Analysis of Long-Term Depression in the Purkinje Cell
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·综述·MTHFR C677T基因多态性与抑郁症关系的研究进展王强,赵鹏,曹秋云,沈迪文,张宇哲,姚志剑摘要: 抑郁症病因复杂,遗传是重要因素之一,其中MTHFR C677T基因多态性因涉及同型半胱氨酸(Hcy)和叶酸代谢而参与抑郁症等精神类疾病的发生。
本文综述了MTHFR C677T基因多态性与抑郁症发病、症状和疗效的关系,以及其对抑郁症脑影像的影响等,总结了目前MTHFR C677T基因多态性与抑郁症关系的研究进展。
希望以此为深入理解抑郁症病理机制提供新的视角,也为未来抑郁症研究提供新的思路。
关键词: MTHFR C677T基因多态性; 抑郁症; 同型半胱氨酸; 叶酸中图分类号: R749 4 文献标识码: A 文章编号: 1005 3220(2023)04 0325 03ResearchprogressontherelationshipbetweenMTHFR C677Tgenepolymorphismandmajordepressivedisorder WANGQiang,ZHAOPeng,CAOQiu yun,SHENDi wen,ZHANGYu zhe,YAOZhi jian.DepartmentofMedicalPsychology,NanjingDrumTowerHospital,AffiliatedHospitalofMedicalSchool,NanjingUniversity,Nanjing210029,ChinaAbstract:Theetiologyofmajordepressivedisorder(MDD)iscomplex,andgeneticsisoneoftheimportantfactors.Amongthem,theMTHFR C677TgenepolymorphismisinvolvedintheoccurrenceofmentaldisorderssuchasMDDduetoitsinvolvementinhomocysteine(Hcy)andfolatemetabolism.ThisarticlereviewstherelationshipbetweenMTHFR C677Tgenepolymorphismandtheonset,symptoms,andefficacyofMDD,aswellasitsimpactonbrainimagingofMDD.ItsummarizesthecurrentresearchprogressontherelationshipbetweenMTHFR C677TgenepolymorphismandMDD.Itmayprovideanewperspectiveforadeeperunderstandingofthepatholog icalmechanismsofMDD,andalsoprovidenewideasforfutureresearchonMDD.Keywords: MTHFR C677Tgenepolymorphism;majordepressivedisorder;homocysteine;folicacid抑郁症的病因复杂,学者们一直尝试从各个方向探寻其发病机制。
DOI: 10.1126/science.1094786, 441 (2004);304Science et al.Mitchell S. Abrahamsen,Cryptosporidium parvum Complete Genome Sequence of the Apicomplexan, (this information is current as of October 7, 2009 ):The following resources related to this article are available online at/cgi/content/full/304/5669/441version of this article at:including high-resolution figures, can be found in the online Updated information and services,/cgi/content/full/1094786/DC1 can be found at:Supporting Online Material/cgi/content/full/304/5669/441#otherarticles , 9 of which can be accessed for free: cites 25 articles This article 239 article(s) on the ISI Web of Science. cited by This article has been /cgi/content/full/304/5669/441#otherarticles 53 articles hosted by HighWire Press; see: cited by This article has been/cgi/collection/genetics Genetics: subject collections This article appears in the following/about/permissions.dtl in whole or in part can be found at: this article permission to reproduce of this article or about obtaining reprints Information about obtaining registered trademark of AAAS.is a Science 2004 by the American Association for the Advancement of Science; all rights reserved. The title Copyright American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the Science o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o m3.R.Jackendoff,Foundations of Language:Brain,Gram-mar,Evolution(Oxford Univ.Press,Oxford,2003).4.Although for Frege(1),reference was established rela-tive to objects in the world,here we follow Jackendoff’s suggestion(3)that this is done relative to objects and the state of affairs as mentally represented.5.S.Zola-Morgan,L.R.Squire,in The Development andNeural Bases of Higher Cognitive Functions(New York Academy of Sciences,New York,1990),pp.434–456.6.N.Chomsky,Reflections on Language(Pantheon,New York,1975).7.J.Katz,Semantic Theory(Harper&Row,New York,1972).8.D.Sperber,D.Wilson,Relevance(Harvard Univ.Press,Cambridge,MA,1986).9.K.I.Forster,in Sentence Processing,W.E.Cooper,C.T.Walker,Eds.(Erlbaum,Hillsdale,NJ,1989),pp.27–85.10.H.H.Clark,Using Language(Cambridge Univ.Press,Cambridge,1996).11.Often word meanings can only be fully determined byinvokingworld knowledg e.For instance,the meaningof “flat”in a“flat road”implies the absence of holes.However,in the expression“aflat tire,”it indicates the presence of a hole.The meaningof“finish”in the phrase “Billfinished the book”implies that Bill completed readingthe book.However,the phrase“the g oatfin-ished the book”can only be interpreted as the goat eatingor destroyingthe book.The examples illustrate that word meaningis often underdetermined and nec-essarily intertwined with general world knowledge.In such cases,it is hard to see how the integration