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骨发育 bone development

Annu.Rev.Cell Dev.Biol.2000.16:191–220Copyright c2000by Annual Reviews.All rights reserved B ONE D EVELOPMENTBjorn R.Olsen 1,Anthony M.Reginato 1,2,Wenfang Wang 11HarvardMedical School,Department of Cell Biology,240Longwood Avenue,Boston,Massachusetts 02115;e-mail:bjorn olsen@;reginato anthony@;wenfang wang@2Massachusetts General Hospital,Arthritis Unit,32Fruit Street,Boston,Massachusetts 02114Key Words patterning,chondrogenesis,ossiﬁcation,growth plate,jointss Abstract Early development of the vertebrate skeleton depends on genes that pattern the distribution and proliferation of cells from cranial neural crest,sclero-tomes,and lateral plate mesoderm into mesenchymal condensations at sites of future skeletal elements.Within these condensations,cells differentiate to chondrocytes or osteoblasts and form cartilages and bones under the control of various transcription factors.In most of the skeleton,organogenesis results in cartilage models of future bones;in these models cartilage is replaced by bone by the process of endochondral ossiﬁstly,through a controlled process of bone growth and remodeling the ﬁnal skeleton is shaped and molded.Signiﬁcant and exciting insights into all aspects of vertebrate skeletal development have been obtained through molecular and genetic studies of animal models and humans with inherited disorders of skeletal morphogen-esis,organogenesis,and growth.CONTENTSINTRODUCTION ................................................192SKELETAL MORPHOGENESIS .....................................193Craniofacial Bone Development ....................................193Development and Disorders of the Axial Skeleton ........................195Development and Disorders of the Limb Skeleton ........................197CHONDROCYTE DIFFERENTIATION AND ENDOCHONDRALBONE FORMATION .............................................200Chondrogenesis—the Role of Sox Genes ..............................200Chondrocyte Maturation and Control of Blood Vessel Invasion into Cartilage ....201Growth Plates and Bone Growth ....................................202OSTEOBLAST DIFFERENTIATION AND FUNCTION ....................205EXTRACELLULAR MATRIX IN SKELETAL DEVELOPMENT .............206CONCLUSIONS .................................................2091081-0706/00/1115-0191$14.00191A n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r gb y G w e n d ic k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y.192OLSENREGINATOWANGINTRODUCTIONThe vertebrate skeleton,composed of cartilage and bone,is the product of cells from three distinct embryonic lineages.The craniofacial skeleton is formed by cranial neural crest cells,the axial skeleton is derived from paraxial mesoderm (somites),and the limb skeleton is the product of lateral plate mesodermal cells.Cells in these lineages migrate to the locations in the embryo where skeletal ele-ments will develop,form characteristic mesenchymal condensations of high cell density,and differentiate into osteoblasts or chondrocytes (Hall &Miyake 1992).In regions of the craniofacial skeleton and the clavicle,differentiation into os-teoblasts produces intramembranous bones directly,whereas differentiation into chondrocytes produces a framework of cartilage models (anlagen)of the future bones in the remaining skeleton.These cartilage models are subsequently replaced by bone and bone marrow through the process of endochondral ossiﬁcation (for review,see Mundlos &Olsen 1997a).What we currently know about the molecular and cellular basis of skeletal development is largely the result of experimental animal studies and investiga-tions of human bone disorders.From studies of transgenic mice and knockouts,correlations between speciﬁc embryological events and gene functions have been made.In addition,genetic studies of mice and humans with inherited disorders of skeletal development have led to the identiﬁcation of novel genes and pathways required to build bone and cartilage and deepened our understanding of previously characterized molecular mechanisms.Given the large number of murine and human inherited skeletal anomalies,the power and speed of current methods for linkage mapping,and the progress in genome sequencing,such genetic studies are increasingly important in identifying new or key genes and regulatory pathways in bone development.Therefore,in this review we have chosen to emphasize data that are relevant to a few selected genetic studies instead of attempting to give a complete discussion of all aspects of the molecular and cell biology of bone development.Also,since the postnatal physiological aspects of bone biology have recently been reviewed from a molec-ular genetic perspective (Karsenty 1999),we have elected to focus the discussion on early embryonic events.In the review,we ﬁrst discuss skeletal morphogenesis,i.e.the migration of mesenchymal cells derived from the neural crest,sclerotomes,or lateral plate mesoderm to their ultimate locations,and their condensation into mesenchymal precursors of cartilage and bone (Figure 1).The genes involved in morphogenesis are frequently transcription factors regulating cellular determination and migration events (see Mundlos &Olsen 1997a).Mutations in such genes cause dysostoses,disorders that affect embryologically deﬁned skeletal elements while the rest of the skeleton is normal.Important insights into skeletal patterning have been obtained from studies of dysostoses that affect the three major divisions of the vertebrate skeleton:craniofacial,axial,and appendicular.A n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .BONE DEVELOPMENT193Figure 1Summary diagram showing how patterning genes (mostly transcription factors)reg-ulate the patterning of cells from cranial neural crest,somites,and lateral plate mesoderm in the craniofacial,axial,and limb anogenesis,the formation of cartilage and bone,is controlled by transcription factors,cytokines,growth factors,and extracellular matrix molecules.We then discuss the control of chondrocyte and osteoblast differentiation and the formation of bones.This organogenesis phase of skeletal development is con-trolled by transcription factors,growth factors,cytokines,and extracellular matrix molecules (Figure 1).Mutations in such genes result in dysplasias,conditions that affect cartilage and bone tissues generally,or dysostoplasias,disorders caused by mutations in genes that have roles both in early patterning and in subsequent organogenesis (Mundlos &Olsen 2000).Organogenesis of cartilage and bone includes the synthesis of specialized ex-tracellular matrices.We conclude our review with a discussion of some of the most critical matrix components and the consequences of mutations in the genes that encode them.SKELETAL MORPHOGENESIS Craniofacial Bone DevelopmentFor the craniofacial skeleton several patterning genes have been identiﬁed as reg-ulators of differentiation and migration of neural crest cells.This is not surprising since most of the craniofacial bones are of neural crest origin (Bronner-FraserA n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .194OLSENREGINATOWANG1994,Noden 1991).These cells migrate from the dorsal aspect of the neural tube into the branchial arches and the frontonasal mass and contribute to a variety of tissues including cartilage and bone.Cell-tracing studies in mice and chick em-bryos have shown that crest cells from the caudal midbrain and rhombomeres 1and 2migrate into the ﬁrst branchial arch,giving rise to maxilla,mandible,incus,malleus,and regions of the temporal bone;whereas cells in the second branchial arch,giving rise to stapes,styloid process of the temporal bone,and part of the hyoid bone,are derived from rhombomere 4(Noden 1983).Neural crest cells also give rise to skull bones such as the frontal and parietal bones (Couly et al 1993,Le Douarin et al 1993).Commitment of neural crest cells to skeletal fates depends on their interactions with epithelial cells (Langille 1994).Cytokine-based signals from overlying epithelium activates signaling pathways and transcription factors in the underlying mesenchyme;the mesenchyme in turn secretes molecules that control growth and differentiation of the epithelium.A large number of genes are consequently essential for craniofacial bone development (Winter 1996).These include several genes encoding homeobox-containing transcription factors such as goosecoid (gsc )(Rivera-Perez et al 1999),Barx1(Barlow et al 1999),Dlx1(Qiu et al 1997),Dlx2(Ferguson et al 2000,Qiu et al 1997,Thomas et al 2000),Dlx5(Acampora et al 1999,Ferguson et al 2000),Msx1(Satokata &Maas 1994,Vastardis et al 1996),Cart1(Zhao et al 1996),Hoxa1(Hunt et al 1998,Rossel &Capecchi 1999),Hoxa2(Hunt et al 1998),Hoxa3(Hunt et al 1998),Hoxb1(Hunt et al 1998,Rossel &Capecchi 1999);polycomb group genes such as rae28(Takihara et al 1997);basic helix-loop-helix transcription factors such as Twist (el Ghouzzi et al 1997,Howard et al 1997);the transcription factors AP-2(Schorle et al 1996,Zhang et al 1996)and Mf1(Kume et al 1998);and Pax genes encoding paired-box-containing transcription factors.Several cytokines and growth factors,including BMP4(St Amand et al 2000),fgf8(Trumpp et al 1999),Tgf-α(Miettinen et al 1999)and endothelin-1(Clouthier et al 1998),and their receptors (Burke et al 1998,Miettinen et al 1999)play important roles in craniofacial bone development.Finally,craniofacial skeletal development depends on controlled proteolytic processes in extracellular matrices mediated by members of the large family of matrix metalloproteases (MMPs)and their physio-logical inhibitors,the tissue inhibitors of metalloproteases (TIMPs)(Chin &Werb 1997).Given the space limitations for this review,a detailed discussion of all these genes and their speciﬁc roles in craniofacial bone development is not possible.We have therefore selected (somewhat arbitrarily)one gene,Pax3,as an example,and discuss how information about its role has been derived from both animal and human studies.Abnormalities that affect neural crest cells and therefore patterning of cran-iofacial bones include several types of Waardenburg syndrome (Read &Newton 1997).Waardenburg syndrome types 1and 3are caused by mutations in the tran-scription factor PAX3(Hoth et al 1993,Tassabehji et al 1992).PAX3is expressed in the dorsal region of the neural tube at a time when neural crest cells are formedA n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .BONE DEVELOPMENT 195and start their migration (Dahl et al 1997).A variety of mutations in PAX3,includ-ing in-frame deletions,premature terminations,and splice site mutations resulting in loss of function,result in craniofacial bone and soft tissue abnormalities,com-bined with partial albinism,hearing loss,and increased risk of spina biﬁda,cleft lip/palate,and scapular anomalies.Pigmentation abnormalities are variable,in part depending on the nature of the mutation.Some mutations,such as the replacement of an asparagine residue with histidine in the paired domain,are associated with a craniofacial and hand phenotype (small maxilla,absent or small nasal bone,ulnar deviation of hands)without pigment abnormalities (Hoth et al 1993).The PAX3gene is one of the nine PAX genes that encode a homeodomain,as well as a pairbox sequence (Dahl et al 1997).Both are DNA-binding domains,but whereas the homeodomain activates transcription of target genes,the paired do-main acts as a transcriptional repressor.In the mouse,point mutations or deletions of Pax3cause the splotch phenotype (Epstein et al 1991).Heterozygotes show white spotting;homozygotes die before or at birth (depending on the mutations)with neural tube defects and exencephaly.Interestingly,staining for chondroitin and heparan sulfate proteoglycans is more intense in splotch homo-and heterozy-gotes than in wild-type embryos,raising the possibility that abnormalities in ex-tracellular matrices may contribute to the tissue consequences of Pax3mutations (Trasler &Morriss-Kay 1991).Another Pax gene,Pax9,is also expressed in the neural crest–derived mes-enchyme involved in craniofacial and tooth development.In addition,it is ex-pressed in the developing axial and limb skeleton (see below)and in the endodermally derived epithelium of the pharyngeal pouches (Peters et al 1998).Mice that are homozygous for Pax9null alleles show various craniofacial abnor-malities and no teeth (Peters et al 1998),and a frameshift mutation in the paired domain of PAX9has been reported in a family with oligodontia (lacking most permanent molars)(Stockton et al 2000).Development and Disorders of the Axial SkeletonThe early patterning of the axial skeleton is controlled by genes that regulate the segmentation of paraxial mesoderm into somites and their subsequent differentia-tion into sclerotomes (Tam &Trainor 1994).The somites give rise to the vertebrae and the dorsolateral portion of the ribs,the dermis of the dorsal skin,and the skele-tal muscle of the body wall and the limbs.Somitogenesis occurs bilaterally,in a precisely timed rostro-caudal sequence.The process is driven by a molecular seg-mentation clock that involves oscillation of hairy 1expression (Palmeirim et al 1997).This in turn drives the expression of lunatic fringe (Forsberg et al 1998,Mc-Grew et al 1998),which controls changes in Notch activity and Delta expression.The importance of the Notch-Delta pathway for somitogenesis is illustrated by the irregular size and asymmetry of somites seen in several mouse knockouts that affect the pathway.These knockouts,including Mesp2(Saga et al 1997),Notch1(Conlon et al 1995),Dll1(Hrabe de Angelis et al 1997),lunatic fringe (EvrardA n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .196OLSENREGINATOWANGFigure 2Diagram showing the migration of sclerotomal cells from the ventromedial area of the somites toward the notochord in response to sonic hedhehog expression by the notochord and ﬂoor plate.Modiﬁed from Mundlos &Olsen 2000.et al 1998,Zhang &Gridley 1998),and Dll3(Kusumi et al 1998),and the pudgy mutation in mice (disruption of Dll3),result in vertebral and rib defects that are similar to many axial abnormalities in humans.These genes are therefore excel-lent candidates for human disorders of segmentation in the vertebral column.In fact,one form of such