抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.

A synaptic model of memory: long-term potentiation in the hippocampus

Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities

The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.

The Ubiquitin System

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

The spatiotemporal expression patterns of the NR2C subunit of the NMDA receptor and PKCT isoform during cerebellar development suggests that both proteins are involved in the molecular mechanisms of synaptogenesis. However, the topographic distribution of WGA-HRP labeled spinocerebellar mossy fiber terminals in NR2C/PKCT double mutants (n = 4) appears similar to controls (n = 3). While the results do not rule out a role for NR2C receptor subunits and the PKCy isoform in cerebellar synaptogenesis, they indicate that neither is necessary for the formation or maintenance of normal spinocerebellar mossy fiber afferent maps.

Short communication Spinocerebellar mossy fiber terminal topography in the NR2C/PKC3/ double mutant cerebellum

Thefrequencies ofdiverse rearrangements of variable (V)Xtojoining (J)X genesegments wereexamined by Southern blothybridization in30murineB-cell lines, each producing animmunoglobulin Xlight chain ofknownsubtype (X1, X2,orX3). For11outof12X1chains, therearrangement wasVX1-AJAl; for9outof9X2chains, itwasVX2-+JX2; andfor8outof9X3chains, itwasVX1- JA3. Similar results wereobtained byconsidering thepartial orcomplete se- quences attheaminoacid orcDNAlevel of44other Xchains (24previously described): for43ofthese chains therear- ranged V-Jgenesegments wereevidently VM1-JA1 for28X1 chains, VX2-JX2 for10X2chains, andVX1-JX3 for5X3 chains. Ofthecombined total of74chains there were3with unusual VXrearrangements, allinvolving theVX2geneseg- ment:for2ofthese unusual chains, theencoding segments wereVX2-JX1-CX1 andforonetheywereVX2-JX3-CX3. Thus, theresults forall74Achains showthat, incontrast to theapparently unrestricted Vow-- JKrearrangements forK chains, foreachofthe3murine A-chain subtypes V-Jrecom- bination isseverely restricted: theVAgenesegment expressed inAlandA3chains wasnearly always VA1(95%and93%, respectively), whereas inA2chains itwaswithout exception VA2(19outof19chains). Therefore VA-JAcombinatorial variation isnotasignificant source ofaminoacidsequence diversity ofAchains ofinbred mice. Iftheorder oftheAgene segments is5'VA2-JA2CAJA4CA4-VA1-JA3CA3JAlCA1 3', as suggested previously andbythepresent findings, itappears that(i) whenaVAgenesegment rearranges inadeveloping B cell itordinarily recombines withaJAgenesegment inthe nearest downstream (3') cluster ofJACAsegments, and(it) VA rearrangement totheupstream (5') cluster isveryrareand possibly maynottakeplace atall. Thecommitment ofadeveloping Blymphocyte toproduce animmunoglobulin (Ig) light (L)chain depends onaprelimi- narystepinwhich avariable region (V)genesegment re- combines with ajoining region (J) genesegment onthesame chromosome (1-5). FormouseLchains oftheKtypethere areseveral hundred VKgenes(6-8), five JKgenesegments (four arefunctional) andoneCK(constant region Kchain) genesegment (4-6), anditseemsthat anyVKsegment can recombine withanyofthefunctional JKsegments. For mouseLchains oftheKtype, thecorresponding geneseg- ments(VA,JA,CA)areorganized differently. Intheinbred strains, there aretwoVA,fourA,andfourCAgeneseg- ments(9,10). EachoftheCAgenesegments ispaired with a unique A segment about 1kilobase (kb) onits upstream (5') side, andthefour paired JK-CK genesegments areorganized intotwoclusters (JK2CX2-JK4CX4 andJO3CO3-JAlCK1), probably with oneVAgenesegment upstream ofeachcluster (9-12). Thesegenesegments specify thethree K-chain sub- types (13-15). Lchains whoseaminoacid residues frompo- sitions 97or98totheCOOHterminus (positions 214or215) areencoded bytheJX1-CX1 ortheJX2-CX2 ortheJX3-CX3 genesegments aredesignated, respectively, asX1,X2,orX3 chains (13-15). Thefourth pair, JX4-CX4, appears tobea pseudogene (11, 12). Aminoacid sequences of19Achains ofthemostabundant subtype (Xl) indicate that eachofthese chains isencoded by aAgeneinwhich theVX1andJX1genesegments arejoined (VX1 - JAl) (13, 16,17). Fortheother subtypes, onlylittle information isavailable about their V -- Jrearrangements. However, theevidence for3X2and2X3chains (14, 18,19) suggests that forthese subtypes there mayalsoberestric- tions intheVX-* JXrecombinations that canoccur.The restrictions areinteresting fortworeasons: (i) Ifconsistent, theyhavetheeffect ofminimizing V-Jcombinatorial varia- tion (4,5,20,21)asasource ofaminoacid sequence diversi- tyofAchains. (ii) Theymaycontribute toourunderstanding oftheorganization andexpression ofAgenes. Tolearn more about theconsistency andimplications ofrestrictions onVX- JArecombination, weanalyzed VAgenerearrangements in 30B-cell tumors ofinbred miceandconsidered theVXrear- rangements responsible for44other chains (24ofthemprevi- ously described). Thecombined evidence demonstrates marked restrictions ofVX-JX rearrangements forX2andX3 chains, aswell asforX1.Three unusual rearrangements were also seenandall oftheminvolved theVX2,nottheVX1, gene segment. Thisdifference between VX1andVX2isstatistical- lysignificant; itreinforces theprevious suggestion (22) that thelinear order ofK-gene segments isprobably 5'V2-

Restricted association ofVandJ-Cgenesegments formouse Alight chains

The present invention provides targets, methods, and reagents for the diagnosis and treatment of schizophrenia and related conditions. The invention provides methods for the diagnosis of schizophrenia and susceptibility to schizophrenia by detection of polymorphisms, mutations, variations, alterations in expression, etc., in calcineurin genes or calcineurin interacting genes, or polymorphisms linked to such genes. The invention provides oligonucleotides, arrays, and antibodies for detection of polymorphisms and variants. The invention provides transgenic mice having alterations in such genes. The invention also provides methods of treating schizophrenia by administering compounds that target these genes. The invention further provides screening methods for identifying such compounds and compounds obtained by performing the screens.

Susumu Tonegawa

Papers

Short communication Spinocerebellar mossy fiber terminal topography in the NR2C/PKC3/ double mutant cerebellum

Restricted association ofVandJ-Cgenesegments formouse Alight chains

Identifying calcineurin activators for treatment of schizophrenia

Identification and Manipulation of Memory Engram Cells