm T rous pilote de 3 mmThumbturn points away from latch Mariposa señala lejos del pestillo Tourniquet se dirigeloin du verrouMeasure Door WidthMida el grosor de la puertaMeasurer l’èpaisseur de la porteBreak bar as indicatedRompa la barra según lo indicado Casser la barre comme indiqué2¹⁄₄” (57 mm)2” (51 mm)1⁷⁄₈” (48 mm)1⁵⁄₈” (41 mm)1¹⁄₂” (38 mm)1³⁄₈” (35 mm)Determine Driver Bar (F) LengthDetermine el tamaño de la barra impulsora (F)Determiner la longeur de la barre de transmission (F)ULB571: Ensure that “Vacant”is centered in its window before inserting driver barB571: Asegure que “Vacant” está centrada en su ventana antes de inserter la barraB571: Assurer que “Vacant” est centré dans sa fenêtre avant d’inserer le barre2 ³₄B581F: 1¹⁄₂” (38 mm) Hole OnlyNote : Screws (R) are required for UL/CUL ApplicationB581F: Agujero de 38 mm solamente Nota : Los tornillos (R) son requerido para la aplicación de UL/CUL B581F: Trou de 38 mm seulementNote : Les vis (R) sont requis pour le application d’UL/CULWood Block (not included)Bloque de madera (no incluido)Bloc en bois (non inclus)OR O OUTopTapa HautLatch Retracted Pasador contraído Le verrou rétractéB581F :2¹⁄₈” Hole Only: Insert UL Fire Cup (Q) Before Deadbolt Agujero de 54 mm: inserte la taza de UL (Q) antes del pasador Trou de 54 mm: insérer le tasse d’UL (Q) avant le pêne dormant2¹⁄₈” (54 mm)I n s i d e o f D o o rD e n t r o d e p u e r t a L'i n t ér i e u rd e p o r t e V A CA NT 67W o o d M a d e r a B o i sN P 1³⁄₁₆”(30m m)1¹⁄₂” (38m m ) ⁷⁄₈” (23m m )LM QAADERFor Strike Side of DoorPara el lado de placa hembra de la puerta Pour la côté de gâche de la porte⁵⁄₃₂”x 3”(4 mm x 76 mm)PGHFL。

Jokab Safety BSR10 安全传感器接入模块说明书

[DE] Die komplette Originalbetriebsanleitung ist zu finden unter:[IT] Le istruzioni originali complete si trovano qui:[FR] La notice originale intégrale est disponible sur:[ES] La versión original de las instrucciones está disponible en:/jokabsafetyABB ABJokab SafetyVarlabergsvägen 11 SE-434 39 Kungsbacka Tel. +46 (0) 21-32 50 /jokabsafetyProduct descriptionBSR10 is a safety relay with basic monitoring functions for 1- and 2-channel sensors and equivalent contacts for expansion of safety modules.InstallationWARNING: The product must be installed by a trained electrician following applicable safety regulations, standards and the machinedirective.CAUTION: The safety relay shall be attached on a 35 mm DIN railin an enclosure that has at least protection class IP54.CAUTION: Make sure there is at least 10 mm distance between the safety relay and other non-Sentry safety relay units to preventuncontrolled heating.CAUTION: Make sure there is at least 50 mm distance above and below the safety relay and other units for correct air flow in the venting holes of the safety relay.ConnectionWARNING: The safety relay and the sensor device for monitoring must be connected to SELV/PELV power supply.B)A. One signal from +24VDC, start and stopB. Two signals from +24VDC / 0VC. One signal from +24VDCD. One signal from +24VDC, startE. One signal from +24VDCLED indicationON/OUT/X4IndicationProcedure for correction off/off/offLoss of power supply or too low voltage. Occurs during regular operation.Measure R1/R2 voltage.green/off/offInput X4 is not powered with correct voltage. Occurs during regular operation.Measure X4/R2 voltage.Troubleshoot the monitored device.green/off/green Safety relay internal error.Exchange the safety relay.off/off/green No signal to R1. Occurs during regular operation.Measure R1/R2 voltage.green/green/greenRelay is activatedTechnical dataMeasurements Height/width/depth120 mm/22.5 mm/120 mmRelay output specification Maximum operating switching voltage250 VAC Overvoltage category IIInput R1, R2 and X1Minimum high/Maximum low voltage 15 V/1 V Maximum current sink 200 mA NO contactAC load (AC15, AC1), ratedoperational voltage, current 1/2/3 contact(s)250 VAC, 5 A/5 A/4.6 A DC load (DC13, DC1), ratedoperational voltage, current 1/2/3 contact(s)+24 VDC, 6 A/5.6 A/4.6 ARequired fuse 6.3 A gG, 1 kA short circuit protection (6 A according to UL248)NC contactAC load (AC15, AC1), rated operational voltage/current 250 VAC/0.5 A DC load (DC13, DC1), rated operational voltage/current +24 VDC/2 ARequired fuse4 A gG, 1kA short circuit protection (4 A according to UL 248)Connection block and wire properties Maximum screw torque 0.8 NmSolid conductor, minimum 1 x 24 AWG (0.2 mm 2), 2 x 24 AWG (0.2 mm 2)Solid conductor, maximum1 x 12 AWG (3.31 mm 2), 2 x 16 AWG (1.31 mm 2)Conductor with crimp sleeve, minimum1 x 24 AWG (0.2 mm 2), 2 x 24 AWG (0.2 mm 2)Conductor with crimp sleeve, maximum 1 x 12 AWG (3.31 mm 2), 2 x 16 AWG (1.31 mm 2)Wire strip length6-7 mm Maximum response time Response time at activation, start 40 ms Response time at deactivation20 ms2TLC010003M0201 Rev BWhile every effort has been taken to ensure the accuracy of information contained in this book and any associated promotional and information material ABB JokabSafety cannot accept responsibility for errors or omissions and reserves the right to make any improvements without notice. It is the users responsibility to ensure that this equipment is correctly designed, specified, installed, cared for and operated to meet all applicable local, national and international codes/regulations. Technical data in our book is correct to the level of accuracy of ABB Jokab Safety´s test procedures as verified by various international approved bodies. Other information (such as application examples, wiring diagrams, operation or use) is intended solely to illustrate the various uses of our products. ABB Jokab Safety does not quarantee or imply that the product when used in accordance with such examples in a particular environment will fulfil any particular safety requirement and does not assume any responsibility or liability for actual use of the product based on the examples given.[DE] Die komplette Originalbetriebsanleitung ist zu finden unter:[IT] Le istruzioni originali complete si trovano qui:[FR] La notice originale intégrale est disponible sur:[ES] La versión original de las instrucciones está disponible en:/jokabsafetyElectrical operations life time Load Σlth² ≤ 64, AC1, AC15160 000 operations Load Σlth² ≤ 64, DC1, DC13100 000 operationsMechanical operations lifetime 107 operations Environmental data Protection class, safety relay IP20Protection class, enclosureAt least IP54Ambient temperature range foroperation within specified operation range-10°C – +65°C Humidity range for operation25 % ≤ Rh ≤ 90 %, non-condensing and without icingSuitable for use at ≤ 2000 metres above sea level.Standard compliance and approvals Functional safety standard complianceEN 61508-1:2010, up to SIL3 EN ISO 13849-1:2008, up to PLe/Cat.4EN 62061:2005, up to SILCL3 EN 61511-1:2003ApprovalsCE, TÜV SÜD, cULus Declaration of conformityCan be found at:/jokabsafety Information for use in USA/Canada Intended use Applications according to NFPA 79Power sourceA suitable isolating source in conjunction with a fuse in accordance with UL 248FuseThe fuse shall be rated max. 4 A and be installed in the +24 VDC power supply to the device in order to limit the available current.MaintenanceWARNING: The safety functions and mechanics shall be testedevery year to confirm that the safety functions work properly.WARNING: Repair and exchange of parts of the safety relay is not permitted since it may accidentally cause permanent damage to the product, imparing safety of the device which in turn could lead to serious injury to personnel. In case of breakdown or damage to the product contact ABB Jokab safety to replace the safety relay with a similar product.。