a disorder has been mapped to the locus of Dll3(Turnpenny et al 1999),and mutations in Dll3have been found (Bulman et al 2000).Patterning and differentiation of cells within the somites are controlled by sig-nals from the notochord and neural tube ﬂoorplate,the surface ectoderm,and the neural tube.These signals induce epithelial-mesenchymal transformation and proliferation of the ventromedial somitic cells and their migration toward the noto-chord (Figure 2).These cells form the sclerotome and become the cartilage in the vertebral bodies and the dorsolateral portion of the ribs.Sonic hedgehog (Shh)is the major signal from the notochord/ﬂoorplate that induces sclerotome formation,but subsequent differentiation of chondrocytes can occur in the absence of Shh.In vitro experiments suggest that the function of Shh is to make sclerotomal cells competent to respond to bone morphogenetic proteins (BMPs)and differentiate into chondrocytes (Murtaugh et al 1999).No sclerotomes develop in mice that are homozygous for Shh null alleles,and there is complete absence of vertebrae and the dorsolateral portion of the ribs (Chiang et al 1996).The mice also show com-plete absence of the distal limb skeleton;this provides a striking demonstration of the crucial role of Shh in patterning of the distal part of the limbs (see below).Under the inﬂuence of Shh,two related Pax genes,Pax1and Pax9,are upregu-lated in sclerotomal cells (Peters et al 1999).The expression of Pax1precedes that of Pax9.It is initially seen in all cells but later is at the highest level in the pos-terior ventromedial region of the sclerotomes.Pax9expression is more intense inA n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .BONE DEVELOPMENT 197the posterior ventrolateral region.As chondrogenesis proceeds,the expression of both Pax genes is downregulated,but it continues in cells in the perichondrium and in intervertebral regions.Studies of natural mutations in Pax1in undulated mouse mutants (Chalepakis et al 1991),as well as of mice with targeted Pax1null alleles (Wilm et al 1998),suggest that homozygosity for loss-of-function mutations in Pax1results in abnormalities in the vertebral column,sternum,and scapula that are not embryonic lethal.In contrast,mice that are homozygous for null alleles of Pax9die shortly after birth;they lack the derivatives of both the 3rd and 4th pha-ryngeal pouches (thymus,parathyroid,ultimobranchial bodies).They also have a cleft palate and other craniofacial defects and no teeth,as well as extra digits in fore-and hindlimbs (Wallin et al 1994),consistent with Pax9expression in those regions of the embryo.It is possible that lack of axial bone defects in Pax9null mice is the result of compensation by Pax1because Pax1and Pax9double-null mutants have no ventral vertebral bodies or intervertebral discs (Peters et al 1999).Patterning of the axial skeleton along the rostrocaudal axis,i.e.the deﬁnition of the identity of individual vertebrae,is accomplished by the expression of homeotic (Hox )genes in overlapping domains along the vertebral column (Burke et al 1995,Favier &Dolle 1997).Ectopic expression or targeted deletion of Hox genes in the mouse leads to addition or deletion of vertebral elements or changes into shapes resembling other elements (Chen et al 1998,Zakany et al 1997).Development and Disorders of the Limb SkeletonThe skeletal tissues in the limb are produced by cells derived from the lateral plate mesoderm (Cohn &Tickle 1996).Other tissues,such as nerves,blood vessels,and muscles,are formed by cells from somites that migrate into the growing limb buds.The patterning of the mesenchyme in the limb and the ultimate shaping of the limb bones are due to a series of interactions between the mesenchyme and the overlying epithelium (Ng et al 1999).The proximodistal outgrowth is directed by ﬁbroblast growth factor signals from the specialized epithelial cells in the apical ectodermal ridge (AER)covering the tip of the limb bud (Ng et al 1999);anteroposterior patterning is directed by sonic hedgehog produced by a small group of cells in the posterior zone of polarizing activity (ZPA)(Riddle et al 1993);and dorsoventral patterning depends on secretion of Wnt7a (Parr &McMahon 1995)and expression of radical fringe by the dorsal ectoderm and expression of the homeobox-containing transcription factor engrailed in the ventral ectoderm (Laufer et al 1997a,Loomis et al 1998,Rodriguez-Esteban et al 1997).Wnt7a induces and maintains expression of the LIM-homeodomain protein Lmx1b in dorsal limb mesenchymal cells;a mutation in Wnt7a is the basis for the mouse mutant postaxial hemimelia (Parr et al 1998).Ectopic expression of Lmx1in ventral mesenchyme generates double-dorsal limbs in chick embryos (Riddle et al 1995),and mutations in LMX1B in humans are the causes of the so-called nail-patella syndrome,a disorder characterized by dysplasia of nails and hypoplasia/aplasia of the patella,combined with renal anomalies (Dreyer et al 1998,V ollrath et al 1998).Since the limbs develop in a proximodistal sequence,the cartilage anlagen of theA n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .198OLSENREGINATOWANGFigure 3Diagram showing how cartilage elements in the developing forelimb are formed in a proximodistal sequence with increasing developmental time (arrow),such that the humerus anlage is formed ﬁrst,the metacarpal anlagen (I-V)last.The elements formed arise through a series of bifurcations and segmentations of mesenchymal condensations along the posterior (ulnar)axis of the limb.The limb genes discussed in the review are listed outside the diagram.On the right are genes controlled by sonic hedgehog and genes related to BMP signaling.At the top are genes expressed by the apical ectodermal ridge;at the bottom are transcription factor genes associated with establishment of limb identity.On the left are genes associated with speciﬁcation of dorsal-ventral properties.Modiﬁed from Shubin &Alberch 1986.limb bones are produced in the same order,with humerus/femur formed ﬁrst and the phalangeal anlagen added last.The cartilages are formed as continuous rods that through a series of bifurcations and segmentations give rise to the characteristic limb skeleton (Shubin &Alberch 1986)(Figure 3).Segmentation and associated apoptotic cell death result in the formation of joints.The development of joints is controlled by BMP and BMP homologues,as well as their extracellular antagonists such as noggin,that bind BMP and reduce signaling through their cell surface receptors (Laufer et al 1997b,McMahon et al 1998,Storm &Kingsley 1999,Zou et al 1997).Several conditions that include shortening of ﬁngers and toes (brachydactylies),either alone or in combination with short bones in the lower limbs (acrome-somelic dysplasia),provide insights into the roles of BMPs and related molecules in limb bone growth and joint formation.Brachydactyly type C is caused by mutations in CDMP1(cartilage-derived morphogenetic protein 1;also called GDF5for growth and differentiation factor 5)that result in functional haploin-sufﬁciency (Polinkovsky et al 1997).In mice,homozygosity for functional null alleles of Gdf5leads to brachypodism (Storm et al 1994).Homozygosity for CDMP1mutations in humans causes acromesomelic dysplasias (Thomas et al 1996,1997).These are disorders characterized by short stature in combination with shortening of forearms and lower legs as well as the long bones of hands and feet.With homozygosity for CDMP1null alleles,the result is the clinical condition called acromesomelic dysplasia Hunter-Thompson type.In the more severe Grebe type,affected individuals have a null allele on one chromosomeA n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .BONE DEVELOPMENT 199and an allele with a dominant-negative mutation on the other chromosome.The dominant-negative effect appears to be the result of the ability of the mutant protein to form heterodimers with other BMPs and prevent their secretion.Interference with BMP signaling is also the cause of inherited absence of proximal interpha-langeal joints,fusion of wrist and ankle bones,and conductive deafness.This disorder,called proximal symphalangism,has been shown to be caused by muta-tions in the BMP-binding molecule noggin.Noggin mutations are also associated with multiple dysostoses syndrome,a disorder characterized by fusion of sev-eral joints (elbows,hips,intervertebral)in addition to joints in the hands and feet (Gong et al 1999).Not surprisingly,mice that are homozygous for targeted noggin alleles have multiple defects,including fusion of limb bones (McMahon et al 1998).Abnormalities of limb bones associated with either anomalies of the heart or breast tissues are seen in Holt-Oram and the ulnar-mammary syndromes.The two conditions are caused by mutations in the transcription factors TBX5and TBX3,respectively (Bamshad et al 1997,Basson et al 1994,Li et al 1997),which are members of the T-box transcription factor family whose canonical member is Brachyury or T ,a transcription factor involved in the development of posterior mesoderm during gastrulation.TBX5is expressed in developing forelimbs but not hindlimbs (Chapman et al 1996),whereas TBX4is expressed only in the developing leg (Isaac et al 1998).It is currently believed that the two factors regulate limb outgrowth and identity (Gibson-Brown et al 1996,1998;Ohuchi et al 1998;Takeuchi et al 1999).The homeodomain transcription factor Pitx1is an upstream regulator of Tbx4(Logan &Tabin).Mice with Pitx1null alleles have abnormalities in tibia,ﬁbula,patella,and tarsal bones so that they look more like the skeletal elements of forelimbs,as well as cleft palate and changes in the pituitary (Lanctot et al 1999,Szeto et al 1999).Misexpression of Pitx1in the wing bud of chick embryos causes the wings to become more like legs (Logan &Tabin 1999),and misexpression of Tbx4and Tbx5in wing buds and leg buds of chick embryos changes the identity,at least partially,of the limbs (Rodriguez-Esteban et al 1999,Takeuchi et al 1999).The importance of sonic hedgehog signaling for anteroposterior patterning of the limb skeleton is dramatically illustrated by several disorders in which an in-creased number of digits,polydactyly,are seen in variable association with fu-sion of soft interdigital tissues or bones,syndactylies.In Greig cephalopolysyn-dactyly,deletions or truncations of the transcription factor gene GLI3,a zinc ﬁnger transcriptional repressor downstream of sonic hedgehog signaling (Marigo et al 1996),result in broad thumbs,polydactyly,syndactyly,and craniofacial anoma-lies (V ortkamp et al 1991).Pallister-Hall syndrome,with a phenotype that overlaps that of Greig syndrome,and isolated postaxial polydactyly with an extra digit on the ulnar or ﬁbular side of the hands or feet have been shown to be caused by frameshift mutations in GLI3(Kang et al 1997,Radhakrishna et al 1997).In mice,mutations in Gli3cause the phenotypes extra-toes (xt )(Hui &Joyner 1993)and polydactyly Nagoya (Pdn )(Thien &Ruther 1999).A n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .200OLSENREGINATOWANGOne of the target genes of sonic hedgehog signaling is Sall1,a zinc ﬁnger transcription factor and vertebrate homologue of Drosophila spalt ,expressed in all known hedgehog signaling areas of the embryo,including the notochord,limb buds,and urogenital ridge-derived structures (Ott et al 1996).This explains why Townes-Brocks syndrome,caused by mutations in SALL1,is characterized by craniofacial anomalies,hand anomalies with polydactyly,as well as renal and anal anomalies (Kohlhase et al 1998).Sonic hedgehog also controls a posterior-anterior nested expression pattern of Hoxd genes in the developing lower arms (legs)and hands (feet).A striking il-lustration of the role of Hoxd genes in the limbs is provided by synpolydactyly,where mutations in HOXD13,the most 5 gene in the HOXD cluster on chromo-some 2,result in syndactyly between ﬁngers three and four and toes four and ﬁve,and duplication of a ﬁnger in the syndactylous web in the hand (Muragaki et al 1996).All mutations,as well as the mutation in a mouse model (Spdh )of the human condition,are in-frame expansions of a 15-residue polyalanine tract in the N-terminal region of HOXD13(Goodman et al 1997,Johnson et al 1998).It is likely that the mutations result in gain-of-function in direct proportion to the size of the expansion.Frameshift mutations in HOXD13that are expected to lead to null alleles have also been described;these mutations cause the same hand phenotype as the polyalanine expansions,but a different foot abnormality,with a rudimentary digit between metatarsals one and two (Goodman et al 1998).CHONDROCYTE DIFFERENTIATION AND ENDOCHONDRAL BONE FORMATION Chondrogenesis—the Role of Sox GenesThe role of the transcription factor SOX9in chondrogenesis was ﬁrst recognized through the discovery that mutations in SOX9cause the rare and severe dwarﬁsm campomelic dysplasia (CD)in humans (Foster et al 1994,Wagner et al 1994).CD patients show bowing and angulation of long bones,scapular and pelvic hy-poplasia,abnormalities of the vertebral column,a decreased number of ribs,and a small chondrocranium resulting in several craniofacial anomalies.These skele-tal abnormalities are frequently associated with XY sex reversal (Mansour et al 1995),consistent with a role for SOX9in testis differentiation (Morais da Silva et al 1996).Mutations in the SOX9coding region are scattered along the protein sequence and are believed to result in haploinsufﬁciency (Meyer et al 1997).These skeletal abnormalities are consequences of a defect in chondrocyte differ-entiation within mesenchymal condensations and deﬁcient synthesis of cartilage matrix.Sox9transcripts are detected in all prechondrogenic mesenchymal con-densations as early as 8.5to 9.5days of mouse embryonic development,and the expression peaks in cartilage primordia at 11.5to 14.5days (Ng et al 1997,Wright et al 1995).Like collagen type II,encoded by Col2a1,Sox9is expressed at high levels in all prechondrocytes and chondrocytes.Consistent with XY reversal,Sox9A n n u . R e v . C e l l . D e v .B i o l . 2000.16:191-220. D o w n l o a d e d f r o m a r j o u r n a l s .a n n u a l r e v i e w s .o r g b y G w e n d i c k e r s o n o n 02/03/06. F o r p e r s o n a l u s e o n l y .。