of lexical meaning and general world knowledge could be strictly separated(3,31).12.W.Marslen-Wilson,C.M.Brown,L.K.Tyler,Lang.Cognit.Process.3,1(1988).13.ERPs for30subjects were averaged time-locked to theonset of the critical words,with40items per condition.Sentences were presented word by word on the centerof a computer screen,with a stimulus onset asynchronyof600ms.While subjects were readingthe sentences,their EEG was recorded and amplified with a high-cut-off frequency of70Hz,a time constant of8s,and asamplingfrequency of200Hz.14.Materials and methods are available as supportingmaterial on Science Online.15.M.Kutas,S.A.Hillyard,Science207,203(1980).16.C.Brown,P.Hagoort,J.Cognit.Neurosci.5,34(1993).17.C.M.Brown,P.Hagoort,in Architectures and Mech-anisms for Language Processing,M.W.Crocker,M.Pickering,C.Clifton Jr.,Eds.(Cambridge Univ.Press,Cambridge,1999),pp.213–237.18.F.Varela et al.,Nature Rev.Neurosci.2,229(2001).19.We obtained TFRs of the single-trial EEG data by con-volvingcomplex Morlet wavelets with the EEG data andcomputingthe squared norm for the result of theconvolution.We used wavelets with a7-cycle width,with frequencies ranging from1to70Hz,in1-Hz steps.Power values thus obtained were expressed as a per-centage change relative to the power in a baselineinterval,which was taken from150to0ms before theonset of the critical word.This was done in order tonormalize for individual differences in EEG power anddifferences in baseline power between different fre-quency bands.Two relevant time-frequency compo-nents were identified:(i)a theta component,rangingfrom4to7Hz and from300to800ms after wordonset,and(ii)a gamma component,ranging from35to45Hz and from400to600ms after word onset.20.C.Tallon-Baudry,O.Bertrand,Trends Cognit.Sci.3,151(1999).tner et al.,Nature397,434(1999).22.M.Bastiaansen,P.Hagoort,Cortex39(2003).23.O.Jensen,C.D.Tesche,Eur.J.Neurosci.15,1395(2002).24.Whole brain T2*-weighted echo planar imaging bloodoxygen level–dependent(EPI-BOLD)fMRI data wereacquired with a Siemens Sonata1.5-T magnetic reso-nance scanner with interleaved slice ordering,a volumerepetition time of2.48s,an echo time of40ms,a90°flip angle,31horizontal slices,a64ϫ64slice matrix,and isotropic voxel size of3.5ϫ3.5ϫ3.5mm.For thestructural magnetic resonance image,we used a high-resolution(isotropic voxels of1mm3)T1-weightedmagnetization-prepared rapid gradient-echo pulse se-quence.The fMRI data were preprocessed and analyzedby statistical parametric mappingwith SPM99software(http://www.fi/spm99).25.S.E.Petersen et al.,Nature331,585(1988).26.B.T.Gold,R.L.Buckner,Neuron35,803(2002).27.E.Halgren et al.,J.Psychophysiol.88,1(1994).28.E.Halgren et al.,Neuroimage17,1101(2002).29.M.K.Tanenhaus et al.,Science268,1632(1995).30.J.J.A.van Berkum et al.,J.Cognit.Neurosci.11,657(1999).31.P.A.M.Seuren,Discourse Semantics(Basil Blackwell,Oxford,1985).32.We thank P.Indefrey,P.Fries,P.A.M.Seuren,and M.van Turennout for helpful discussions.Supported bythe Netherlands Organization for Scientific Research,grant no.400-56-384(P.H.).Supporting Online Material/cgi/content/full/1095455/DC1Materials and MethodsFig.S1References and Notes8January2004;accepted9March2004Published online18March2004;10.1126/science.1095455Include this information when citingthis paper.Complete Genome Sequence ofthe Apicomplexan,Cryptosporidium parvumMitchell S.Abrahamsen,1,2*†Thomas J.Templeton,3†Shinichiro Enomoto,1Juan E.Abrahante,1Guan Zhu,4 Cheryl ncto,1Mingqi Deng,1Chang Liu,1‡Giovanni Widmer,5Saul Tzipori,5GregoryA.Buck,6Ping Xu,6 Alan T.Bankier,7Paul H.Dear,7Bernard A.Konfortov,7 Helen F.Spriggs,7Lakshminarayan Iyer,8Vivek Anantharaman,8L.Aravind,8Vivek Kapur2,9The apicomplexan Cryptosporidium parvum is an intestinal parasite that affects healthy humans and animals,and causes an unrelenting infection in immuno-compromised individuals such as AIDS patients.We report the complete ge-nome sequence of C.parvum,type II isolate.Genome analysis identifies ex-tremely streamlined metabolic pathways and a reliance on the host for nu-trients.In contrast to Plasmodium and Toxoplasma,the parasite lacks an api-coplast and its genome,and possesses a degenerate mitochondrion that has lost its genome.Several novel classes