野生兜兰菌根真菌对带叶兜兰生长和生理指标的效应

热带亚热带植物学报2022, 30(1): 88 ~ 96Journal of Tropical and Subtropical Botany野生兜兰菌根真菌对带叶兜兰生长和生理指标的效应陈宝玲, 杨开太*, 龚建英, 唐庆, 苏莉花, 汪小玉, 龙定建(广西壮族自治区林业科学研究院，南宁530002)摘要：为探究兰科菌根真菌对带叶兜兰(Paphiopedilum hirsutissimum)生长的影响，用4个分离自广西野生兜兰根部的兰科菌根真菌(Cladosporium perangustum、Kirschsteiniothelia tectonae、Phialophora sp.和Cyphellophora sp.)与带叶兜兰试管苗和营养钵苗进行菌-苗共生试验，对其生长和生理指标的变化进行了研究。

结果表明，接菌处理具有明显的促进生长作用和生理效应，Cladosporium perangustum和Phialophora sp.对试管苗的接种效果最佳，鲜质量增量、3种保护酶活性和叶绿素总量均与对照存在显著或极显著差异，鲜质量增加了360%~380%。

Kirschsteiniothelia tectonae、Phialophora sp.对营养钵苗的接种效果最佳，鲜质量增量、叶面积及3种保护酶活性均与对照存在显著或极显著差异，鲜质量增加了261%~330%。

因此，实际生产中可在带叶兜兰不同生长阶段接种适当菌株，Phialophora sp.对带叶兜兰表现出较好的促生效应，可研发为带叶兜兰育苗期通用型有益菌剂。

关键词：带叶兜兰；兰科菌根真菌；生理特性；保护酶doi: 10.11926/jtsb.4411All Rights Reserved.Effects of Wild Paphiopedilum Mycorrhizal Fungi on Growth andPhysiological Indexes of Paphiopedilum hirsutissimum SeedlingsCHEN Baoling, YANG Kaitai*, GONG Jianying, TANG Qing, SU Lihua, WANG Xiaoyu,LONG Dingjian(Guangxi Zhuang Autonomous Region Forestry Research Institute,Nanning 530002, China)Abstract: To investigate the effects of mycorrhizal fungi on the growth of Paphiopedilum hirsutissimum, fourstrains, such as Cladosporium perangustum, Kirschsteiniothelia tectonae, Phialophora sp. and Cyphellophora sp.,isolated from roots of wild Paphiopedilum, were inoculated to tissue-cultured and potting seedlings of P.hirsutissimum for 120 days, and then the changes in growth and physiological characters were studied. The resultsshowed that the biomass and physiological indexes of tissue-cultured seedlings increase inoculated withCladosporium perangustum and Phialophora sp., the fresh weight, activities of three protective enzymes, andtotal chlorophyll content had significant differences compared with the control. Especially the fresh weight wasmore than control for 360%-380%. Two strains, Kirschsteiniothelia tectonae and Phialophora sp. had the besteffect for the potting seedlings, which the fresh weight, leaf area, and activities of three protective enzymes hadsignificant difference compared with the control, and the fresh weight increased 261%-330% than control.Therefore, appropriate strains could be inoculated to P. hirsutissimum at different growth stages in actualproduction. Phialophora sp., which showed a good promoting effect on P. hirsutissimum, could be developed as a收稿日期: 2021-03-12 接受日期: 2021-06-03基金项目:广西自然科学基金项目(2020GXNSFAA259028); 广西重点研发计划项目(桂科AB18221003)资助This work was supported by the Project for Natural Science in Guangxi (Grant No.2020GXNSFAA259028); and the Project for Key Research & Developmentin Guangxi (Grant No. AB18221003).作者简介: 陈宝玲(1981~ )，高级工程师，硕士，主要从事兰科植物的保育与繁育研究工作。

p16 INK4A基因与宫颈癌早期防治

维普资讯

医学综述２００８年６月第１４卷第１期２
ＭｅｉａＲｃｐ堕ｄｃｌｅｊ！ａ！
：：：：
・
１０５・８
ｐ６Ａ基因与宫颈癌早期防治１
武
中图分类号：７１７；７７３Ｒ６Ｒ１．４Ｒ３．３；３５
，
ｐ６１
基因及其产物在人类
许多原发性肿瘤和细胞株中发生改变，脑肿瘤、颈癌、管癌、如头食肺癌、腺癌、胱癌、腺癌、胰膀乳黑
ＳＯＮＧＪｎｈｉ．ｉｇ．ｕ
（．ｎｅｎｏｉＭｅｉｌＣｌｇ，ｕｈｔ１００Ｃｉａ．ｅａｔｅｔｏｓｔｃａｄＧｎｃｌｙ１ＩｎｒＭｏｇｌｄｃｏｌｅＨｈｏ０５，ｈｎ；２ＤｐｒｎｆＯｂｅｉｎｙｅｏｏ，ａａｅ０ｍｔｒｓｇＦｒｆｌｔｏｐｔｌＩｎｒｎｏａＭｅｉｌｏｌｅＨｈｏ００５ＣｉａｉｔｉｉｅＨｓｉ，ｅｇｌｄａｌｇ，ｕｈｔ１００，ｈｎ）ｓＡａｄａｎＭｏｉｃＣｅ
的过表达发生在宫颈癌和癌前病变阶段，可作为一种肿瘤标志物用于官颈癌的临床筛查及诊断中。关键词：１；颈癌；颈上皮内瘤变；ｐ６官宫非典型鳞状细胞
ｐ６ＫＧｅｅａｄＥａｆｒＰｒｖｎｏｎＣｕｒｆＣｅｖｃｌＣａｃｒＷＵｉｇｌ４ｎｎｒｅｅｅｔｎａｄｉｉｅｏｒｉａｎｅＬｎ