老年学概论第一章人类个体和群体老龄化

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复习思考题： 1.人口老龄化的科学含义是什么？ 2.影响人类寿命的主要因素有哪些？
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21世纪人口学系列教材
老年学概论
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邬沧萍姜向群主编
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中国人民大学出版社
第一章人类个体和群体老龄化
第一节人类个体的衰老和寿命第二节人口老龄化第三节老龄工作
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任何科学都产生于实践的需要。科学是系统知识，要求认识事物的本质（客观规律）：任何科学都有它研究的客体或研究的现象和过程。任何科学理论都是用于指导实践。如果没有实践工作可指导，理论是没有任何价值的。
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（二）环境因素 1.原生环境 2.次生环境 3.、人口老龄化的理论解释
人类认识个体老龄化比较容易。人们在实际生活中认识到增龄现象，即随着时间推进每一个日历年增长1岁。到一定年龄后，增龄现象便伴随着生理的衰老而发生。衰老也称为老化现象，但增龄又不是同衰老同步发生的。
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二、生产力发展导致死亡率下降——人口老龄化的基础
在历史上，人类的寿命很短。在奴隶社会和封建社会，人类的平均寿命只有20岁～30 岁。在19世纪上半叶，今天的发达国家死亡率仍高达32‰，是今天中国死亡率的几倍。
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三、生产力发展加速出生率下降——人口老龄化的决定性因素
出生率下降是人口老龄化的一个必要条件。在18世纪，全世界各国毫无例外都是高出生率国家，那时欧洲国家每个妇女平均生育六个孩子，亚非拉国家每个妇女生育七八个孩子是很平常的事情，在那个年代人们还不知道人口老龄化为何物。
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二、老龄问题的人道主义问题和发展问题
把老龄问题区分为人道主义方面和发展方面，对于深入认识人口老龄化和采取适当的对策都是很有意义的，二者既有联系也有区别。