of cell-surface and secreted proteins with a potential role in host interactions and pathogenesis were also detected.Elu-cidation of the core metabolism,including enzymes with high similarities to bacterial and plant counterparts,opens new avenues for drug development.Cryptosporidium parvum is a globally impor-tant intracellular pathogen of humans and animals.The duration of infection and patho-genesis of cryptosporidiosis depends on host immune status,ranging from a severe but self-limiting diarrhea in immunocompetent individuals to a life-threatening,prolonged infection in immunocompromised patients.Asubstantial degree of morbidity and mortalityis associated with infections in AIDS pa-tients.Despite intensive efforts over the past20years,there is currently no effective ther-apy for treating or preventing C.parvuminfection in humans.Cryptosporidium belongs to the phylumApicomplexa,whose members share a com-mon apical secretory apparatus mediating lo-comotion and tissue or cellular invasion.Many apicomplexans are of medical or vet-erinary importance,including Plasmodium,Babesia,Toxoplasma,Neosprora,Sarcocys-tis,Cyclospora,and Eimeria.The life cycle ofC.parvum is similar to that of other cyst-forming apicomplexans(e.g.,Eimeria and Tox-oplasma),resulting in the formation of oocysts1Department of Veterinary and Biomedical Science,College of Veterinary Medicine,2Biomedical Genom-ics Center,University of Minnesota,St.Paul,MN55108,USA.3Department of Microbiology and Immu-nology,Weill Medical College and Program in Immu-nology,Weill Graduate School of Medical Sciences ofCornell University,New York,NY10021,USA.4De-partment of Veterinary Pathobiology,College of Vet-erinary Medicine,Texas A&M University,College Sta-tion,TX77843,USA.5Division of Infectious Diseases,Tufts University School of Veterinary Medicine,NorthGrafton,MA01536,USA.6Center for the Study ofBiological Complexity and Department of Microbiol-ogy and Immunology,Virginia Commonwealth Uni-versity,Richmond,VA23198,USA.7MRC Laboratoryof Molecular Biology,Hills Road,Cambridge CB22QH,UK.8National Center for Biotechnology Infor-mation,National Library of Medicine,National Insti-tutes of Health,Bethesda,MD20894,USA.9Depart-ment of Microbiology,University of Minnesota,Min-neapolis,MN55455,USA.*To whom correspondence should be addressed.E-mail:abe@†These authors contributed equally to this work.‡Present address:Bioinformatics Division,Genetic Re-search,GlaxoSmithKline Pharmaceuticals,5MooreDrive,Research Triangle Park,NC27009,USA.R E P O R T S SCIENCE VOL30416APRIL2004441o n O c t o b e r 7 , 2 0 0 9 w w w . s c i e n c e m a g . o r g D o w n l o a d e d f r o mthat are shed in the feces of infected hosts.C.parvum oocysts are highly resistant to environ-mental stresses,including chlorine treatment of community water supplies;hence,the parasite is an important water-and food-borne pathogen (1).The obligate intracellular nature of the par-asite ’s life cycle and the inability to culture the parasite continuously in vitro greatly impair researchers ’ability to obtain purified samples of the different developmental stages.The par-asite cannot be genetically manipulated,and transformation methodologies are currently un-available.To begin to address these limitations,we have obtained the complete C.parvum ge-nome sequence and its predicted protein com-plement.(This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the project accession AAEE00000000.The version described in this paper is the first version,AAEE01000000.)The random shotgun approach was used to obtain the complete DNA sequence (2)of the Iowa “type II ”isolate of C.parvum .This isolate readily transmits disease among numerous mammals,including humans.The resulting ge-nome sequence has roughly 13ϫgenome cov-erage containing five gaps and 9.1Mb of totalDNA sequence within eight chromosomes.The C.parvum genome is thus quite compact rela-tive to the 23-Mb,14-chromosome genome of Plasmodium falciparum (3);this size difference is predominantly the result of shorter intergenic regions,fewer introns,and a smaller number of genes (Table 1).Comparison of the assembled sequence of chromosome VI to that of the recently published sequence of chromosome VI (4)revealed that our assembly contains an ad-ditional 160kb of sequence and a single gap versus two,with the common sequences dis-playing a 99.993%sequence identity (2).The relative paucity of introns greatly simplified gene predictions and facilitated an-notation (2)of predicted open reading frames (ORFs).These analyses provided an estimate of 3807protein-encoding genes for the C.parvum genome,far fewer than the estimated 5300genes predicted for the Plasmodium genome (3).This difference is primarily due to the absence of an apicoplast and mitochondrial genome,as well as the pres-ence of fewer genes encoding metabolic functions and variant surface proteins,such as the P.falciparum var and rifin molecules (Table 2).An analysis of the encoded pro-tein sequences with the program SEG (5)shows that these protein-encoding genes are not enriched in low-complexity se-quences (34%)to the extent observed in the proteins from Plasmodium (70%).Our sequence analysis indicates that Cryptosporidium ,unlike Plasmodium and Toxoplasma ,lacks both mitochondrion and apicoplast genomes.The overall complete-ness of the genome sequence,together with the fact that similar DNA extraction proce-dures used to isolate total genomic DNA from C.parvum efficiently yielded mito-chondrion and apicoplast genomes from Ei-meria sp.and Toxoplasma (6,7),indicates that the absence of organellar genomes was unlikely to have been the result of method-ological error.These conclusions are con-sistent with the absence of nuclear genes for the DNA replication and translation machinery characteristic of mitochondria and apicoplasts,and with the lack of mito-chondrial or apicoplast targeting signals for tRNA synthetases.A number of putative mitochondrial pro-teins were identified,including components of a mitochondrial protein import apparatus,chaperones,uncoupling proteins,and solute translocators (table S1).However,the ge-nome does not encode any Krebs cycle en-zymes,nor the components constituting the mitochondrial complexes I to IV;this finding indicates that the parasite does not rely on complete oxidation and respiratory chains for synthesizing adenosine triphosphate (ATP).Similar to Plasmodium ,no orthologs for the ␥,␦,or εsubunits or the c subunit of the F 0proton channel were detected (whereas all subunits were found for a V-type ATPase).Cryptosporidium ,like Eimeria (8)and Plas-modium ,possesses a pyridine nucleotide tran-shydrogenase integral membrane protein that may couple reduced nicotinamide adenine dinucleotide (NADH)and reduced nico-tinamide adenine dinucleotide phosphate (NADPH)redox to proton translocation across the inner mitochondrial membrane.Unlike Plasmodium ,the parasite has two copies of the pyridine nucleotide transhydrogenase gene.Also present is a likely mitochondrial membrane –associated,cyanide-resistant alter-native oxidase (AOX )that catalyzes the reduction of molecular oxygen by ubiquinol to produce H 2O,but not superoxide or H 2O 2.Several genes were identified as involved in biogenesis of iron-sulfur [Fe-S]complexes with potential mitochondrial targeting signals (e.g.,nifS,nifU,frataxin,and ferredoxin),supporting the presence of a limited electron flux in the mitochondrial remnant (table S2).Our sequence analysis confirms the absence of a plastid genome (7)and,additionally,the loss of plastid-associated metabolic pathways including the type II fatty acid synthases (FASs)and isoprenoid synthetic enzymes thatTable 1.General features of the C.parvum genome and comparison with other single-celled eukaryotes.Values are derived from respective genome project summaries (3,26–28).ND,not determined.FeatureC.parvum P.falciparum S.pombe S.cerevisiae E.cuniculiSize (Mbp)9.122.912.512.5 2.5(G ϩC)content (%)3019.43638.347No.of genes 38075268492957701997Mean gene length (bp)excluding introns 1795228314261424ND Gene density (bp per gene)23824338252820881256Percent coding75.352.657.570.590Genes with introns (%)553.9435ND Intergenic regions (G ϩC)content %23.913.632.435.145Mean length (bp)5661694952515129RNAsNo.of tRNA genes 454317429944No.of 5S rRNA genes 6330100–2003No.of 5.8S ,18S ,and 28S rRNA units 57200–400100–20022Table parison between predicted C.parvum and P.falciparum proteins.FeatureC.parvum P.falciparum *Common †Total predicted proteins380752681883Mitochondrial targeted/encoded 17(0.45%)246(4.7%)15Apicoplast targeted/encoded 0581(11.0%)0var/rif/stevor ‡0236(4.5%)0Annotated as protease §50(1.3%)31(0.59%)27Annotated as transporter 69(1.8%)34(0.65%)34Assigned EC function ¶167(4.4%)389(7.4%)113Hypothetical proteins925(24.3%)3208(60.9%)126*Values indicated for P.falciparum are as reported (3)with the exception of those for proteins annotated as protease or transporter.