宫颈病变组织中Vimentin、P16INK4A、Smad4的定位、表达及其在EMT中的作用

（ｒ＝一０．２７４，一０．３８７，ａｌｌＰ＜０．０１），ａｌｓｏｎｅｇａｔｉｖｅｌｙｃｏｒｒｅｌａｔｅｄｗｉｔｈｔｈｅｅｘｐｒｅｓｓｉｏｎｏｆｎｕｃｌｅａｒｖｉｍｅｎｔｉｎ（ｒ：一０．２０９，
ｉｎｔｈｅｎｕｃｌｅａｒｗａｓｒｅｄｕｃｅｄｉｎｌｏｗ — ｒａｇｄｅＣＩＮ，ｈｉｇｈ — ｇｒａｄｅＣＩＮａｎｄｃｅｒｖｉｃｌａｃａｎｃｅｒ（ａｌｌＰ＜０．０１）．Ｓｐｅａｒｍａｎｃｏｒｒｅｌａｔｉｏｎａ－
系（Ｐ均＞０．０５）。结论Ｖｉｍｅｎｔｉｎ、Ｐ１６Ｋ４Ａ和Ｓｍａｄ４在各宫颈病变组织细胞质和细胞核中呈不同程度阳性表达。Ｖｉｍｅｎｔｉｎ核表达是反映宫颈癌细胞ＥＭＴ的良好指标，Ｐ１６核表达和Ｓｍａｄ４核表达与宫颈癌细胞ＥＭＴ密切相关。
ｎｌｙａｓｉｓｓｈｏｗｅｄｎｕｃｌｅａｒＳｍａｄ４ｅｘｐｒｅｓｓｉｏｎｗａｓｎｅｇａｔｉｖｅｌｙｃｏｒｅｌａｔｅｄｗｉｔｈｔｈｅｅｘｐｒｅｓｓｉｏｎｏｆｎｕｃｌｅｒａａｎｄｃｙｔｏｐｌａｓｍｉｃＰ１６
（ｌａｌＰ＜０．Ｏ１）．Ｓｍａｄ４ｉｎｔｈｅｎｕｃｌｅｕｓａｎｄｃｙｔｏｐｌａｓｍｗａｓｈｉｇｈｌｙｅｘｐｒｅｓｓｅｄｉｎｃｈｒｏｎｉｃｅｅｖｉｒｃｉｔｉｓｔｉｓｓｕｅｓ，Ｓｍａｄ４ｅｘｐｒｅｓｓｉｏｎ

泾渭16k有准备的人的英语作文

泾渭16k有准备的人的英语作文标题，The Prepared Minds of the Jingwei 16k。

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In the realm of modern innovation, the concept of preparedness has transcended its conventional boundaries. As the era of technology continues to evolve, the demand for individuals equipped with the necessary skills and knowledge has intensified. Amidst this backdrop, the phenomenon of the Jingwei 16k emerges as a testament to the fusion of preparedness and technological prowess.The term "Jingwei 16k" encapsulates a breed of individuals who are not merely proficient, but deeply prepared for the challenges of the digital age. Originating from the Chinese proverb "泾渭分明," which signifies a clear demarcation between two different realms, the Jingwei 16k epitomizes the seamless integration of diverse skills and expertise.At the core of the Jingwei 16k ethos lies a multifaceted approach to learning and adaptation. These individuals are characterized by their ability to traverse the boundaries between disciplines, effortlessly blending technical acumen with creative ingenuity. Equipped with a comprehensive understanding of diverse fields ranging from artificial intelligence and data science to humanities and social sciences, they possess a holistic perspective that transcends traditional silos.Furthermore, the Jingwei 16k are not merely passive recipients of knowledge but active agents of innovation. Fueled by a relentless curiosity and a thirst for exploration, they continually seek to push the boundaries of what is possible. Whether through collaborative endeavors or individual pursuits, they harness the power of technology to address complex challenges and drive meaningful change.Moreover, the prepared minds of the Jingwei 16k are characterized by their adaptability and resilience in the face of uncertainty. In an era defined by rapidtechnological disruption and societal transformation, they embrace change as an opportunity for growth rather than a source of apprehension. Armed with a diverse toolkit of skills and a mindset rooted in flexibility, they navigate shifting landscapes with confidence and poise.Central to the ethos of the Jingwei 16k is the recognition that true preparedness extends beyond technical proficiency to encompass ethical responsibility and social consciousness. As stewards of technology, they are mindful of the implications of their actions and strive to ensure that innovation serves the greater good. Whether through advocating for ethical standards in artificial intelligence or leveraging technology for social impact, they embody a commitment to using their skills for the betterment of humanity.In essence, the phenomenon of the Jingwei 16k represents a paradigm shift in the landscape of modern expertise. It transcends the traditional dichotomy between specialization and versatility, offering a glimpse into a future where individuals are not constrained by disciplinary boundaries but empowered by their ability to adapt, innovate, and make a positive difference in the world. As we navigate the complexities of the digital age, the prepared minds of the Jingwei 16k serve as beacons of inspiration, guiding us towards a future defined by knowledge, creativity, and humanistic values.。