寿命是自己一点一滴努力来的读后感

寿命是自己一点一滴努力来的读后感英文版Reflections on "Life Span is Earned Drop by Drop"As I reflected on the title "Life Span is Earned Drop by Drop,"I was reminded of the profound truth behind its simple words. This phrase encapsulates the essence of our existence, the idea that every moment, every choice, and every effort we make contributes to the length and quality of our lives.Firstly, the phrase reminds us of the power of small actions. It's not just the grandiose moments or the significant achievements that shape our lives; it's the consistent, daily efforts that truly matter. Whether it's the choice to eat healthily, the decision to exercise regularly, or the effort to stay positive in difficult times, these small actions accumulate over time to create significant change.Moreover, this phrase encourages us to take ownership of our lives. Our lifespan is not just a matter of genetics or fate; it'sa result of our choices and actions. We have the power to shape our own destiny by making conscious decisions about our health, happiness, and growth.Furthermore, it underscores the importance of balance. A life well-lived is not just about working hard; it's also about taking time to rest, recharge, and enjoy the moments that make life worth living. By prioritizing our well-being and finding joy in the simple pleasures of life, we can create a richer, more fulfilling existence.In conclusion, "Life Span is Earned Drop by Drop" is a powerful reminder that our lives are shaped by the choices we make and the efforts we put in every day. It encourages us to take control of our destiny, to cherish every moment, and to make the most of every opportunity to create a longer, healthier, and happier life.中文版《寿命是自己一点一滴努力来的》读后感在深入思考“寿命是自己一点一滴努力来的”这句话后，我被其中所蕴含的深刻真理所打动。

病生名解大题总结@医学生联盟

病理生理学名解简答名词解释1、病理生理学（pathophysiology）：是一门研究疾病发生、发展规律和机制的学科。

任务是以患病机体为对象，研究整个疾病过程中机体的机能、代谢的动态变化及其变化机制，从而揭示疾病发生、发展和转归的规律，阐明疾病的本质，为疾病的防治提供理论基础。

2、疾病（disease）：是在致病因素的损伤与机体的抗损伤作用下，因机体稳态调节紊乱而发生的异常生命活动过程。

此时体内有一系列功能、代谢和形态的改变，临床出现许多不同的症状与体征，机体与外环境间的协调发生障碍。

3、脑死亡（brain death）：是枕骨大孔以上全脑死亡；大脑、小脑、脑干功能永久性消失。

4、高渗性脱水（hypertonic denydration）：是指体液容量减少，以失水多于失钠，血清钠浓度＞150mmol/L，血浆渗透压＞310mmol/L为主要特征的病理过程。

5、水中毒（water intoxication）：是指患者肾排水功能降低，或再输入大量水，使细胞内外液容量均增加，血清钠浓度＜130mmol/L，血浆渗透压＜280mmol/L，又称高容量性低钠血症。

6、水肿（edema）：过多的液体在组织间隙或体腔内积聚的病理过程，称为水肿。

7、酸碱平衡紊乱（acid-base disturbance）：在一些病理情况下，由于酸碱负荷过度、不足或调节机制障碍而导致体液酸碱度稳态破坏，形成酸碱平衡紊乱。

8、代谢性酸中毒（metabolic acidosis）:是指细胞外液H+增加和（或）HCO3-丢失而引起的以血浆[HCO3-]减少为特征的酸碱平衡紊乱。

呼吸性酸中毒（respiratory acidosis）:是指CO2排出障碍或吸入过多引起的以血浆H2CO3（或PaCO3）增高为特征的酸碱平衡紊乱。

9、代谢性碱中毒（metabolic alkalosis）：是指细胞外液H+丢失或碱过多而引起血浆HCO3-浓度升高为特征的酸碱紊乱。

2017年12月大学英语四级真题及答案解析(全三套)