†TBLASTN hits (e Ͻ–5)between C.parvum and P.falciparum .‡As reported in (3).§Pre-dicted proteins annotated as “protease or peptidase”for C.parvum (CryptoGenome database,)and P.falciparum (PlasmoDB database,).Predicted proteins annotated as “trans-porter,permease of P-type ATPase”for C.parvum (CryptoGenome)and P.falciparum (PlasmoDB).¶Bidirectional BLAST hit (e Ͻ–15)to orthologs with assigned Enzyme Commission (EC)numbers.Does not include EC assignment numbers for protein kinases or protein phosphatases (due to inconsistent annotation across genomes),or DNA polymerases or RNA polymerases,as a result of issues related to subunit inclusion.(For consistency,46proteins were excluded from the reported P.falciparum values.)R E P O R T S16APRIL 2004VOL 304SCIENCE 442 o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o mare otherwise localized to the plastid in other apicomplexans.C.parvum fatty acid biosynthe-sis appears to be cytoplasmic,conducted by a large(8252amino acids)modular type I FAS (9)and possibly by another large enzyme that is related to the multidomain bacterial polyketide synthase(10).Comprehensive screening of the C.parvum genome sequence also did not detect orthologs of Plasmodium nuclear-encoded genes that contain apicoplast-targeting and transit sequences(11).C.parvum metabolism is greatly stream-lined relative to that of Plasmodium,and in certain ways it is reminiscent of that of another obligate eukaryotic parasite,the microsporidian Encephalitozoon.The degeneration of the mi-tochondrion and associated metabolic capabili-ties suggests that the parasite largely relies on glycolysis for energy production.The parasite is capable of uptake and catabolism of mono-sugars(e.g.,glucose and fructose)as well as synthesis,storage,and catabolism of polysac-charides such as trehalose and amylopectin. Like many anaerobic organisms,it economizes ATP through the use of pyrophosphate-dependent phosphofructokinases.The conver-sion of pyruvate to acetyl–coenzyme A(CoA) is catalyzed by an atypical pyruvate-NADPH oxidoreductase(Cp PNO)that contains an N-terminal pyruvate–ferredoxin oxidoreductase (PFO)domain fused with a C-terminal NADPH–cytochrome P450reductase domain (CPR).Such a PFO-CPR fusion has previously been observed only in the euglenozoan protist Euglena gracilis(12).Acetyl-CoA can be con-verted to malonyl-CoA,an important precursor for fatty acid and polyketide biosynthesis.Gly-colysis leads to several possible organic end products,including lactate,acetate,and ethanol. The production of acetate from acetyl-CoA may be economically beneficial to the parasite via coupling with ATP production.Ethanol is potentially produced via two in-dependent pathways:(i)from the combination of pyruvate decarboxylase and alcohol dehy-drogenase,or(ii)from acetyl-CoA by means of a bifunctional dehydrogenase(adhE)with ac-etaldehyde and alcohol dehydrogenase activi-ties;adhE first converts acetyl-CoA to acetal-dehyde and then reduces the latter to ethanol. AdhE predominantly occurs in bacteria but has recently been identified in several protozoans, including vertebrate gut parasites such as Enta-moeba and Giardia(13,14).Adjacent to the adhE gene resides a second gene encoding only the AdhE C-terminal Fe-dependent alcohol de-hydrogenase domain.This gene product may form a multisubunit complex with AdhE,or it may function as an alternative alcohol dehydro-genase that is specific to certain growth condi-tions.C.parvum has a glycerol3-phosphate dehydrogenase similar to those of plants,fungi, and the kinetoplastid Trypanosoma,but(unlike trypanosomes)the parasite lacks an ortholog of glycerol kinase and thus this pathway does not yield glycerol production.In addition to