Cellular senescence from physiology to pathology

More than five decades ago Leonard Hayflick and Paul Moorhead discovered that normal human fibroblasts have a finite proliferative capacity in culture, a phenom-enon that they named ‘cellular senescence’, and specu-lated that it could be an underlying cause of ageing1. This property of normal cells is in contrast to the behav-iour of cancer cells, which possess an indefinite capacity to proliferate. Today, we know that the phenomenon observed by Hayflick and Moorhead in fibroblasts reflects one particular type of cellular senescence pro-duced by the loss of telomeres after extensive prolifera-tion in the absence of endogenous telomerase activity. The various stimuli and cellular contexts that induce senescence in multiple physio l ogical and pathological processes are becoming increasingly appreciated, and this is the main focus of this Review.Senescent cells differ from other non-dividing cells (such as quiescent or terminally differentiated cells) by several markers and morphological changes (BOX 1). These features include the absence of proliferative mark-ers, senescence-associated β-galactosidase (SAβGAL) activity, expression of tumour suppressors and cell cycle inhibitors, and often also of DNA damage markers, nuclear foci of constitutive heterochromatin and promi-nent secretion of signalling molecules. Although none of these markers is on its own completely specific or univer-sal for all senescence types, there is ample consensus that senescent cells express most of them.Work during the past decade has convincingly dem-onstrated that senescence has beneficial and detrimental roles (as detailed in this Review). In general, transient induction of senescence followed by tissue remodelling is beneficial, because it contributes to the elimination of damaged cells. Conversely, persistent senescence or the inability to eliminate senescent cells is detrimental. In our view, the general biological purpose of senescence is to eliminate unwanted cells, which is conceptually similar to apoptosis. Senescence and apoptosis are the most important mechanisms to eliminate damaged cells. This is particularly relevant in cancer and ageing, which are both characterized by the accumulation of severe cellular damage. In agreement with this, senescence is a crucial barrier against cancer progression (see below), and senescent cells accumulate with ageing (BOX 2). We begin by describing the most important molecu-lar mechanisms underlying cellular senescence. Then, we focus on the most recent findings that implicate senescence both in normal physiology and in a remark-ably wide range of pathological disorders. This is fol-lowed by the proposal of a unified model for senescence as a tissue remodelling mechanism. Finally, we review current emerging pro-senescent and antisenescent ther-apies, and their therapeutic potential for cancer, chronic disorders and ageing.Mechanisms of senescenceThe number of stimuli that induce senescence is con-stantly increasing and the mechanisms involved have been extensively reviewed2–8. These stimuli are signalled through various pathways, many of which activate p53 (encoded by TP53 in humans and by Trp53 in mice), and essentially all of them converge in the activationT umour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, E-28029, Spain. Correspondence to M.S.e-mail:mserrano@cnio.es doi:10.1038/nrm3823Cellular senescence: from physiology to pathologyDaniel Muñoz-Espín and Manuel SerranoAbstract | Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events — senescence, followed by clearance and then regeneration — may not be efficiently completed in aged tissues or in pathological contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro-senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.482 | JULY 2014 | VOLUME 15 /reviews/molcellbioof the cyclin-dependent kinase (CDK) inhibitors p16 (also known as INK4A; encoded by CDKN2A), p15 (also known as INK4B; encoded by CDKN2B), p21 (also known as W AF1; encoded by CDKN1A) and p27 (encoded by CDKN1B) (FIG. 1). The inhibition of CDK–cyclin com-plexes results in proliferative arrest, and the crucial comp-onent responsible for the implementation of senescence is the hypo-phosphorylated form of RB9. In addition to multiple senescence triggers and senescence-activating pathways, it is conceivable that the mechanisms that ultimately lead to senescence may also vary depending on the cell type and conditions. Similar to apoptosis, for which several subtypes of apoptotic cell death have been recently defined10, future studies may define senescence subtypes. In this section, we briefly summarize the main mechanisms involved in ‘damage-induced senescence’, which includes various subtypes, such as ‘replicative senescence’, ‘DNA-damage-induced senescence’, ‘stress-induced senescenc e’ and ‘oncogene-induced senescence’. Telomer e shor tening and DNA-damage r esponse. Telomeres function as molecular clocks that keep a record of the replicative history of primary cells11. In particular, telo m ere ‘erosion’ through consecutive cell divisions that fail to maintain telomere length can result in critically short telomeres and a type of senes-cence known as ‘replicative senescence’ (REF. 2). The loss of telomeres is sensed by cells as a type of DNA dam-age and therefore triggers a DNA-damage response (DDR), which is similar to that produced by external DNA-damaging agents, such as ionizing radiation and chemotherapeutic drugs. In addition to telomere short-ening, telomeres are particularly sensitive to external DNA damage12,13 owing in part to the fact that telomeres, from yeast to humans, are poorly accessible to the DNA damage repair machineries14. The main mediators of the DDR are the DNA damage kinases ATM, ATR, CHK1 and CHK2, which phosphorylate and activate several cell cycle proteins, including p53 (REF. 2)(FIG. 1). In turn, phosphorylated p53 protein activates the expression of p21, which binds to and inhibits some CDK–cycli n complexe s, particularly those involving CDK2.CDKN2A locus derepression. Replicative senescence is also linked to the CDKN2A locus (also known as INK4A and ARF), which encodes two crucial tumour suppres-sors, p16 and ARF (FIG. 1). Whereas p16 is an inhibitor of CDK4 and CDK6, ARF regulates p53 stability through inactivation of the p53-degrading E3 ubiquitin protein ligase MDM2 (REFS 15,16). The CDKN2A locus is nor-mally expressed at very low levels in young tissues but becomes derepressed with ageing17. Although the molec-ular mechanisms responsible for CDKN2A derepression are not completely understood, it is well established that it depends to a large extent on the loss of Polycomb repres-sive complexes18,19. Of note, DNA damage may reduce ARF protein levels by inducing its degradation20,21. Stress-induced senescence and reactive oxygen species. Levels of reactive oxygen species (ROS) increase after many different types of stresses, including chemo-therapeutic drugs, loss of telomeric protective functions, DNA damage and oncogene activation22,23. The relevant role of oxidative stress to senescence is demonstrated by the fact that treatment with antioxidants delays or pre-vents senescence24–26. Mechanistically, high intracellular levels of ROS induced by the RAS–RAF–MEK–ERK cascade activate the p38 MAPK, which leads to increased transcriptional activity of p53 and upregulation of p21 (REF. 27) (FIG. 1).Oncogene-induced senescence. Normal cells respond to the activation of many oncogenes by undergoing cellular senescence. Oncogene-induced senescence was originally observed when an oncogenic form of RAS was expressed in human fibroblasts28. The list of oncogenes able to induce senescence has since increased to about 50 onco-genes5. Similarly, loss of tumour suppressors can trigger senescence as exemplified by the losses of PTEN29, NF1 (also known as neurofibromin)30 or von Hippel-Lindau disease tumour suppressor (VHL)31. Importantly, it