2017年12月大学英语四级真题及答案解析(全三套) 四级听力第一套：News Report 1A 9-year-old girl in New Mexico has raised more than $500 for her little brother who needs heart surgery in Houston, Texas this July. Addison Witulski's grandmother Kim Allred, said Addison probably overheard a conversation between family members talking about the funds needed to get her little brother to treatment. "I guess she overheard her grandfather and me talking about how we're worried about how we're going to get to Houston, for my grandson's heart surgery," said Allred. She decided to go outside and have a lemonade stand and make some drawings and pictures and sell them.” That's when Addison and her friends Erika and Emily Borden decided to sell lemonade for 50 cents a cup and sell pictures for 25 cents each.Before Allred knew it, New Mexico State Police Officers were among the many stopping by helping them reach a total of $568. The family turned to social media expressing their gratitude saying, "From the bottom of our hearts, we would like to deeply thank each and every person that stopped by!"1: Who did Addison raise the money for?2: How did Addison raise the money?1.D) Her little brother.2.B) By selling lemonade and pictures.News Report 2:Last week, France announced that the country will pave 621 miles of road with solar panels over the next five years with the goal of providing cheap, renewable energy to five million people. Called the Ward Way, the roads will be built through joint efforts with the French road building company Colas and the National Institute of Solar Energy. The companyspent the last five years developing solar panels that are only about a quarter of inch thick and are strong enough to stand up to heavy highway traffic without breaking or making the roads more slippery. The panels are also designed so that they can be installed directly on top of the existing roadways, making them relatively cheap and easy to install. France is the first country to kick around the idea of paving its roads with solar panels. In November 2015, the Netherlands completed a 229-foot long bike path paved with solar panels as a test for future projects. However, this is the first time a panel has been designed to be laid directly on top existing roads and the first project to install the panels on public highways.3: What was France’s purpose of constructing the Ward Way?4: What is special about the solar panels used in the Ward Way?3.B) Providing clean energy to five million people.4.C) They can be laid right on top of existing highways.News Report 3Lions have disappeared from much of Africa, but for the past few years scientists have wondered if the big cats were hanging on in remote parts of Sudan and Ethiopia. Continuous fighting in the region has made surveys difficult. But scientists released a report Monday documenting with hard evidence the discovery of "lost lions." A team with Oxford University’s Wildlife Conservation Research Unit, supported by a charity organization, spent two nights in November camping in a national park in northwest Ethiopia on the Ethiopia-Sudan border. The researchers set out six camera traps, capturing images of lions, and the identified lion tracks. The scientists concluded that lions are also likely to live in a neighboring national park across the border in Sudan. The International Union for Conservation of Nature had previously considered the area a "possible range" for the species, and local people had reported seeing lions in the area, but no one presented convincing evidence.5: What has made it difficult to survey lions in remote parts of Sudan and Ethiopia?6: What was the main purpose of the research?7: What did the researchers find in the national park?5.C)Endless fighing in the region.6.D)To find evidence of the lions'disappearance.7.A)Lions'tracks.Conversation OneM: I beg you’re looking forward to the end of this month. Aren’t you?W: Yes, I am. How did you know?M: David told me you had a special birthday coming up.W: Oh, yes. That’s right. This year would be my golden birthday.M: What does that mean? I’ve never heard of a golden birthday.W: I’ve actually just learned of this concept myself. Fortunately, just in time to celebrate. A golden or lucky birthday is when one turns the age of their birth date. So, for example, my sister’s birthday is December 9th and her golden birthday would have been the year she turns 9 years old. Come to think of it , my parents did throw her a surprise party that year. M: Intere sting. Too bad I missed mine. My golden birthday would’ve been four years ago.I assumedly got a big plan then.W: Actually yes. My husband is planning a surprise holiday for the two of us next week. I have no idea what he’s gotten in mind, but I’m excited to find out. Has he mentioned anything to you?M: He might have.W: Anything you’d like to share? I’m dying to know what kind of trip he has planned where we’re going.M: Yeah, nothing at all.W: Not a clue. Hard to imagine, isn’t it! Though I must say, I think it has been even more fun keeping the secret for me the past few weeks.M: I’m sure both of you will have a fantastic time. Happy golden birthday! I can’t wait to hear all about it when you get back.8. What does the woman looking forward to?9. W hat did the woman’s parents do on her sister’s lucky birthday?10. What is the woman eager to find out about?11. What does the man say at the end of the conversation?8.D) Her "lucky brithday".9.A) Threw her a superise party.10.C) The trip her husband has planned.11.B) He is eager to learn how the couple's holiday turns out.Conversation TwoW: Mr. Green, What do you think makes a successful negotiator?M: Well, It does hard to define, but I think successful negotiators have several things in common. They are always polite and rational people, they are firm, but flexible. They can recognize power and know how to use it. They are sensitive to the dynamics in the negotiation, the way it raises and falls, and how may change the direction. They project the image of confidence, and perhaps most importantly, they know when to stop.W: And what about an unsuccessful negotiator?M: Well, this probably all of us when we start out. We are probably immature and over-trusting, too emotional or aggressive. We are unsure of ourselves and want to be liked by everyone. Good negotiators learn fast, pool negotiators remain like that and go on losing negotiations,W: In your opinion, can the skills of negotiation be taught?M: Well, you can teach someone how to prepare for negotiation. There perhaps six stages in every negotiation, get to know the other side, stay your goals, start the process, clarify there is a disagreement or conflict, reassess your position, making acceptable compromise, and finally reach some agreements and principals. These stages can be studied, and strategies to be used in each can be planned before-hand. But I think the really successfulnegotiator is probably born with the sixth sense that may respond properly to the situation at hand.W: The artistic sense you just described?M: Yes, that’s right12. What’s the man say about good negotiators?13. What does the man say, maybe the most important thing to a successful negotiator?14. How is a good negotiator different from a poor one?15. What’s th e first stage of a negation according to the man?12. A) They are sensitive to the dynamics of a negotiation.13. B) They know when to stop.14. C) They learn quickly.15. D) Get to know the other side.Passage OneSome people wonder why countries spend millions of dollars on space projects. They want to know how space research helps people on earth. Actually, space technology helps people on earth every day. This is called spin-off technology. Spin-off technology is space technology that is now used on earth. In early space programs, such as the Apollo missions of the 1960s and 1970s and in the space shuttle missions today, scientists developed objects for the astronauts to use on the moon and in space. We now use some of these objects every day. For example, we have quartz crystal clocks and watches accurate to within one minute a year. We purify the water we drink with the water filter designed for the astronauts to use in space. The cordless hand held tools we use in our homes, such as vacuum cleaners, flashlights, drills came from the technology of these early space programs. On cold winter days, we can stay warm with battery-operated gloves and socks, especially made coats and jackets. All the clothes are similar to the space suits designs that kept astronauts comfortable in the temperatures of the moon, in our spin offs from space technology. These products are only a few examples of the many ways spacetechnology helps us in our everyday lives. No one knows how new spin off technology from the international space station will help us in the future.16. What do some people want to know about space exploration?17. What did scientist do for the space shuttle missions?18. What does the speaker say about the quartz crystal clocks and watches?16. D) How space research benefits people on Earth.17. B) They developed objects for astronauts to use in outer space.18. C) They are extremely accurate.Passage TwoWell, if I could get back in history and live, I'd like to get back to the 18th century and perhaps in colonial America in Yankee new England where one of my ancestors lived, because it was the beginning of something. By the 18th century, there was a feeling of community that had grown. My ancestor was the preacher traveling around countryside. People lived in small communities. It was fisherman and farmers who provided fresh food that tasted and looked like food. Unlike today’s supermarkets, and there were small towns and New York wasn't that far away. I'm deeply attached to the puritan tradition not in a religious sense. But they believed in working for something, working for goals. And I like that. They worked hard at whatever they did, but they had a sense of achievement. They believed in goodness, in community, and helping one another. I love the colonial fabrics or the silver works, the furnishings, the combination of elegance simplicity. I'd love it. The printing, the books, I’m very attached to all that kind of thing. That may not all be very entertaining in the modern sense of the world, but I would have enjoyed spending my evenings in that environment, discussing new ideas, building a new world, and I can see myself sitting on a small chair by the fire doing needle work.19. Why does the speaker say she would like to go back and live in the 18th century America?20. What does the speaker say about the Puritans?21. What would the speaker like doing if she could go back to the past?19. C)It marked the beginning of something new.20. A)They believed working for goals.21. D)Doing needlework by the fire.Passage threeIf you are lost in the woods, a little knowledge concerned with some people called a hardship into an enjoyable stay away from the troubles of modern society. When you think you're lost,sit down on the log or rock, or lean against the tree, and recite something you are memorized to bring your mind to the point where is under control. Don’t run blindly if you must move, don't follow stream unless you know it, and in that case you're not lost. Streams normally flow through wide land before they reach a lake or river though there are more eatable plants, there may also be wild animals, poisonous snakes, and other hazards. Many experts feel it is the wisest to walk up hill. At the top of most hills and mountains are trails living back to civilizations. If there are no trails, you're much easier to be seen on top of the hill. And you may even spot the highway or railroad from this point. Nowadays, the first way some of you search for you is by air. In the wide lands or in dense grass, we're very hard to spot. Anytime you are going to the woods, somebody should know where you're going, and when you are expected to return, also when someone comes to looking, you should be able to signal to them.22. What does the speaker advise you to do first if you are lost in the woods?23. What will happen if you follow an unknown stream in the woods?24. What do many experts think is the wisest thing to do if you're lost in the woods?25. What should you do before you go into the woods?22. C) Sit down and try to calm yourself23. B) You may expose yourself to unexpected dangers.24. D) Walk uphill.25. A) Inform somebody of your plan.四级听力第二套：答案：1.D) It has got one of its injured.2.C) Its videos were posted on social media.3.A) The distance travelled.4.B) Gas consumption is soaring.5.B) He helps a stranger to carry groceries to his car.6.C) He raised a large sum of money for him.7.A) He works hard to support his family.8. A) Attend an economics lecture9. C) Attend his brother’s birthday party10. D) Join him in his brother’s birthday celebration11. B) By train12. A) Taking a vacation abroad.13. C) Working part time as a waiter.14. B) Save enough money..15. A) He has rich sailing experience.16. D) She was also a Nobel Prize winner.17. B) She developed X-ray facilities for military hospitals.18. A) Both died of blood cancer.19. C) They discovered Iceland in the ninth century.20. D) It was a rocky mass of land covered with ice.21. A) Thee Viking’s ocean explorations.22. C) Dream about the future.23. B) Change what he has for his past imaginary world.24. D) International business.25. B) Be content with what you have.四级阅读第一套：选词填空26. [K] superior27. [D] nuisance28. [M] tip29. [O] visual30. [A] associated31. [F] preventing32. [H] sensitive33. [I] slight34. [C] indicate35. [J] specify匹配题36. [I] Elderly students find it hard to keep up with the rapid changes in education.37. [E] Some believe take-home exams may affect students' performances in others courses.38. [C] Certain professors believe in-class exams are ultimately more helpful to students39. [D] In-class exams are believed to discourage cheating in exams.40. [B] The author was happy to learn she could do some exams at home.41. [H] Students who put off their work until the last moment often find the exams more difficult than they actually are.42. [G] Different students may prefer different types of exams.43. [F] Most professors agree whether to give an in-class or a take-home exam depends on the type of course being taught.44. [A] The author dropped out of college some forty years ago.45. [J] Some students think take-home exams will eat up their free time.仔细阅读46. B They just cannot do anything about it.47. A It might be prevented and treated.48. D It will motivate doctors and pharmacists to find ways to treat aging.49. C They can contribute to people's health only to a limited extent.50. A The human lifespan cannot be prolonged.51. C More males than females are likely to get outstanding letters of recommendation.52. C Men are believed to be better able to excel in STEM disciplines.53. B They contain nothing that distinguishes the applicants.54. D They deleted all information about gender.55. D Start a public discussion on how to raise women's status in academic circles.四级阅读第二套：选词填空We all know there exists a great void（空白）in the public educational system when itcomes to 26 to STEM (Science, Technology, Engineering andMathematics) courses. One educator named Dori Roberts decided to do somethingto change this system. Dori taughthigh school engineering for 11 years. Shenoticed there was a real void in quality STEM education at all 27 ofthe public educational system. She said, “I started Engineering For Kids (EFK)after noticing a real lack of math, science and engineering programs to 28 myown kids in.”She decided to start an afterschool programwhere children 29 in STEM-based competitions. The clubgrew quickly and when it reached 180 members and the kids in the program wonseveral state 30 , she decided to devote all her time tocultivating and 31 it. The global business EFK was born.Dori began operating EFK out of her Virginiahome, which she then expanded to 32 recreation centers. Today, the EFK program 33 over 144 branches in 32 states within theUnited States and in 21 countries. Sales have doubled from $5 million in 2014to $10 million in 2015, with 25 new branches planned for 2016. The EFK websitestates, “Our nation is not 34 enough engineers. Our philosophy is to inspirekids at a young age to understand that engineering is a great 35 .”26. G exposure27. L levels28. F enroll29. O participated30. C championships31. E developing32. M local33. N operates34. J graduating35. B career匹配题36. To be curious, we need to realize first of all thatthere are many things we don’t know.H）Moreover,in order to be curious , ” you have to aware of a gap in your knowledge in thefirst place.” Although Leslie perhaps paints a bit broadly in contending thatmost of usare unaware of how much we don’t know, he’s surely right to pointout that the problem is gro wing:”Google can give us the powerful illusion thatall questions have definite answers.”37. According to Leslie, curiosity is essential to one’ssuccess.D) Thejournalist Ian Leslie, in his new and enjoyable book Curious: The Desire to Know and Why Yo ur Future Depends on It,insists that the answer to that last question is “Yes”. Leslie argues thatcuriosity is a much-overlooked human virtue, crucial to our success, and thatwe are losing it.38. We should feel happy when we pursue knowledge forknowledg e’s sake.O) All of which brings us back to Goodelland the Christie case and Benghazi. Each critic in those examples is charging,in a different way, that someone in authority is intentionally being incurious.I leave it to the reader's political preference to decide which, if any,charges should stick. But let’s be careful about demanding curiosity about theother side’s weaknesses and remaining determinedly incurious about our own. Weshould be delighted to pursue knowledge for its own sake—even when what we findout is something we didn't particularly want to know.39. Political leaders’ lack of curiosity will result inbad consequences.M) AlthoughLeslie’s book isn’t about politics, he doesn’t entirely shy away from theproblem. Political leaders, like leaders of other organizations, should becurious. They should ask questions at crucial moments. There are seriousconsequences, he warns, in not wanting to know.40. There are often accusations about politicians’ andthe media’s l ack of curiosity to find out the truth.B) Theaccusation of incuriosity is one that we hear often, carrying the suggestionthat there is something wrong with not wanting to search out the truth. “I havebeen bothered for a long time about the curious lac k of curiosity,” said aDemocratic member of the New Jersey legislature back in July, referring to aninsufficiently inquiring attitude on the part of an assistant to New JerseyGovernor Chris Christie who chose not to ask hard questions about the GeorgeWashi ngton Bridge traffic scandal. “Isn’t the mainstream media the least bitcurious about what happened?” wrote conservative writer Jennifer Rubin earlierthis year, referring to the attack on Americans in Benghazi, Libya.41. The less curious a child is, the less knowledge thechild may turn out to have.L) Schooleducation, he warns, is often conducted in a way that makes children incurious.Children of educated and upper-middle-class parents turn out to be far morecurious, even at early ages, than children of working class and lower classfamilies. That lack of curiosity produces a relative lack of knowledge, and thelack of knowledge is difficult if not impossible to compensate for later on.42. It is widely accepted that academic accomplishmentlies in both intelligence and diligence.K) Citingthe work of psychologists and cognitive（认知的）scientists, Leslie criticizes the received wisdomthat academic success is the result of a combination of intellectual talent andhard work. Curiosity, he argues, is the third key factor—and a difficult one topreserve. If not cultivated, it will not survive：“Childhood curiosity is a collaboration between childand adult. The surest way to kill it is to leave it alone.”43. Visiting a bookshop as curiosity leads us can be agood way to entertain ourselves.J) Somewhatnostalgically（怀旧地），he quote John Maynard Keynes’s justlyfamous words of praise to the bookstore:”One should enter it vaguely, almost ina dream, and allowwhat is there freely to attract and influence the eye. Towalk the rounds of the bookshops, dipping in as curiosity dictates, should bean afternoon’s entertainment.” If only!44. Both the rise of the Internet and reduced appetitefor literary fiction contribute to people’s declining curiosity.G) Lesliepresents considerable evidence for the proposition that the society as a wholeis growing less curious. In the U.S. and Europe, for example, the rise of theInternet has led to a declining consumption of news from outside the reader’sborders. But not e verything is to be blamed on technology. The decline ininterest in literary fiction is also one of the causes identified by Leslie.Reading literary fiction, he says, make us more curious.45.Mankind wouldn’t be so innovative without curiosity.F) Why isthis a problem? Because without curiosity we will lose the spirit of innovationand entrepreneurship. We will see unimaginative governments and dyingcorporations make disastrous decisions. We will lose a vital part of what hasmade humanity as a whole so successful as a species.仔细阅读46. What do we learn from the passage about cities in sub-Saharan Africa?B）They are growing fast without becoming richer47. What does the author imply about urbanisation in other parts of the world?B) It started whe n people’s income was relatively high.48. Why is sub-Saharan Africa unappealing to investors?A) It lacks adequate transport facilities.49. In what way does author say African cities are different?C) They have developed at the expense of nature.50. What might be a solution to the problems facing African cities?D) A more responsible government51. It used to be commonly acknowledged that to succeed in America, one had to have___.B) an ambition to get ahead52. What is the finding of the latest National Journal poll concerning the American dream?C) Americans’ idea of it has changed over the past few decades.53. What do Americans now think of the role of college education in achieving success?A) It still remains open to debate.54. How do some people view college education these days?D) It helps broaden their minds.55. What is one factor essential to success in America, according to Will Fendley?D) A clear aim and high motivation.四级阅读第三套：选词填空26. K superior27. D nuisance28. M tip29. O visual30. A associated31. F preventing32. H sensitive33. I slight34. C indicate35. B examine匹配题36. I37. E38. C39. D40. B41. H42. G43. F44. A45. J仔细阅读46. What do people generally believe about aging?B) They just cannot do anything about it.47. How do many scientists view aging now?A) It might be prevented and treated.48. What does Alex Zhavoronkov think of “describing aging as a disease”?D) It will motivate doctors and pharmacists to find ways to treat aging.49. What do we learn about the medical community?C) They can contribute to people’s health only to a limited extent.50. What does Professor Leonard Hayflick believe?A) The human lifespan cannot be prolonged.51. What do we learn about applicants to postdoctoral positions in geosciences?C) More males than females are likely to get outstanding letters of recommendation.52. What do studies about men and women in scientific research show?C) Men are believed to be better able to excel in STEM disciplines.53. What do the studies find about the recommendation letters for women applicants?B) They contain nothing that distinguishes the applicants.54. What did Dutt and her colleagues do with the more than 1,200 letters of recommendation?D) They deleted all information about gender.55. What does Dutt aim to do with her study?D) Start a public discussion on how to raise women’s status in academic circles.四级翻译一：泰山位于山东省西部。

肝性脑病练习题

肝性脑病练习题2013-12-08 14:10:08|分类：病生习题|标签：|举报|字号大中小订阅1.导致肝性脑病的假性神经递质有：A.苯乙胺和酸乙等B.苯乙醇胺和羟苯乙醇胺C.苯乙醇胺、羟苯乙醇胺和5－羟色胺等D.苯乙胺、酪胺和GABA等E.苯乙胺、酪胺和5羟色胺等2.假性神经递质引起肝性脑病的机制是：A.干扰脑的能量代谢B.使脑细胞产生抑制性突触后电位 C.干扰脑细胞膜的功能D.与正常递质竞争受体，但其效应远较正常递质为弱 E.引起血浆氨基酸失衡3.肝性脑病患者氨升高的最主要原因是：A.肠道产氨增多B.氨的清除不足C.肌肉产氨增多 D.血中NH4+向NH3转化增多E.肾小管向血液弥散的氨增多4.氨对脑的毒性作用不包括：A.干扰脑的能量代谢B.使脑内兴奋性递质产生减少 C.使脑内抑制性递质产生增多D.使脑的敏感性增高E.抑制脑细胞膜的功能5.肝性脑病患者血浆支链氨基酸减少的原因是：A.血浆胰高血糖素浓度升高所致B.高胰岛素血症所致 C.肝对支链氨基酸灭活减少D.支链氨基酸合成来源减少E.血浆芳香族氨基酸增多引起6.肝性脑病时，患者氨生成过多的最常见原因是：A.肠道产氨增多B.肌肉产氨增多C.脑产氨增多D.肾产氨产多、并向血液弥散增多E.血液NH4+向NH3转化增多7.使正常递质生成增多、加强正常递质竞争作用的药物是：A.谷氨酸B.精氨酸C.谷氨酸钠D.乳果糖E.左旋多巴8.肝性脑病患者氨清除不足的原因主要见于：A.三羟酸循环障碍B.谷氨酸合成障碍C.谷氨酰胺合成障碍 D.鸟氨酸循环障碍E.肾小管分泌氨减少9.血浆氨基酸失衡学说中所说的支链氨基酸包括：A.亮氨酸、异亮氨酸和缬氨酸B.苯丙氨酸、酪氨酸和色氨酸C.亮氨酸、缬氨酸和色氨酸D.亮丙氨酸和色氨酸和缬氨酸E.苯丙氨酸和酪氨酸10．苯乙醇胺的生成过程是：A 酪氨酸脱羧B 苯丙氨酸脱羧C酪氨酸先脱羧，再羟化D苯丙氨酸先脱羧，再羟化E 酪氨酸先羟化，再脱羧11．列哪一项因素直接影响脑的能量代谢A 苯乙醇氨B 羟苯乙醇氨C 谷氨酰胺血D 5-羟色氨酸E 氨12．哪项氨基酸不是产生肝性脑病的主要因素：A 苯丙氨酸B 酪氨酸C色氨酸D 亮氨酸E 蛋氨酸13．左旋多巴治疗肝性脑病的理论基础是A 氨中毒学说B 血浆氨基酸学说C 假神经递质学说D GABA学说E 神经毒素综合学说14．下列哪项不是肝性脑病的特点：A 大脑形态学有典型改变B 主要以代谢障碍为主C 扑翼样震颤D 神经精神系统变化E 晚期病人出现肝昏迷15．乳果糖治疗肝性脑病的理论基础：A氨中毒学说B 血浆氨基酸学说C 假神经递质学说D GABA学说E 神经毒素综合学说16．肝硬化病人血氨增高的主要原因是：A. 胃肠运动增强B. 胃肠道出血C. 脂肪摄入减少D. 碳水化合物增多E. 肠道细菌活动减弱答案CDBDB AEDAD EDCAA B肾功能衰竭习题-22013-11-26 20:00:52|分类：病生习题|标签：|举报|字号大中小订阅21．昼夜尿比重均在左右,主要反映：A．肾脏浓缩功能障碍；B．肾脏稀释功能障碍；C．肾脏浓缩稀释功能障碍；D．ADH分泌异常；E．肾小球滤过功能受损；22．慢性肾衰病人在快速纠正酸中毒后会发生手足搐搦，是由于：A．促进肠道形成磷酸钙；B．肠道钙吸收减少；C．促进血磷浓度升高；D．钙解离度降低；E．抑制骨骼脱钙；23．慢性肾功衰晚期典型的化验结果是：A．血清钙,血清磷酸盐；B．血清钾,血清氯离子浓度；C．血清尿素氮减少,血清肌酐增多；D．血清钾,血清肌酐增多；E．血清钠,血清钙增多。