is well demonstrated that o n cogene-induced senescence occurs in vivo, functioning as a brake during the early stages of tumorigenesis4. A general feature of oncogene-induced senescence is the derepression of the CDKN2A locus15,16. NATURE REVIEWS |MOLECULAR CELL BIOLOGY VOLUME 15 | JULY 2014 |483ParacrineRefers to a mode of signalling in which the cell responding to a signalling molecule is near the cell secreting the molecule. AutocrineActivation of cellular receptors by ligands produced by the same cell. In addition, this type of senescence may also induce arobust DDR owing to the DNA damage that is caused byaberrant DNA replication32,33 and/or ROS22,23(FIG. 1). Therelative importance of these mechanisms (p16, ARF orDDR-induced p53) varies across cell types. For example,in the case of PTEN loss, DNA damage does not seemto have an important role in senescence29. Also, in micethe ARF–p53 pathway is a crucial activator of oncogene-induced senescence34, whereas in humans the DDR–p53pathway seems to have a more important role than theARF–p53 pathway35. Finally, p16 plays a modest part inpromoting senescence in mice but is prominent in humancells36.Senescence-associated secretory phenotype. Senescent cellsimplement a complex pro-inflammatory response knownas senescence-associated secretory phenotype (SASP)36–39(FIG. 1).The SASP is mediated by the transcription fac-tors nuclear factor-κB (NF-κB) and CCAAT/ e nhancer-binding protein-β (CEBPβ), and includes the secretionof pro-inflammatory cytokines (interleukin-6 (IL-6) andIL-8), chemokines (monocyte chemoattractant proteins(MCPs) and macrophage inflammatory proteins (MIPs)),growth factors (transforming growth factor-β (TGFβ)and granulocyte–macrophage colony-stimulating factor(GM-CSF)) and proteases40–42. The secretion of these andsimilar proteins by senescent cells causes inflammationand, at least in some cases, it may be pivotal for the clear-ance of senescent cells by phagocytosis43,44. SASP compo-nents, most notably TGFβ, can also trigger senescencein neighbouring cells in a paracrin e manner, through amechanism that generates ROS and DNA damage45–47.Therefore, the SASP has powerful autocrine and parac-rine activities, which suggests that senescence creates aninflammatory microenvironment that may lead to theelimination of senescent cells.Senescence in development and physiologyThe role of senescence has been mostly restricted to con-texts of cellular damage or stress. This view, however, hasbeen recently expanded by the identification of senes-cence in a large number of embryonic structures andin some specialized normal adult cells (FIG. 2;TABLE 1).Senescence in the embryo. The surprising finding thatsenescence occurs during development is mostly basedon the analysis of mouse embryos48,49. However, develop-mental senescence has also been observed in human48,chicken49 and quail50 embryos, which suggests that thisis a conserved feature of embryonic development acrossvertebrates (FIG. 2;TABLE 1). Examples of senescence-positiv e structures include the mesonephric tubulesduring mesonephros involution, the endo l ymphatic sacof the inner ear, the apical ectodermal ridge (AER) ofthe limbs, the regressing interdigital webs and the closingneural tube48,49. Indeed, senescence was detected at multi-ple additional embryonic structures, and we anticipatethat more comprehensive analyses will reveal even moredevelopmental processes associated with senescence.In the particular cases of the mesonephros, theendolymphatic sac, the AER and the neural tube, theoccurrence of senescence was substantiated not only bySAβGAL staining but also by other features of senes-cence (BOX 1), such as absence of proliferation (nega-tive Ki67 staining and 5-bromodeoxyuridine (BrdU)incorporation), increased heterochromatin markers(histone 3 Lys9 trimethylation (H3K9me3) and hetero-chromatin protein 1 homologue-γ (HP1γ; also known asCBX3)) and increased expression of cell cycle inhibitors(p15, p21 and p27)48,49. Of note, DNA damage markerswere absent in the structures undergoing developmentalsenescence. It should also be mentioned that SAβGAL-positive staining has been reported in the visceral endo-derm of the early mouse embryo (embryonic day 5.5(E5.5)–E7.5) and in the visceral endoderm layer of theyolk sac51. However, this SAβGAL signal was not asso-ciated with proliferative arrest or with other markersof senescence, and it was concluded that, in this par-ticular case, SAβGAL is not indicative of senescence51.Altogether, cellular senescence seems to be commonthroughout the developing embryo, but it has distinctivefeatures compare d to damage-induced senescence.Mechanisms of developmental senescence. Three par-ticular developmental structures have been analysedin detail regarding senescence: the mesonephros (thetransitory embryonic kidney), the endolymphatic sac(a filtering tube that regulates the pressure and compo-sition of the endolymph of the inner ear) and the AER(a transient structure of specialized ectoderm mark-ing the dorsoventral boundary of the limb bud)48,49.Remarkably, genetic analysis of senescence in thesestructures revealed an essential role of the cell cycle484 | JULY 2014 | VOLUME 15 /reviews/molcellbio|Molecular Cell Biologyinhibitor p21, as shown by the absence of senescence hallmarks (including SAβGAL, proliferative arrest and senescence-associated heterochromatin foci) in Cdkn1a-null embryos48,49. This dramatic effect was not observed in embryos lacking other cell cycle inhibitors, including Cdkn2a-null or even Trp53-null embryos. The gene expression profiles of the senescent mesonephros and AER demonstrated gene expres-sion changes that are characteristic of developmental pathways, particularly TGFβ, WNT and Hedgehog, and a secretory phenotype similar to the SASP, nota-bly including fibroblast growth factor 4 (FGF4) and FGF8 (REFS 48,49). Mechanistic and genetic analyses of the mesonephros and endolymphatic sac have revealed that p21upregulation and senescence is controlled by the TGFβ–SMAD and PI3K–forkhead box protein O (FOXO)pathway s48(FIG. 1). Of note, these pathways also participate in d a mage-induced senescence in adult somatic cells (FIG. 1). In addition, the secretion of growth factors, such as FGF4 and FGF8, activates the ERK pathway in mesenchymal cells that are proximal to the AER and, in turn, mesenchymal cells signal back to the AER to maintain senescence49. Altogether, these studies suggest that develop-mentally programmed senescence is characterized by develop m ental cues that converge on p21.Clearance, compensatory processes and morphological defects. There is compelling evidence showing that cells that undergo damage-induced senescence are often removed by immune-mediated clearance43,44,52. In the case of the regressing mesonephros and the AER, macro-phages surround senescent cells at days E13.5–E14.5 (REFS 48,49). Interestingly, in the absence of Cdkn1a, the mesonephros is free of macrophages at day E14.5, thereby suggesting a causal connection between senes-cence and macrophage recruitment. Remarkably, how-ever, both the mesonephros and the AER are eventually eliminated in Cdkn1a-null embryos in a process that involves compensatory apoptosis and late infiltration of macrophages48,49.The importance of apoptosis during embryonic development is well established53. However, inhibition of the apoptotic programme during development produces modest morphological defects restricted to imperforated vaginas and partial persistence of interdigital webs54,55, which indicates the existence of compensatory mecha-nisms. Similarly, failure to undergo senescence activates a compensatory apoptotic programme48,49, which again illustrates the robustness of embryonic development. It is therefore conceivable that senescence and apop-tosis are interconnected, which enables their mutual compensatio n during development.Figure 1 | Molecular pathways of senescence. Multiple stressors and damaging agents (triggers) activatesignalling