considered to be a predictors

considered to be a predictors
"be considered to be a predictor"的意思是“被认为是一个预测指标”。

下面是两个例子：
研究团队在查阅了所有数据之后，注意到了一个明显的趋势：领取养老金的个人所经历的智力下降速度比仍在工作的人快得多。

退休人员智力下降最显著的特征是记忆延迟，这一特征被广泛认为是痴呆症的准确预测指标。

一个人的血液胆固醇浓度被认为是其患上致命心脏病或中风的可能性的预测指标，胆固醇水平越高，预期发病的时间越早。

因此，应该避免摄入过量的食物胆固醇。

2024年教师资格(初级中学)-英语知识与教学能力(高中)考试历年真题摘选附带答案版

2024年教师资格（初级中学）-英语知识与教学能力（高中）考试历年真题摘选附带答案第1卷一.全考点押密题库(共100题)1.(单项选择题)(每题2.00 分) —Do you mind if I______the TV a bit?—Yes, I do, because Fm busy with my homework now.A. turn onB. turn upC. turndownD. turnoff2.(单项选择题)(每题 2.00 分) A Chinese student makes a sentence as follows： He is a rich man who like traveling. The error in that sentence is the result of______.A. negative transferB. positive transferC. overgeneralizationD. pragmatic failure3.(单项选择题)(每题 2.00 分) The party’s reduced vote was______of lack of support for its policies.A. indicativeB. positiveC. revealingD. evident4.(单项选择题)(每题 2.00 分) Which of the following assumptions about vocabulary learning contradicts the modem language teaching theories?A. The best way to learn words is to use them.B. The best way to learn vocabulary is via rote learning.C. An English dictionary is an important aid to students.D. Learning a word involves learning more than just the word itself.5.(单项选择题)(每题 2.00 分) I will always remember my mother^ last few days in this worlD.On February 14th,2000, my class went on a field trip to the beach. I had so much fun. When we returned to school, my teacher told me to go t o the headmaster’s office. When I got into the office，I saw a police officer. Suddenly I realized something was wrong. The police officer told me what had happened and we went to pick my sister up. After that, we went to the hospital and waiteD. Time went slowly.Finally, we got to see our mother, it was terrible.On the next day, the headmaster came and told my two teachers what had happeneD. I was taking a rest that day. I knew it had something to do with my mother. I kept thinking that she either died or had got better. How I wished that she had got better. When my teacher took me outside, my sister ran up to me. She started crying, “She’s gone. Teresa mommy’s gone. She’s deaD. ”1 couldn’t believe it. We jumped into the car and drove straight to the hospi tal. Most of my family were there. The silence was terrible. I knew I had to say goodbye.Today when I look back, I still miss my mother very much, but I know that I will live. My mother was a strong mother，who had the biggest heart. My mother was an angel walking on the earth. I will always remember her as she is living. When someone is asked who their heroes are ,they usually say someone famous, like Michael Jordan or Britney Spears. When someone asks me who my hero is, I tell them, my mother. My mother lives every day. That is what makes her a true hero.What did the headmaster tell the two teachers on the next day?______.A. Her mother had been very ill.B. Her mother had been deaD.C. Her mother had gotten better.D. Her sister came to see her.6.(单项选择题)(每题 2.00 分) The men who race the cars are generally small, with a tight, nervous look. They range from the early 20s to the middle 40s, and it is usually their nerves that go first.Fear is the driver’s constant companion, and tragedy can be just a step behinD. Scarcely a man in the 500 does not carry the scars of accident crashes. The mark of the plastic surgeon is everywhere, and burned skin is common. Sometimes a driver^ scars are invisible, part of his heritage. Two young drivers, Billy Vukovich and Gary Bettenhausen, raced in their first 500 in 1968. Less than 20 years before, their fathers also competed against one another on the Indy track-and died there.All this the drivers accept. Over the years, they have learned to trust their own techniques, reflexes, and courage. They depend, too, on a trusted servant-scientific engineering. Though they may not have had a great deal of schooling (an exception is New Zealand’s Bruce McLaren, who had an engineering degree), many drivers are gifted mechanics， with a feeling for their engines that amount to kinship.A few top drivers have become extremely wealthy, with six-figure incomes from prize money, endorsement, and jobs with auto-product manufacturers. Some have businesses of their own. McLaren designs racing chassis (底盘).Dan GumeyJs California factory manufactured the chassis of three of the first four cars in the 1968 Indy 500, including his own second place car. Yet money is not the only reason why men race cars. Perhaps it isn’t even the major reason. Three times Indy winner(1961, 1964, 1967).A. J. Foyt, for example, can frequently be found competing on dirty tracks in minor-league races, where money, crowds and safety features are limiteD. and only the danger is not. Why does he do it? Sometimes Foyt answers, “It’s in my blooD. ’’Other times he says, “It is good practice.” Now and then he replies, “Don’t ask dumb questions. ’’A. J. Foyt often takes part in minor-league races fo r______ .A. prize moneyB. blood testC. cheers from the crowdD. enjoyment7.(单项选择题)(每题 2.00 分)A teacher may encourage students to__________ when they come acrossnew words infast reading.A. take notesB. ask for helpC. guess meaning from contextD. look up the words in a dictionary8.(单项选择题)(每题 2.00 分) You II find this Travel Guide to be of great ( ) in helping you and your children to get around Malaysia.A. costB. priceC. valueD. expenditure9.(单项选择题)(每题 2.00 分) If a teacher attempts to implement the top-down model to teachA. new word sifter playing the tapeB. new words before playing the tapeC. background information after playing the tapeD. background information before playing the tape10.(单项选择题)(每题 2.00 分) I’ve tried very hard to improve my English. But by no means______with my progress.A. the teacher is not satisfiedB. is the teacher not satisfiedC. the teacher is satisfiedD. is the teacher satisfied11.(单项选择题)(每题 2.00 分) What stage can the following grammar activity be usedat?______.The teacher asks the students to arrange the words of the sentences into different columns marked subject, predicate, object, object complement, adverbial and so on.A. PresentationB. PracticeC. ProductionD. Preparation12.(单项选择题)(每题 2.00 分) Operations which left patients______and in need of long periods of discovery time now leave them feeling relaxed and comfortable.A. unhealthyB. exhaustedC. fearfulD. upset13.(单项选择题)(每题 2.00 分) Mr. King works in a shop and drives a car for the manager. He drives carefully and can keep calm in time of danger, and he has escaped from several accidents. The manager pays him more and the traffic policemen often speak highly of him.Mr. Baker, one of his friends, works in a factory outside the city. Ifs far from his house and he has to go to work by bus. As the traffic is crowded in the morning, sometimes he’s late for the work. His manager warns the young man that he will be sent away unless he gets to his office on time. He hopes to buy a car，but he hasn’t enough money. He decides to buy an old one. He went to the flea market and at last he chose a beautiful but cheap car. He said he wan— ted to have a trial drive, and the seller agreeD. He called Mr. King and asked him to give a hanD.Mr. King examined the car at first and then drove it away. It was five in the morning and there were few cars in the street. At first he drove slowly and it worked well. Then he drovefailed and nearly hit an old woman who was crossing the street. A policeman told him to stop, but the car went on until it hit a big tree by the roaD.“Didn’t you hear me?” the policeman asked angrily.“Yes，I did，sir，” said Mr. King，“ Since it doesn’t listen to me，can it obey you?”Mr. Baker went to the flea market to______.A. buy a second-hand carB. have a trial driveC. choose a new carD. sell his old car14.(单项选择题)(每题 2.00 分)What is the author′ s attitude towards America′ s policies on global warming?A. Critical.B. Indifferent.C. Supportive.D. Compromising.15.(单项选择题)(每题 2.00 分) Which of the following activities helps to train the skill of listening for gist?A. After listening, the students are required to figure out the relationship between the characters.B. After listening, the students are required to sequence the sentences according to the story.C. After listening, the students are required to identify the characters appearing in the story.D. After listening, the students are required to decide upon the title for the text.16.(单项选择题)(每题 2.00 分) —Did you return Tom?s call?—I didn’t need to______, Fll see him tomorrow.A. thoughtB. unlessC. whenD. because17.(单项选择题)(每题 2.00 分) This skirt was made______your mother______her own measure.A. for; toC. to; toD. for; by18.(单项选择题)(每题 2.00 分)She is __________ , from her recording, the diaries of Simon Forman.A. transcribingB. keepingC. paraphrasingD. recollecting19.(单项选择题)(每题 2.00 分) There is no doubt______you will pass the exam this time. You have worked so hard in the past months.A. whetherB. thatC. ifD. what20.(单项选择题)(每题 2.00 分) 阅读下面的短文，从每题所给的四个选项中选出最佳选项（请选择唯一正确的答案）Passage OneThere are many wetlands in China and some of them have become the world’s important wetlands. The Chinese Yellow Sea Wetlands are among them. They are in Yancheng, Jiangsu Province. They are home for many different kinds of birds and animals. The worlds largest Milu Deer Nature Reserve is in them. More than 700 milu deer live freely there. There are not many red-crowned cranes in the world, but every winter you can see some in the Red-crowned Cranes Nature Reserve in the Yellow Sea Wetlands.The temperature in the wetlands is usually neither too high nor too low. There is a lot of rain and sunshine, too. They are really good places for wildlife. Offering food and home for some special kinds of animals and birds is not the only reason why we need to protect wet-lands. Wetlands are important because they can also prevent floods. But some people want to change the wetlands to make more space for farms and buildings. This means there will be less and less space for wildlife.Luckily, more and more people are beginning to realize the importance Of wetlands and wildlife. Every year, on February 2, many activities are held to tell people more about wet-lands.The World Wetlands Day is on. ______ .B. June 25C. February 2D. March 2221.(单项选择题)(每题 2.00 分)The committee __________ a conclusion only after days of discussion.A. releasedB. achievedC. reachedD. accomplished22.(单项选择题)(每题 2.00 分) Passage OneMove over Methuselah. Future generations could be living well into their second century and still doing Sudoku, if life expectancy predictions are true. Increasing by two years every decade, they show no signs of flattening out. Average lifespan worldwide is already double what it was 200 years ago. Since the 1980s, experts thought the increase in life expectancy would slow down and then stop, but forecasters have repeatedly been proved wrong.The reason behind the steady rise in life expectancy is “the decline in the death rate of the elderly”, says Professor Tom Kirkwood from Newcas tle University. He maintains that our bodies are evolving to maintain and repair themselves better and our genes are investing in →this process ←to put off the damage which will eventually lead to death. As a result, there is no ceiling imposed by the real ities of the ageing process. “There is no use-by-date when we age. Ageing is not a fixed biological process," Tom says.A large study of people aged 85 and over carried out by Professor Kirkwood discovered that there were a remarkable number of people enjoying good health and independence in their late 80s and beyonD. With people reaching old age in better shape, it is safe to assume that this is all due to better eating habits, living conditions, education and medicine.There are still many people who suffer from major health problems, but modem medicine means doctors are better at managing long-term health conditions like diabetes, high blood pres- sure and heart disease. “We are reaching old age with less accumulative damage than previous generations, we are less damaged," says Professor KirkwooD. Our softer lives and the improvements in nutrition and healthcare have had a direct impact on longevity.Nearly one-in-five people currency in the UK will live to see their 100th birthday, the Office for National Statistics predicted last year. Life expectancy at birth has continued to increase in the UK——from 73.4 years for the period 1991 to 1993 to 77.85 years for 2007 to 2009. A report in Science from 2002 which looked at life expectancy patterns in different countries since 1840 concluded that there was no sign of a natural limit to life.Researchers Jim Oeppen and Dr. James Vaupel found that people in the country with the highest life expectancy would live to an average age of 100 in about six decades. But they stopped short of predicting anything more."This is far from eternity: modest annual increments in life expectancy will never lead to immortality,” the researchers saiD.We do not seem to be approaching anything like the limits of life expectancy, says Professor David Leon from the London School of Hygiene and Tropical Medicine. “There has been no flattening out of the best the groups which everyone knows have good life expectancy and→ low mortality←. ”he says.These groups, which tend to be in the higher social and economic groups in society, can live for several years longer than people in lower social groups, prompting calls for an end to inequalities within societies.Within populations, genes also have an important role to play in determining how long we could survive for, but environment is still the most important factor.It is no surprise that healthy-living societies like Japan have the highest life expectancies in the worlD. But it would still be incredible to think that life expectancy could go on rising forever. “I would bet there will be further increases in life expectancy and then it will probably begin to slow,” says Tom, “but we just don’t know.”The underlined phrase “low mortality” in Paragraph 8 could best be replaced by “→←".A. short life spanB. low death rateC. low illness rateD. good health condition23.(单项选择题)(每题 2.00 分) For grammar teaching, if the rule is given first and explained and the student then has to apply the rule to given situation, the method is definedas______methoD.A. deductiveB. inductiveC. Grammar-translationD. audio-translation24.(单项选择题)(每题 2.00 分)The most suitable question type to check students′ comprehension and developtheir critical thinking is __________.A. rhetorical questionsB. referential questionsC. close questionsD. display questions25.(单项选择题)(每题 2.00 分) Which of the following is NOT the advantage of group work?A. creating some peaceful and quiet time in classB. encouraging cooperation and negotiation skills among studentsC. encouraging different opinions and contributions to the workD. promoting students5 autonomy rather than follow the teachers26.(单项选择题)(每题 2.00 分)--Would you like some noodles, Celia?--Yes, just___________, please.A. a fewB. fewC. a littleD. little27.(单项选择题)(每题 2.00 分) Modem scientists divide the process of dying into two stages-clinical or temporary death and biological death. Clinical death occurs when the vital organs, such as the heart or lungs, have ceased to function, but have not suffered permanent damage. The organism can still be reviveD. Biological death occurs when changes in the organism lead to the disintegration of vital cells and tissues. Death is then irreversible and final.Scientists have been seeking a way to prolong the period of clinical death so that the organism can be revived before biological death occurs. The best method developed so far involves cooling of the organism, combined with narcotic sleep. By slowing down the body^ metabolism, cooling delays the processes leading to biological death.To illustrate how this works, scientists performed an experiment on a six-year-old female monkey called KetA. The scientists put Keta to sleep with a narcotic. Then they surrounded her body with ice-bags and began checking her body temperature. When it had dropped to 28 degrees the scientists began draining blood from its body. The monkey’s blood pressure decreased and an hour later both the heart and breathing stopped; clinical death set in.this point the scientists pumped blood into its body in the direction of the heart and started artificial breathing. After two minutes the monkey’s heart became active once more. Aft er fifteen minutes, spontaneous breathing began, and after four hours Keta opened her eyes and lifted her heaD. After six hours, when the scientists tried to give her a penicillin injection. Keta seized the syringe and ran with it around the room. Her behavior differed little from that of a healthy animal.One characteristic of clinical death is______.A. lasting damage to the lungsB. destruction of the tissuesC. temporary non-functioning of the heartD. that the organism cannot be revived28.(单项选择题)(每题 2.00 分) Which of the following activities actually does not involve writing?→ ←.A. Completion according to outlines.B. Completion with multiple choices.C. Completion according to topic sentences.D. Completion with detailed examples related to the topiC.29.(单项选择题)(每题 2.00 分) English teachers often ask students to ______ a passage to get the gist of it.A. skimB. scanC. predictD. describe30.(单项选择题)(每题 2.00 分) —Must I finish the work today, Mom?__No, you_____. You can finish it tomorrow.A. mustn’tB. can’tC. shouldn’tD. needn’t31.(单项选择题)(每题 2.00 分) ______ she heard her grandfather was bom in Germany.A. That was from her mumB. It was her mum thatC. It was from her mum thatD. It was her mum whom32.(单项选择题)(每题 2.00 分) When we analyze the salt salinity (盐浓度)of ocean waters, we find that it varies only slightly from place to place. Nevertheless, some of these small changes are important. There are three basic processes that cause a change in oceanic salinity. One of these is the subtraction of water from the ocean by means of evaporation. In thisextreme, of course, white salt would be left behind; this, by the way, is how much of the table salt we use is actually obtaineD.The opposite of evaporation is precipitation, such as rain, by which water is added to the ocean. Here the ocean is being diluted so that the salinity is decreaseD. This may occur in areas of high rainfall or in coastal regions where rivers flow into the ocean. Thus salinity may be increased by the subtraction of water by evaporation, or decreased by the addition of fresh water by precipitation.Normally, in hot regions where the sun is very strong, the ocean salinity is somewhat higher than it is in other parts of the world where there is not as much evaporation. Similarly, in coastal regions where rivers dilute the sea, salinity is somewhat lower than in other oceanic areas.A third process by which salinity may be altered is associated with the formation and melting of sea ice. When seawater is frozen, the dissolved materials are left behinD. In this manner, seawater directly beneath freshly formed sea ice has a higher salinity than it did before the ice appeareD. Of course, when this ice melts, it will tend to decrease the salinity of the surrounding water.In the Weddell Sea, the densest water in the ocean is formed as a result of this freezing process, which increases the salinity of cold water. This heavy water sinks and is found in the deeper portion of the oceans of the worlD.It can be known from the passage that increase in the salinity of ocean water is caused by______.A. melting of sea iceB. precipitationC. evaporationD. supplement of salt33.(单项选择题)(每题 2.00 分) Mr. King works in a shop and drives a car for the manager. He drives carefully and can keep calm in time of danger, and he has escaped from several accidents. The manager pays him more and the traffic policemen often speak highly of him.Mr. Baker, one of his friends, works in a factory outside the city. Ifs far from his house and he has to go to work by bus. As the traffic is crowded in the morning, sometimes he’s late for the work. His manager warns the young man that he will be sent away unless he gets to his office on time. He hopes to buy a car，but he hasn’t enough money. He decides to buy an old one. He went to the flea market and at last he chose a beautiful but cheap car. He said he wan— ted to have a trial drive, and the seller agreeD. He called Mr. King and asked him to give a hanD.Mr. King examined the car at first and then drove it away. It was five in the morning and there were few cars in the street. At first he drove slowly and it worked well. Then he drovefailed and nearly hit an old woman who was crossing the street. A policeman told him to stop, but the car went on until it hit a big tree by the roaD.“Didn’t you hear me?” the policeman asked angrily.“Yes，I did，sir，” said Mr. King，“ Since it doesn’t listen to me，can it obey you?”What is a flea market?______.A. A market where fleas are solD.B. A market where cars are solD.C. A market where used and cheap goods are soldD. A supermarket.34.(单项选择题)(每题 2.00 分) To their credit the Department of Energy______these ideas and funded a detailed study.A. took toB. took onC. took overD. took up35.(单项选择题)(每题 2.00 分) The phoneme/n/in the first word of all the following phrases changes to/m/except______.A. moon shineB. moon beamC. common propertyD. common wealth36.(单项选择题)(每题 2.00 分)The author holds that the current collective doctrine shows__________.A. generally distorted valuesB. unfair wealth distributionC. a marginalized lifestyleD. a rigid moral code37.(单项选择题)(每题 2.00 分) Which of the following can be regarded as a communicative language task? ______ .A. Information-gap activityC. Sentence transformationD. Blank-filling38.(单项选择题)(每题 2.00 分) Passage OneMove over Methuselah. Future generations could be living well into their second century and still doing Sudoku, if life expectancy predictions are true. Increasing by two years every decade, they show no signs of flattening out. Average lifespan worldwide is already double what it was 200 years ago. Since the 1980s, experts thought the increase in life expectancy would slow down and then stop, but forecasters have repeatedly been proved wrong.The reason behind the stead y rise in life expectancy is “the decline in the death rate of the elderly”, says Professor Tom Kirkwood from Newcastle University. He maintains that our bodies are evolving to maintain and repair themselves better and our genes are investing in →this process ←to put off the damage which will eventually lead to death. As a result, there is no ceiling imposed by the realities of the ageing process. “There is no use-by-date when we age. Ageing is not a fixed biological process," Tom says.A large study of people aged 85 and over carried out by Professor Kirkwood discovered that there were a remarkable number of people enjoying good health and independence in their late 80s and beyonD. With people reaching old age in better shape, it is safe to assume that this is all due to better eating habits, living conditions, education and medicine.There are still many people who suffer from major health problems, but modem medicine means doctors are better at managing long-term health conditions like diabetes, high blood pres- sure and heart disease. “We are reaching old age with less accumulative damage than previous generations, we are less damaged," says Professor KirkwooD. Our softer lives and the improvements in nutrition and healthcare have had a direct impact on longevity.Nearly one-in-five people currency in the UK will live to see their 100th birthday, the Office for National Statistics predicted last year. Life expectancy at birth has continued to increase in the UK——from 73.4 years for the period 1991 to 1993 to 77.85 years for 2007 to 2009. A report in Science from 2002 which looked at life expectancy patterns in different countries since 1840 concluded that there was no sign of a natural limit to life.Researchers Jim Oeppen and Dr. James Vaupel found that people in the country with the highest life expectancy would live to an average age of 100 in about six decades. But they stopped short of predicting anything more."This is far from eternity: modest annual increments in life expectancy will never lead to immortality,” the researchers saiD.We do not seem to be approaching anything like the limits of life expectancy, says Professor David Leon from the London School of Hygiene and Tropical Medicine. “There has been no flattening out of the best the group s which everyone knows have good life expectancy and→ low mortality←. ”he says.for several years longer than people in lower social groups, prompting calls for an end to inequalities within societies.Within populations, genes also have an important role to play in determining how long we could survive for, but environment is still the most important factor.It is no surprise that healthy-living societies like Japan have the highest life expectancies in the worlD. But it would still be incredible to think that life expectancy could go on rising forever. “I would bet there will be further increases in life expectancy and then it will probably begin to slow,” says Tom, “but we just don’t know.”Which statement below is TRUE concerning life expectancy according to thepassage?→←.A. Life expectancy goes on rising forever.B. There could be further increases in life expectancy.C. Life expectancy has slowed down since 1980s and it will stop.D. Life expectancy in Japan doubles what it was 200 years ago.39.(单项选择题)(每题 2.00 分)The message came to the villagers __________ the enemy had already fledthe village.A. whichB. whoC. thatD. where40.(单项选择题)(每题 2.00 分)Which of the letter "u"in the following words has a different pronunciation from others?A. abuseB. useC. excuseD. lure41.(单项选择题)(每题 2.00 分)Based on the experiment, which of the following may signal that the subjectis nearing the solution?A. The subject is begging to work.B. The subject looks away at something else.C. The subject is distracted from the given words.D. The subject concentrates on the given words all the time.42.(单项选择题)(每题 2.00 分) New curriculum promotes the three-dimensional teaching objective which includes_______.A. knowledge, skills and method sB. emotional attitude and valuesC. knowledge, skills and emotionD. knowledge and skills； process and methods； emotional attitude and values43.(单项选择题)(每题 2.00 分) Which of the following nominating patterns can a teacher adopt to ensure that all students are actively involved in classroom activities?→ ←.A. Nominating those who are good at English.B. Asking questions in a predicable sequence.C. Nominating students after the question is given.D. Nominating students before giving the question.44.(单项选择题)(每题 2.00 分) Electronic books could revolutionize reading, but people ought to consider their far-reaching. “The e-book promises to wreak a slow havoc on life as we know it,” Jason Ohler, professor of technology assessment, University of Alaska Southeast in Juneau, warned the World Future Society, Bethesda, MD. His assessment weighed the pros and cons of e-book technology’s impact on social rela tionships, the environment, the economy，etC. Before you curl up with an e-book, consider the disadvantages.They increase eyestrain due to poor screen resolution, replace a relatively cheap commodity with a more expensive one, and displace workers in print book production and traditional publishing. E-books make it easy to share data, thereby threatening copyright agreements and reducing compensation of authors, as well as creating no biodegradable trash. On the other hand, e-books save paper and trees, reduce the burden of the carrying and storing of printed books, promote self- sufficiency in learning, and make reading a collaborative experience online. They also create new jobs for writers and artists and encourageself-publishing. In final analysis, Ohler points out, e-books should gain society’s approval if a few conditions are met: make them biodegradable and recyclable，solve the problem of eye fatigue，be sure the “have-nots” get the technology，and support e-book training in schools and business.What is e-books negative impact on social relationships?______.A. They create new jobs only for writers.B. Fewer and fewer people have access to new technology.C. They may threaten some traditional trades.。

PCB 成品检验规范(完整版)

PCB 成品检验规范(完整版)作业指导书文件编号：XXX-XXXX-XX 生效日期：20XX-XX-XX 版本号：标准化检查会签：品质部、生产部成品检验规范批准收文单位：文件修改履历表表格编号：************ 版本：A1.0 目的本文旨在制定成品接收标准，以确保产品质量符合公司或客户要求，为质量判定工作提供依据。

2.0 适用范围本标准适用于本公司对PCB成品质量的判定。

3.0 参考文件3.1 客户标准3.2 《生产指示MI》3.3 《IPC-A-600印刷电路板允收水准》3.4 《IPC-6012刚性多层印刷电路板性能规范》3.5 《IPC-TM-650.PCB可靠性测试规范》3.6 《IFPA-F 001软件电路板（FPC）外观允收标准》3.7 运作过程中发现检验标准有抵触时，应按以下先后顺序为参考：A。