cascades (pathways) that converge on the activation of cell cycle inhibitors and the tumour suppressor RB.DNA damage agents and telomere loss activate the DNA-damage response (DDR), which directly activates p53and its downstream transcriptional target p21. Many types of senescence are associated with the epigeneticderepression of the cyclin-dependent kinase inhibitor 2A (CDKN2A)locus (encoding the cell cycle inhibitor p16 andthe p53 activator ARF). Reactive oxygen species (ROS) activate p16 and p53 through the kinases MKK3 (also knownas MAPKK3) and MKK6 (also known as MAPKK6), and their downstream kinase effector p38. Oncogenic signalling orloss of tumour suppressors activate p16 and p53 with the participation of the DDR and ARF. Transforming growthfactor-β (TGFβ) is a notable component of the senescence-associated secretory phenotype (SASP) pathway, whichupregulates the cell cycle inhibitors p21, p27 and p15 through the SMAD complex. Developmental cues inducesenescence through p21 by inducing the PI3K and TGFβ pathways (see above). Polyploidization and cell fusion alsoupregulate p21 through the DDR and p53, and also by RAS-induced activation of the transcription factor earlygrowth response protein 1 (EGR1). FOXO, forkhead box protein O.NATURE REVIEWS |MOLECULAR CELL BIOLOGY VOLUME 15 | JULY 2014 |485| Molecular Cell BiologyDevelopmentally programmed senescence Damage-induced senescenceHindbrain ClosingmidlineThe endolymphatic sac exemplifies another role of developmental senescence that is different from the elimi-nation of transient structures. The epithelium of the endolymphatic sac is composed of different cell popula-tions, with one of them identified by the expression of protein pendrin (an anion exchanger that is important for the function of the endolymphatic sac). Interestingly, senescence only affects a proportion of the epithelial cells and this occurs concomitantly with an expansion of pendrin-positive cells 48. However, in Cdkn1a -null embryos, the increase of p e ndrin-positiv e cells is nota-bly reduced, which indicates that senescence in this case regulates the relative ratios of different cell populations within the same structure. The absence of Cdkn1a results in numerous aberrant infoldings of the endolymphatic sac epithelium into the lumen, but these aberrant infoldings are eliminated at birth by macrophages independently of senescence.Despite compensation by apoptosis, absence of senes-cence produces some morphological defects affecting a proportion of adult animals 48. The Wolffian duct is a longitudinal canal that connects the mesonephric tubules with the kidney and the cloaca. In females, the Wolffian duct undergoes Cdkn1a -dependent senescence 48, and, during this process, it participates in the formation of the vagina (by guiding the Müllerian duct). Interestingly, a small proportion of Cdkn1a -null females present with vaginal septa, which is consistent with an abnormal func-tion of the Wolffian duct in vaginal morphogenesis 48.Consequently, at least in the case of the mesonephros and its derived structures, an impaired senescent programme results in morphologica l defects in the adult.Physiological senescence in adult cells. Apart from embry-onic development, senescence also occurs in a physio-logically programmed manner in adult organisms. In particular, normal megakaryocytes 56 and placental syn-cytiotrophoblasts 57 undergo senescence as part of their natural maturation programmes. In the case of mouse and human megakaryocytes, senescence is characterized by SAβGAL activity, proliferative arrest and accumula-tion of HP1γ56. Interestingly, megakaryocyte senescence, similar to developmentally programmed senescence, is dependent on p21 but is independent of p16, p53 or p27 (REF . 56) (FIG. 1). Remarkably, megakaryocytes from myelo-proliferative disorders, such as primary myelofibrosis, do not express p21 and do not undergo senescence, which suggests that senescence is physiologically relevant 56.The human placenta shows marked SAβGAL activity at the syncytiotrophoblast in association with DNA dam-age markers, p16, p21 and p53 (REF . 57) (FIG. 1). This special-ized structure consists of a large syncytium that covers the vascular embryonic villi and that is formed by the fusion of underlying cytotrophoblasts, which become themselves polyploid through a process of endoreduplication.It is remarkable that these two cell types, megakaryo-cytes and syncytiotrophoblasts, are among the few mam-malian cell types that undergo endoreduplication, whichFigure 2 | Location of senescence in development and in adult diseases . Structures and organs undergoing programmed senescence during embryonic development (left) and pathological processes associated with damage-induced senescence (right) are depicted. Diseases in which senescence has known beneficial (indicated in blue boxes) or detrimental (indicated in red boxes) roles are listed in addition to diseases in which a beneficial or detrimental role of senescence has not been established (indicated in beige boxes). COPD, chronic obstructive pulmonary disease; IPF , idiopathic pulmonary fibrosis; OSMF , oral submucous fibrosis.486 | JULY 2014 | VOLUME 15/reviews/molcellbioleads to poliploidy58. The occurrence of physiologically programmed senescence in two cases of natural poly-ploidy suggests that this could be the underlying cause. In support of this, fusion of various unrelated cell types, including cancer cells, also induces senescence57. These findings may also have a pathological correlate during infectious processes with fusogenic viruses, such as mea-sles virus57. It is worth mentioning that mature osteoclasts, which are multinucleated cells formed by a process of cell fusion, also have SAβGAL activity59. However, further studies are necessary before concluding that osteoclasts constitute another case of physiologica l senescence. Finally, natural killer (NK) cells are abundant at the maternal–fetal interface, where they contribute to a suc-cessful pregnancy by remodelling the maternal vascula-ture. Interestingly, decidual NK cells, as well as NK cells stimulated with fetal antigens, manifest hallmarks of senescence, including SAβGAL, DDR markers, HP1γ, p21 and SASP185.Beneficial effects of senescence in diseasesIn addition to normal development and physiology, senescent cells have been associated with multiple path-ological processes (FIG. 2;TABLE 2), in which senescence can have both beneficial and detrimental effects. The dis-cussed pathologies are subdivided according to the current understandin g of the role of senescence in each disease.Senescence counteracts cancer progression. It is well established that the intensity of the oncogenic signal-ling flux progressively increases during the early stages of tumorigenesis until it reaches a threshold that acti-vates the key tumour suppression pathways p16 and p53 (FIG. 1). When this happens, cell cycle inhibitors offset the oncogenic signalling and cells enter into senes-cence, which prevents the expansion of pre-cancerous cells. Accordingly, at the pathological level, senescence is detectable in the benign stage of tumorigenesis, which depending on the tissue type is known as adenoma, tumour in situ, intraepithelial neoplasia and others4. Compelling evidence exists that cells that undergo damage-induced senescence can be removed by immune-mediated clearance43,44,52. This is due in part to direct immune recognition of the senescent cells by T helper cells52 and is also due to the recruitment of inflammatory phagocytic cells43, which are probably attracted by SASP factors37,39.In addition, there is evidence for the therapeutic effect of pro-senescent therapies in already established malignant tumours. In particular, acute activation of p53 in hepatocellular carcinomas and sarcomas induces senescence, which is followed by tumour elimination43,60. Also, as discussed below in further detail, pharmaco-logic CDK4 inhibitors induce senescence in many cancer cells61–63 and are showing promising activity in human clinical trials64–66. As a word of caution, however, DNA-damage-induced senescence that is associated with cyclical chemotherapeutic regimes may promote disease progression through SASP components, such as WNT16B67.Attenuation of liver fibrosis. Liver fibrosis, being a main precursor of cirrhosis, is characterized by the accu-mulation of fibrotic tissue and the concomitant loss of liver function. It is triggered by chronic liver damage associated with hepatitis virus infection, alcohol abuse or liver steatosis (fatty liver disease). During chronic damage, hepatic stellate cells (HSCs) become activated and abnormally proliferate as myofibroblasts (damage-activated fibroblasts).Eventually, these myofibroblasts become senescent and produce a stable fibrotic scar with abundant collagen and other extracellular matrix components. In human patients, SAβGAL-positive cells accumulate in the periphery of the fibrotic scar68. In rodents, chronic treatment with carbon tetra c hloride (a liver-damaging agent) or bile duct ligation produces liver fibrosis, which is characterized by positive SAβGAL staining69–71. Histological analyses indicated that these SAβGAL-positive cells derive from activated HSCs that upregulate p53, p21 and p16 (REF. 69). The acquisi-tion of senescence by the HSCs is associated with the SASP, attraction of immune cells, clearance of the senes-cent HSCs by NK cells and partial elimination of the fibrotic scars.Table 1 |Developmental and physiological senescenceNATURE REVIEWS |MOLECULAR CELL BIOLOGY VOLUME 15 | JULY 2014 |487488 | JULY 2014 | VOLUME 15 /reviews/molcellbioThe beneficial role of senescence in restricting liver fibrosis is demonstrated by the analysis of senescence-deficient mice. In particular, upon liver damage, mice lacking Trp53 and/or Cdkn2a present senescence-negativ e fibrotic areas that are larger than those in senescenc e-competent mice69,73. Similarly, the extra-cellular matrix protein CCN1 (also known as CYR61;a member of the CCN family (comprising CYR61, con-nective tissue growth factor (CTGF) and protein NOV homologue (NOV))) produced by damaged hepatocytes is a key mediator for the induction of senescence in HSCs. Accordingly, mice with Cyr61-null hepatocytes do not execute HSC senescence and this results in a lower secretion of matrix metalloproteinases (MMPs) and an exacerbated fibrotic response71. Also, production of IL-22 by activated HSCs induces HSC senescence in association with p53 activation through STAT3 (signal transducer and activator of transcription 3)–SOCS3 (suppressor of cytokine signalling 3) and increased pro-duction of MMPs74. In agreement with this, transgenic mice overexpressing IL-22 in the liver show a more efficien t and faster resolution of fibrosis74. Together, the above studies suggest that the induction of HSC senescence could be a possible therapeutic strat-egy to limit liver fibrosis. There are promising results in mouse models indicating that treatments with recom-binant protein CCN1, or with adenoviruses expressing CCN1 or IL-22 are able to revert already established hepatic fibrosis by promoting HSC senescence70,71,74. Moreover, statins also induce senescence in HSCs and thereby attenuate hepatic fibrosis upon bile duct ligatio n in rats75.Reduction of skin scarring and oral fibrosis. Skin fibro-sis is part of the process of wound healing and it shows remarkable similarities to liver fibrosis. In particular, the above-mentioned matricellular protein CCN1 is crucial for the induction of senescence in dermal fibro-blasts, the associated expression of pro-inflammatory cytokines and antifibrotic MMPs76. As in the case of liver fibrosis, Cyr61-deficient mice do not activate senescence in the dermal fibroblasts that participate in cutaneous healing, which leads to an exacerbated fibrosis76. Moreover, topical treatment with recombi-nant purified CCN1 protein restricts fibrosis during wound healing76. Mechanistically, CCN1 activates NADPH oxidase 1 (NOX1) through RAC1 and this, in turn, generates ROS that induce the DDR, ERK and p38 MAPK pathways, which results in the upregula-tion of p53 and p16 (REFS 76,77). These studies have led to a model in which wound-activated fibroblasts (myofibroblasts), characterized by the abundant pro-duction of extracellular matrix, are converted by CCN1 into senescent fibroblasts, which are then characterized by their capacity to degrade the extracellular matrix. Therefore, senescence participates in restricting the initial fibrotic wound response77.Senescence of activated fibroblasts has also been proposed to ameliorate the effect of oral submucous fibrosis, a disease associated with tobacco and areca nut chewing78. In particular, senescent fibroblasts accumulate during oral submucous fibrosis progres-sion by a telomere-independent mechanism involving DDR, ROS and increased p16 expression, and senes-cence may reduce fibrosis by the increased expression of MMPs78.Mitigation of renal fibrosis. In the case of the kidney, increased activity of senescence pathways has been observed in multiple renal diseases (reviewed in REF. 79). In particular, reports in humans, rats and mice have documented high levels of p16 and p21 expression, and SAβGAL activity in association with renal damage and ageing80–86. Interestingly, renal injury by urethral obstruc-tion results in renal fibrosis associated with SAβGAL activity, whereas, in Cdkn2a-null mice, SAβGAL is absent and renal fibrosis is aggravated72. Conversely, in a model of renal injury by ischaemia, treatment of mice with a CDK4 inhibitor (which can be considered a ‘p16 mimetic’; see below) reduces the extent of renal damage87. However, it should be mentioned that in a similar model of ischaemia renal repair was improved in the absence of Cdkn2a encoding p16and ARF88.Limitation of cardiac fibrosis upon infarction. Cellular senescence has additionally been shown to play a part in regulating cardiac fibrosis after myocardial infarction89. Myocardial infarction promotes the accumulation of senescent myofibroblasts in the heart and the expres-sion of key senescence regulators, especially p53 but also p16, p21 and ARF, which decrease collagen production and cardiac fibrosis. Importantly, ablation of Trp53 significantly attenuates cardiac fibroblast senescence, inflammation, macrophage infiltration and MMP pro-duction, and increases collagen deposition at the fibrotic scar, thereby aggravating cardiac fibrosis89. Based on the above-mentioned findings regarding the reversion of liver and skin fibrosis by pro-senescent treatments71,74,76, it is possible that similar treatments could also revert cardiac fibrosis and improve heart function recovery. Protection against atherosclerosis. Cellular senescence has been increasingly linked to the development of vascular pathologies, in particular to atherosclerosis, which has been the topic of excellent recent reviews90–93. Advanced atherogenic plaques consist of a cap, which is formed by vascular smooth muscle cells (VSMCs) and collagen, that surrounds a necrotic core comprising lipids, lipid-laden macrophages (foam cells) and debris. Plaque formation involves a series of events initiated by endothelial cell dysfunction, vascular permeability, and the monocyte-and macrophage-mediated release of pro-inflammatory cytokines. These events induce an initial phase of VSMC proliferation that is subsequently followed by the onset of senescence92. The SASP associated with senescent VSMCs amplifies the pro-atherogenic inflammatory environment and spreads senescence in a paracrine manner to other VSMCs, as well as to endothelial cells92. This is in line with the observation that atherosclerotic plaques from human coronary arteries contain endothelial cells and VSMCs that are positive for SAβGAL and express high levels of p15, p16, p21, p53 and ARF (REFS 93–95). In addition toNATURE REVIEWS |MOLECULAR CELL BIOLOGY VOLUME 15 | JULY 2014 |489。