客户标准B。

国标标准C。

公司内部标准D。

IPC标准4.0 定义和职责品质部XXX：对PCB进行外观全检，对所发现的缺陷依据本标准进行判定和检验，并按照标准进行记录填写和异常反馈。

品质部XXX：对生产部检查合格的进行抽查，对所发现缺陷依据本标准进行判定。

品质部MRB：对工序提出报废申请的报废板依据本标准进行判定。

5.0 定义5.1 客户有要求之标准依客户的要求执行，客户没有提供或特别指定接收标准的，按此规范中的允收标准执行。

5.2 本标准中没有明确规定的，可提交品质部进行仲裁、备案及更新。

5.3 合格品与不合格品的定义及处理方式A。

合格品与不合格品的定义①合格品：符合规格之产品即为良品（质量之定义：符合规格）。

②不合格品：不确定产品、可疑产品以及不符合规格之产品均认定为不合格品范畴。

B。

不合格品的处理方式：①重工（Rework）②特采(UAI: Use as it)③报废(Scrap)④折让(Discount)5.4 本公司产品按其功能可靠度(nal Reliability)与性能(Performance Requirements)两方面，共分为三级。

人的寿命的计划方法

人的寿命的计划方法The methods of planning human lifespan are varied and complex. In today's modern world, people are living longer than ever before due to advancements in medicine, technology, and an increased understanding of health and wellness. The ability to plan for one's own lifespan is an important aspect of personal and financial planning, but it also raises ethical and philosophical questions about the nature of life and death.人的寿命的计划方法是多种多样且复杂的。

如今，在现代世界，由于医学、技术的进步和对健康及福祉的增强理解，人们的寿命比以往任何时候都要长。

规划自己的寿命是个人和财务规划的重要方面，但它也引发了对生命和死亡本质的伦理和哲学问题。

The first perspective on planning human lifespan centers around the idea of preventive medicine and healthy lifestyle choices. By engaging in regular exercise, maintaining a balanced diet, and avoiding harmful habits such as smoking and excessive alcohol consumption, individuals can increase their chances of living a longer and healthier life. Additionally, regular visits to healthcareprofessionals for check-ups and screenings can aid in the prevention and early detection of potentially life-threatening illnesses.关于规划人类寿命的第一个观点集中在预防医学和健康的生活方式选择上。