Nighthawk 路由器使用指南与APP操作教程

1das Symbol für Sicherheit , um Ihre Finden Sie heraus, welche Funktionen Ihnen mit der Nighthawk App zur Verfügung stehen! Sie können den Internetzugriff unterbrechen, einen Geschwindigkeitstest durchführen, die intelligente Kindersicherung nutzen und vieles mehr. Erfahren Sie hier, ob Smart Parental Controls in Ihrer Region verfügbar ist: /NETGEAR-SPC-availability2Sichern Sie 3Nutzen Sie die AppInhaltÜberblickSupport und CommunityUnter /support finden Sie Antworten auf Ihre Fragen und die neuesten Downloads.Hilfreiche Tipps finden Sie auch in unserer NETGEAR Community unter .unterschiedlich)AWLAN-Ein-/Aus-Schalter mit LEDENetzwerkanschlüsse 1–4Power-LED LEDsNetzwerkanschlüsse 1–4B WPS-Taste mit LEDFInternetanschlussInternet-LED USB 3.0-LEDC Reset-Taste G Netzanschluss 2,4-GHz-WLAN-LED D USB 3.0-Port H Ein/Aus-Taste5-GHz-WLAN-LEDAntennen x 4Informationen zur Einhaltung der rechtlichen Vorschriften, einschließlich der EU-Konformitätserklärung, finden Sie unter: https:///about/regulatory/.Lesen Sie das Dokument zur Einhaltung rechtlicher Vorschriften, bevor Sie das Gerät an die Stromversorgung anschließen.RechtsvorschriftenFehlerbehebungWenn Sie Probleme mit der Einrichtung haben, versuchen Sie Folgendes:•Schalten Sie das Modem und den Router aus und trennen Sie die Verbindung. Starten Sie Ihr Modem neu. Stellen Sie die Verbindungzwischen Ihrem Router und Ihrem Modem wieder her, und versuchen Sie erneut, die Einrichtung mit der Nighthawk App durchzuführen.•Wenn Sie Ihren Router immer noch nicht mit der Nighthawk Appeinrichten können, installieren Sie ihn manuell über die Web-Schnittstelle des Routers.Rufen Sie auf, um auf die Web-Schnittstelle des Routers zuzugreifen.Wenn Sie bereits einen anderen NETGEAR Router besitzen und dieNighthawk App bereits verwenden, gehen Sie zum Dashboard und tippen Sie auf > NEUE KONFIGURATION , um Ihren neuen Router zu installieren.NETGEAR, Inc.350 East Plumeria Drive San Jose, CA 95134, USA© NETGEAR, Inc., NETGEAR und das NETGEAR Logo sind Marken von NETGEAR, Inc. Jegliche nicht zu NETGEAR gehörende Marken werden nur zu Referenzzwecken verwendet.NETGEAR INTERNATIONAL LTD Floor 1, Building 3University Technology Centre Curraheen Road, Cork, T12EF21, IrelandNovember 2021。

ER、VIM、CEA和p16四联检测在宫颈原发腺癌和子宫内膜癌诊断和鉴别中的应用

ER、VIM、CEA和p16四联检测在宫颈原发腺癌和子宫内膜癌诊断和鉴别中的应用胡维维;陶金华;李广民;许欣;杨秀媚【摘要】目的探讨ER、VIM、CEA和p16四联检测在官颈原发腺癌和子宫内膜腺癌诊断和鉴别诊断中的应用价值.方法采用免疫组化EnVison法染色,观察ER、VIM、CEA和p16蛋白在31例官颈原发腺癌和30例子宫内膜腺癌组织中的表达情况,比较四联检测和三联检测(ER、VIM和CEA)诊断官颈原发腺癌和子宫内膜腺癌的特异性、敏感性、阳性预告值、阴性预告值和准确度.结果 ER、VIM、CEA和p16在官颈原发腺癌中的阳性表达率分别为35.5%、19.4%、77.4%和67.7%.在子宫内膜腺癌中则分别为70%、73.3%、40%和13.3%.差异均有统计学意义.四联检测对于诊断官颈原发腺癌的特异性、敏感性、阳性预告值和准确度要高于三联检测-分别为96.3%(90.2%),65.1%(57.6%),94.9%(89.4%)和85.8%(80.6%),对于诊断子宫内膜腺癌的阴性预告值和准确度要高于三联检测-分别为58.7%(51.9%)和75.4%(68.6%),其他指标则基本相当.结论在传统三联检测中加入p16对于提高官颈原发腺癌和子宫内膜腺癌的诊断和鉴别诊断准确有重要临床意义,尽管对于诊断敏感性的提高不够显著.【期刊名称】《南方医科大学学报》【年(卷),期】2010(030)003【总页数】4页(P526-528,531)【关键词】官颈原发腺癌;子宫内膜腺癌;ER;VIM;CEA;p16;鉴别诊断【作者】胡维维;陶金华;李广民;许欣;杨秀媚【作者单位】佛山市第一人民医院病理科,广东,佛山,528000;佛山市第一人民医院病理科,广东,佛山,528000;佛山市第一人民医院病理科,广东,佛山,528000;佛山市第一人民医院病理科,广东,佛山,528000;佛山市第一人民医院病理科,广东,佛山,528000【正文语种】中文【中图分类】R730.2;R711.74近年来大量研究表明宫颈原发腺癌的发病率相对于宫颈鳞癌逐年上升，在西方国家约占宫颈癌的1/4，且其发病呈现年轻化趋势，尤其是40岁以下妇女发病越来越多见［1-2］。

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