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Predicting Plated Through Hole Life at Assemblyand in the Field from Thermal Stress DataMichael FredaSun Microsystems, Inc.Menlo Park, CADr. Donald BarkerUniversity of MarylandCollege Park, MDAbstract:Over the past ten years, two new test methods: Interconnect Stress Test [1] and Highly Accelerated Thermal Shock [2] have been developed to perform thermal cycling testing and in particular, to measure plated through hole reliability. Both of these test methods have proved useful in their ability to quantify plated through hole reliability and have gained a wide level of acceptance and creditability within the industry. Along with more tradition air-to-air and liquid-to-liquid thermal cycle methods, these two new test methods expand the test methods available to the interconnect industry. While the number of testing options for plated through hole thermal cycling has increased, there has been little work performed within the industry on developing methods to analyze and use the data coming from these new test methods.This paper covers use of IST testing to obtain plated through hole cycle to failure data followed by methods to analyze and plot the data over a wide range of temperatures. In particular, the paper will focus on the use of material properties like the modulus as a function of temperature and the coefficient of thermal expansion as a function of temperature to calculate the stress on a plated through hole versus temperature. In this paper we will also explore the use of the Inverse Power Law (IPL) to analyze the plated through hole stress versus cycle to failure relationship. Once we have used IPL to established the cycle to failure relationship to stress for a given laminate and PCB design, it is then possible to estimate the number of cycles to failure in the field as a function of the number of cycles of assembly stress, the peak assembly temperature, and the maximum temperature in the field.KeywordsIST, HATS, Lead-Free, CTF, Cycles to Failure, Via Reliability, PTH ReliabilityIntroductionSun Microsystems, Inc. has utilized IST for the past seven years. Early in that usage of IST Sun performed testing using multiple preconditioning steps from ambient to 230°C to simulate eutectic tin/lead assembly and rework followed by testing from ambient to 150°C. IST test equipment has a minimum temperature of ambient so, all further references will list only the peak temperature and ambient is 22°C. Typical preconditioning levels used were 0x, 3x, and 6x at 230°C and test results clearly show the negative impact of thermal cycling at assembly peak temperatures. As the high-end server product that initially utilized IST for plated through hole reliability confirmation moved into full production, Sun standardized our IST test protocol at 6x preconditioning at 230°C followed by thermal cycling to 150°C. The typical IST cycle is a linear ramp from ambient to peak in three minutes followed by a two-minute cool down back to ambient. In-situ electrical resistance heating circuits heat the IST coupon to peak temperature. Blowers using ambient air cool the IST coupon down. During Sun’s initial three-four years of using IST and as pcb fabricator processes improved, IST testing at 6x at 230°C followed by thermal cycling at 150°C often led to long test times, due in part to Sun’s requirement for test to failure.About three years ago, Sun started to introduce thermally resistant, phenolic cured laminate materials into production to gain experience for the upcoming industry wide shift to lead-free assembly. Using phenolic laminate materials, the cycles to failure increased dramatically making IST test times burdensome, especially when preconditioning at 230°C for eutectic solder assembly. Additionally, Sun began test of lead-free laminate materials during this period, but the actual peak temperatures that would be required for lead-free assembly remained a bit of an unknown. For all the reasons discussed above, Sun started to use cycle to failure testing at temperatures above laminate material Tg. Figure 1 shows a comparison of HATS and IST test temperature range. You can see that the test temperature range of IST is well suited for testing above laminate material Tg. IST testing above laminate material Tg is quick and cost effective due to low cycles to failure. With appropriate reliability software, it is possible to use this data to predict cycles to failure at any potential lead-free assemblySun has previously reported on IST testing performed on thick, high aspect ratio pcb fabs using test to failure at multiple temperatures [3, 4]. This work showed promise in our effort to develop a new test and data analysis method, but since that work had many design of experiment (DoE) factors relating to board design, a couple of pcb fabrication variables, plus DoE factors in the testing and analysis the result was a small sample size per cell. Therefore, the testing that reported in this paper focuses on the development of improved test and data analysis methods. The IST coupons used are from a high volume, high-end server CPU card. By using a mature pcb fab design with no design or pcb fabrication variables, we are able to focus on the test and data analysis variables and use a larger sample size per cell.Figure 1 – Comparison of HATS and IST test temperatureranges to Field Life and Lead-Free Assembly temperatures.Test and Analysis DoE DescriptionThe product selected for test in this paper is the CPU Uniboard that is used in a number of Sun’s high-end servers. The current version of the Uniboard has four dual core processors per card, and 32 DIMM sockets that accommodate up to 64 Gb of on-board random access memory. There are also eight level 2 cache memory cards with 512 Mb of SRAM memory each. The largest system manufactured that utilizes the Uniboard CPU card has a maximum configuration of 144 CPU cores per system. The CPU board and IST coupons which are fabricated on the same panel are 26 layers, 2.8mm thick (110 mil), high resin percent, 0.35mm (13.8 mil) minimum drill diameter, uses a phenolic cured FR-4 laminate material, and has bothCu/HASL plating and selective Cu/Ni/Au plating. For this paper, only the Cu/HASL IST coupons were tested.Figure 1 – Pictures of Sun high-end servers. The two largest systemson the left use the Uniboard CPU card shown on the right.The IST coupon fabricated on the Uniboard panel has the following design features:•27.9 x 76.2 x 2.8mm (1.1 x 3.0 x .110 inch)• 1.5mm hole pitch (.060 inch)•144 PTH interconnect holes drilled at .35mm (.0138 inch) diameter; a 8:1 aspect ratio•PTH interconnect daisy chain runs from layer 1 to 26 to 1 to 26…•144 POST interconnect holes drilled at .85mm (.0335 inch) diameter; a 3.3:1 aspect ratio•POST interconnect daisy chain runs from layer 2 to 3 to 2 to 3… and from layer 25 to 24 to 25 to 24…•The PTH interconnect holes are orientated interstitial to the POST interconnect holesIST Testing and Data Analysis Above TgInitial IST testing was performed above Tg as shown in Table 1. Testing was performed at four temperatures above Tg: 215°C, 235°C, 255°C, and 275°C. Shown is the sample size for both the initial DoE plan and the actual DoE. Graph 1 shows the Lognormal plot of cycles to failure versus cumulative failure percent for the IST testing above Tg. The data follows expected trends, i.e., the higher the test temperature, the shorter plated through hole life. For this reason, a sample size of 12 coupons per cell was deemed sufficient.Table 1 – Planned and actual DoE sample size per cell.Graph 2 uses the same raw data as Graph 1. The difference is the analysis method used where instead of performing an independent Lognormal analysis on the cycle to failure data for each test temperature; the analysis uses all data from the multiple test temperatures to obtain a best fit to both a Lognormal distribution and an Inverse Power Law (IPL) relationship. Sun typically uses a Lognormal distribution since our experience shows that it is a better fit than a two-parameter Weibull distribution in the majority of cases (Lognormal goodness of fit parameter is better than Weibull in >50% of the cases). An added benefit is the Lognormal distribution usually has a better fit to early life failures that is Sun’s primary concern. Nonetheless, use of a Weibull distribution should yield similar results to those in this paper. Sun uses the 1% cumulative failure rate to rank laminate materials and the pcb fabricators plated through hole formation processes; it is hard to separate the effect of these two from each other. Mathematical descriptions in terms like Scale Factor, Location, MTTF, Characteristic Life, Eta, Beta, etc. are difficult to relate to for many people. It is easy to explain T1%, it is the number of cycles where one would expect a 1% cumulative failure or when you would expect the first failure if testing 100 parts. Additionally, T1% is sensitive to both the location (indicative of process used) and slope (indicative of process variation) of the Lognormal distribution making it a useful “single” parameter to summarize results from multiple parameter distributions.We used the Inverse Power Law relationship since it is widely recognized that non-ferrous metals like copper usually follow the IPL relationship [5, 6]. Models like Arrhenius or Eyring are not appropriate since they deal with failure modes that are thermally induced. At first glance, this may also appear to be the case with the fatigue failure of plated through holes during thermal cycle testing. Nonetheless, in the temperature range that we study in this paper, metallic copper is not going through any physical change. Since it is a pure metal and there are no chemical reactions to occur, an activation energy based model like Arrhenius is not appropriate. What is happening is that there is stress applied due to the high Z-axis coefficient of thermal expansion of the epoxy/glass laminate material which surrounds the copper plated through hole structure and creates tensile stress on the copper. This makes the IPL relationship the appropriated model to follow. Latter in this paper we will discuss converting data from temperature versus cycles to failure to the more correct stress versus cycles to failure relationship.The equation for the IPL relationship follows. As shown in equation 2, it is easy to perform a Logarithmic transformation on the IPL relationship followed by rearrangement so it follows a conventional linear slope/intercept model of f(x) = m*x + c. In the graphs that follow it is common to see a Log/Log scale in use.L(V) = 1/KV n eq. 1Log10 L(V) = - nLog10V - Log10K eq. 2Where,L represents a quantifiable life measure; for this paper both Mean life and T1% life are usedV represents the stress levelK is one of the model parameters to be determined, (K>0)N is another model parameter to be determinedDuring our testing above Tg, we decided to IST test at four temperatures for a number of reasons:1.To allow making an estimate of cycles to failure over the full range of assembly temperatures2.By graph cycles to failure versus test temperature we gain insight into the shape of the failure curve3.To see if testing at high temperatures introduces new failure modes4.To better understand the safety margins of the laminate materialsIn selecting four temperatures above Tg, 215°C is about the lowest you can go and still be far enough above the Tg transition zone where there are significant changes in laminate material properties. The rational for using 275°C is to see if there are changes in via failure modes at temperatures above the expected maximum Sn/Ag/Cu lead-free soldering temperature zone.relationship used to establish the best fit to the data at multipletemperatures. The RED lines show estimated CTF at 245°C.Neither Graph 1 nor Graph 2 display an obvious failure mode shift as the test temperature is increased. Nonetheless, IST test at 275°C did result in two POST interconnect failures out of 12 IST coupons. To check if a failure mode shift was occurring, we looked at the resistance shift on the POST interconnect daisy chain in the IST coupon versus temperature. A typical IST coupon design has two daisy chains referred to as a PTH and POST daisy chain. The PTH daisy chain is for test of small via diameters, runs from layer 1 to 26 to 1 to26…, and is sensitive to fatigue in the center of the via. The POST daisy chain is for test of large via diameters, runs from layer 2 to 3 to 2 to 3… and from layer 24 to 25 to 24 to 25…, and is sensitive to interconnect separation between the plating in the hole to the inner layer connection pad.In large, thick, high-end server pcb fabs with small pitch BGA components, the normal failure mode is fatigue of the small diameter plated through holes. The failure criteria used by Sun is a 10% resistance increase over the initial resistance of either daisy chain, which ever fails first. With the exception of the two IST coupons that failed for POST interconnect separation at 275°C, the remaining 46 coupons from test above Tg were all PTH failures. Graph 3 is important, it clearly shows the increase in resistance on the POST interconnect daisy chain as the IST test temperature is increased. So, even though only 2 of 48 IST coupons failed due to POST interconnect failure, Graph 3 shows there is a definite shift from small plated through hole interconnect failure to large plated through hole POST interconnect separation failure as the assembly peak temperature increased. Due to this failure mode shift on the 275°C IST data and concern that the cycle to failure data at 215°C is too close to the Tg transition zone, data from 235°C and 255°C is used to make the IPL/Lognormal estimate of cycles to failure at a Sn/Ag/Cu assembly temperature of 245°C. We will use 245°C as our lead-free assembly temperature for the remainder of this paper. From the data obtained from cycle to failure test of laminate material above Tg and data analysis method we utilized, it is easy to estimate cycles to failure at other temperatures within the range of 215°C to 275°C. Graph 4 shows the IPL/Lognormal plot and Table 2 summarizes the analysis from the three temperature combinations investigated.255°C. The RED lines show estimated CTF at 245°C.Table 2 – Cycle to failure estimates versus failure rate.CTF at 245C from IPL/Log Normal ModelT1%T50%Temperatures Used for Model LCI Nominal UCI215, 235, 255, and 275C 15.35 17.70 19.27 31.23215, 235,and 255C 13.58 16.45 18.30 29.35255C 12.34 15.94 17.92 28.93235andIST Testing and Data Analysis Below TgAfter completion of IST testing and data analysis above Tg, the team at Sun selected the preconditioning temperature to use (245°C) and the number of preconditioning cycles to use (2x, 6x, and 10x). Since IST test equipment is small and modular with each test machine holding six coupons, we started testing with preconditioning and then cycle to failure at the higher temperature of 150°C. At no time did we attempt to test more than six coupons of any single test condition at a time. In hindsight, this was fortunate since the cycles to failure for IST coupons with low preconditioning cycles and coupons testedpreconditioning of 18x at 245°C and forego testing in three cells with either a low number of preconditioning cycles, a low peak temperature below Tg, or both since they would have taken too long to cycle to failure. See Table 1 for the original DoE plan and the actual DoE we ended up using.From the perspective of data analysis, combining data from test above Tg, and test below Tg using different levels of preconditioning was a challenge. As previous mentioned, while the IPL relationship is valid for non-ferrous metals, we need to understand the stress versus temperature to enable plotting of cycles to failure versus stress. This is due to the large change in laminate material properties below and above Tg. In past work Sun has tested Miner’s Rule (also called the Palmgren-Miner cycle-ratio summary theory) [8], but the amount of data was not statistically significant. Miner’s Rule does not deal with temperature versus stress issue already discussed, and over the wide temperature range in which we are interested, changes in failure modes can invalidate predictions made at low temperature. This paper will now look at a number of data analysis techniques, including Miner’s Rule, to address these problems.Table 3 – All data from the IST testing discussed in this paperlisted below. The method used to derive the stress levels discussed later.Graph 5 uses a graphical method plotting the T1%, 90% lower two-sided confidence interval and using 6x thermal cycles at 245°C to estimate cycles to failure at a 95°C peak field use condition. From this, we estimate 550,000 cycles to failure in the field. At 365 thermal cycles per year (considered worst case for high-end servers), this is equivalent to over 1,500 years of field life! In Graph 6, we plotted all the raw data to give a feel for the variation. Instead of using the T1% value, we try to stay below the worse case data point. On both Graph 5 and Graph 6, we assume there is an inflection point (or discontinuity) in the laminate Tg transition zone with data below Tg and data above Tg following a different trend line. While this is a good assumption, where to place this inflection point is a matter of judgment that can have a significant effect on the cycle to failure estimates at a 95°C field life temperature. It also should be noted that on both graphs, the data for 6x and 10x preconditioning seems to be reversed with 10x having life close to 6x or if anything a bit longer. We have no good explanation for this other than a combination of a relatively small sample size and random chance.confidence interval versus temperature.Graph 6 – Log-log plot of all cycle to failure data versus temperature.In earlier work of this type performed at Sun [3, 4], we noticed a discontinuity in the IPL/Lognormal distribution in data below Tg versus data above Tg. In that earlier analysis, the data to the left (below Tg) had a steeper slope than the data to the right (above Tg). This data does not appear to follow the same trend. At this point we do not know if this is due differences in the laminate material used or due differences in the pcb fab design, e.g., a much thinner pcb fab.Regression Analysis using Miner’s RuleOne common method to analyze paired data is the use of multiple regression. In this analysis example, we decided to use Miner’s Rule that has the form of:n1/N1 + n2/N2 + + n i/N i = C eq. 3Where n 1, 2, … i is the number of thermal cycles applied to the IST coupon at a specific temperature or stress level N 1, 2, … i is the know number of cycles to failure, i.e., the life at a specific temperature or stress level C is a constant determined by experimentation and is usually found in the range of 0.7 ≤ C ≤ 2.2 If C=1 then Miner’s Rule becomes a simple equation of what proportion of life is used at each temperatureSince we performed all testing below Tg with preconditioning, we do not know the values for N 120C , N 135C , or N 150C . From testing above Tg, we do know the value of N 245C . From testing below Tg, we know the number of preconditioning cycles used, the number of cycles to failure after preconditioning at three temperatures, and have a large set of data to utilize. We have 138 data points to use to predict the four unknowns: N 120C , N 135C , N 150C , and C. At first glance, equation 3 does not seem to follow the format for multiple regression. Therefore, our first step is to transform the general equation 3, customize it for our data, and then transform it to fit a multiple regression format.n 120C /N 120C + n 135C /N 135C + n 150C /N 150C + n 245C /N 245C = C eq. 4next, define INVN x = 1/N x and then substitute it into eq. 4 to get eq. 6eq. 5n 120C *INVN 120C + n 135C *INVN 135C + n 150C *INVN 150C + n 245C *INVN 245C = Ceq. 6Since n 245C *INVN 245C is know, we can further rearrange this to- n 245C *INVN 245C = n 120C *INVN 120C + n 135C *INVN 135C + n 150C *INVN 150C - C eq. 7This equation now has the form of f(x, y, z) = a*x + b*y + c*z + d eq. 8and we will solve it for INVN 120C , INVN 135C , INVN 150C , and C (a, b, c, and d)We performed regression analysis using Minitab Release 14. The regression equation obtained is:- n 245C *INVN 245C = n 120C *.00002103 + n 135C *.00008322 + n 150C *.00019318 - .67899eq. 9.67899 = n 120C *.00002103 + n 135C *.00008322 + n 150C *.00019318 + n 245C *INVN 245C eq. 10.67899 = n 120C /47,551 + n 135C /12,016 + n 150C /5,177 + n 245C *INVN 245Ceq. 11Table 4 – Regression analysis output using Miner’s Rule with Minitab Release 14.We can make a number of observations from the regression analysis results. Review of the R-Sq value of 54.4% and R-Sq(adj) value of 53.4% in Table 4 that are indicators of the goodness of fit of the model shows they are not the highest numbers, but they are reasonable. Considering that the cycle to failure data for each precondition level and subsequent thermal cycling below Tg had a minimum range of 2:1 from high to low, than with this amount of variation in the raw data used to construct the model, you will not get a high R-Sq value. If you look at the Analysis of Variance section in Table 4, the largest portion of sum of squares (SS) error is due the regression factors with n120 and n150 being the largest two contributors to the SS variation.Graphs 7 through 9 are various residual plots from the regression analysis. Although we looked hard at the residual plots, no specific cause for the residuals was determined. We thought that the manufacturing date/lot code of the IST coupon might be a factor. To test this we rated each combination of preconditioning level and subsequent thermal cycling below Tg. IST coupons in the upper quartile of cycles to failure in each combination were assigned a value of +1, coupons in the lower quartile were assigned a value of -1, and those in between were assigned a value of zero. Then we totaled each date/lot code score and divided the total by the number of coupons in each date/lot code. We then used the resulting score to order the date/lot codes from one (the best with highest positive score) to seven (the worst with lowest negative score). We than ran the multiple regression analysis again, but this time we included a term for the rating of the date/lot code. The R-Sq values from this analysis did not support adding another term and the residual plot (Graph 9) did not show any strong date/lot code relationship.Graph 8 shows the residuals versus the number of preconditioning cycles at 245°C. This graph does show a trend, but we were unable to identify the cause at the time of writing this paper. One suspect is the 18x preconditioning since the cells with this high level of preconditioning also had the most outliers. In addition, all but one of the 18x residuals was less than zero.cycles shows a dip in cycles to failure with more preconditioning.not seem to be a trend between date codes. Therefore, the final regressionmodel does not include a term for the data code.One final observation is that the size of the coefficients from the multiple regression study, i.e., the predicted N x values, are a good indicator of both the cycles to failure and the acceleration factors (AF) one would expect for thermal cycling without preconditioning.N120 = 47,551 cycles to failure, obtained from multiple regression AF245-120 = 1,644N135 = 12,016 cycles to failure, obtained from multiple regression AF245-135 = 415.3N150 = 5,177 cycles to failure, obtained from multiple regression AF245-150 = 178.9N245 = 28.93 cycles to failure, obtained from Lognormal distribution AF245-245 = 1After completion of the Miner’s Rule regression analysis, there remain two major issues with the analysis: 1) it returns averaged numbers for estimates of cycles to failure at temperature hiding the inherent variability of the raw data and 2) it does not address the large change in laminate material properties below and above Tg. Graph 10 shows one answer to the first issue, a Monte Carlo simulation that uses the coefficients from the Miner’s Rules regression model and the coefficients for the standard error to predict cycles to failure with variation. Once the Monte Carlo model is developed, it is very easy to vary the number of preconditioning cycles at 245°C to gage the effect on field life with a 95°C peak temperature. The second issue, addressing the large change in laminate material properties below and above Tg requires a new analysis approach. We discuss this in the next section.Graph 10 – Shows CTF versus Peak-Ambient temperature as assemblypreconditioning at 245°C is varied from 2 cycles to 15 cycles. Each of thefour temperatures per graph contains 1000 simulated data points.Using TMA and DMA Data to Derive the Temperature versus Stress RelationshipGraphs 11 and 12 both show the large change in laminate material properties below and above Tg. Each graph shows the results from laminate material testing on one of the five date/lot codes tested (lot 0505C). Graph 11 shows an increase in the coefficient of thermal expansion (Z-axis CTE) tested using thermal mechanical analysis (TMA) from 28.9 PPM/°C below Tg to 128.7 PPM/°C above Tg; a 4.45 times increase. Graph 12 shows a decrease in the tested storage modulus using dynamic mechanical analysis (DMA) from 18,000 MPa below Tg to 2500 MPa above Tg; a 7.2 times decrease. Tables 4 and 5 summarize the laminate material test data for five date/lot codes.Graph 11 – TMA plot of Z-axis expansion versus temperature for board date code 0505C.Graph 12 – DMA plot of modulus versus temperature for board date code 0505C.Table 4 – Z-axis expansion rate and Tg data from TMA testing.Table 5 – Modulus and Tg data from DMA testing.We used a simple 1st order approximation to derive the temperature versus stress relationship:e the expansion rate data from TMA in small increments and use it to calculate the strain for each smalltemperature increment (typically <1°C)a.Where Strain = (L higher temp – L original temp)/L original temp where L is the length2.Look-up the Modulus at temperature for each expansion increment3.Calculate the incremental stress (Stress = Strain × Storage Modulus) for each temperature increment4.Calculate the cumulative stress by adding each increment of stress as temperature rises from ambient to 275°C peak Graph 13 shows the Temperature versus Stress relationship obtained using this method for one of the laminate material date/lot codes tested. Table 6 is a convenient cross reference of temperature versus stress on the copper plated through hole for the temperatures used in this paper. Knowing this relationship allows us to quantify the stress on the copper plated through hole from some of the temperature differences. For example, the lead-free assembly stress for Sn/Ag/Cu solder at 245°C is 111.6 MPa; this is 9% higher than the comparable eutectic solder assembly stress of 102.4 MPa at 215°C.Table 6 – Cross-reference table from temperature to Z-axis stress on the copper PTH.Analysis of Cycle to Failure Data versus StressNow that we understand the stress on the copper plated through hole versus temperature relationship, we will use that information to make additional plots of cycles to failure versus stress. Graph 14 is a log-log scatter plot of all the raw data. The lines projecting to 95°C use Miner’s Rule. In fact, switching from cycle to failure versus temperature to cycle to failure versus stress has no effect on the Miner’s Rule relationship. Classic Miner’s Rule plots are S-N plots so Graph 14 should be closer to Palmgren and Miner’s original intend, but in the Table 7 comparison of results, Graph 14 shows the highest cycles to failure estimates of any of the analysis methods.Graphs 15 through 17 use the IPL/Lognormal curve fitting capability of Reliasoft ALTA Version 6. The difference between the three graphs is the preconditioning at 245°C ranging from 6x, 10x, and 18x. In addition, we established a separateIPL/Lognormal relationship for data below and above Tg. Nonetheless, it does look like the data from 215°C (102.4 MPa) falls close to the relationship established from data below Tg. It is possible that 215°C was at a low enough temperature that it did not exhibit any hint of the failure mode shift from PTH to POST interconnect failure. Table 7 shows four estimates using this analysis method including 18x with four outliers removed (graph not included) and 18x with all data including four obvious outliers. As noted earlier, we added 18x preconditioning to the original DoE plan after testing had started. 18x used due to very long cycles to failure at lower preconditioning cycles and lower thermal cycle temperatures. In hindsight, may be 15x preconditioning would have been a better choice, 18x does appear to be a bit excessive. Graph 17 clearly shows the effect of including the four outliers, it leads to a large drop in the cycles to failure and a skewed distribution. Once again, the cause is excessive preconditioning, if we had looked more carefully at the data analysis from testing above Tg, we would have selected a lower number of preconditioning cycles at 245°C.。