themodular fatty acid synthase(Cp FAS1)andpolyketide synthase homolog(Cp PKS1), C.parvum possesses several fatty acyl–CoA syn-thases and a fatty acyl elongase that may partici-pate in fatty acid metabolism.Further,enzymesfor the metabolism of complex lipids(e.g.,glyc-erolipid and inositol phosphate)were identified inthe genome.Fatty acids are apparently not anenergy source,because enzymes of the fatty acidoxidative pathway are absent,with the exceptionof a3-hydroxyacyl-CoA dehydrogenase.C.parvum purine metabolism is greatlysimplified,retaining only an adenosine ki-nase and enzymes catalyzing conversionsof adenosine5Ј-monophosphate(AMP)toinosine,xanthosine,and guanosine5Ј-monophosphates(IMP,XMP,and GMP).Among these enzymes,IMP dehydrogenase(IMPDH)is phylogenetically related toε-proteobacterial IMPDH and is strikinglydifferent from its counterparts in both thehost and other apicomplexans(15).In con-trast to other apicomplexans such as Toxo-plasma gondii and P.falciparum,no geneencoding hypoxanthine-xanthineguaninephosphoribosyltransferase(HXGPRT)is de-tected,in contrast to a previous report on theactivity of this enzyme in C.parvum sporo-zoites(16).The absence of HXGPRT sug-gests that the parasite may rely solely on asingle enzyme system including IMPDH toproduce GMP from AMP.In contrast to otherapicomplexans,the parasite appears to relyon adenosine for purine salvage,a modelsupported by the identification of an adeno-sine transporter.Unlike other apicomplexansand many parasitic protists that can synthe-size pyrimidines de novo,C.parvum relies onpyrimidine salvage and retains the ability forinterconversions among uridine and cytidine5Ј-monophosphates(UMP and CMP),theirdeoxy forms(dUMP and dCMP),and dAMP,as well as their corresponding di-and triphos-phonucleotides.The parasite has also largelyshed the ability to synthesize amino acids denovo,although it retains the ability to convertselect amino acids,and instead appears torely on amino acid uptake from the host bymeans of a set of at least11amino acidtransporters(table S2).Most of the Cryptosporidium core pro-cesses involved in DNA replication,repair,transcription,and translation conform to thebasic eukaryotic blueprint(2).The transcrip-tional apparatus resembles Plasmodium interms of basal transcription machinery.How-ever,a striking numerical difference is seenin the complements of two RNA bindingdomains,Sm and RRM,between P.falcipa-rum(17and71domains,respectively)and C.parvum(9and51domains).This reductionresults in part from the loss of conservedproteins belonging to the spliceosomal ma-chinery,including all genes encoding Smdomain proteins belonging to the U6spliceo-somal particle,which suggests that this par-ticle activity is degenerate or entirely lost.This reduction in spliceosomal machinery isconsistent with the reduced number of pre-dicted introns in Cryptosporidium(5%)rela-tive to Plasmodium(Ͼ50%).In addition,keycomponents of the small RNA–mediatedposttranscriptional gene silencing system aremissing,such as the RNA-dependent RNApolymerase,Argonaute,and Dicer orthologs;hence,RNA interference–related technolo-gies are unlikely to be of much value intargeted disruption of genes in C.parvum.Cryptosporidium invasion of columnarbrush border epithelial cells has been de-scribed as“intracellular,but extracytoplas-mic,”as the parasite resides on the surface ofthe intestinal epithelium but lies underneaththe host cell membrane.This niche may al-low the parasite to evade immune surveil-lance but take advantage of solute transportacross the host microvillus membrane or theextensively convoluted parasitophorous vac-uole.Indeed,Cryptosporidium has numerousgenes(table S2)encoding families of putativesugar transporters(up to9genes)and aminoacid transporters(11genes).This is in starkcontrast to Plasmodium,which has fewersugar transporters and only one putative ami-no acid transporter(GenBank identificationnumber23612372).As a first step toward identification ofmulti–drug-resistant pumps,the genome se-quence was analyzed for all occurrences ofgenes encoding multitransmembrane proteins.Notable are a set of four paralogous proteinsthat belong to the sbmA family(table S2)thatare involved in the transport of peptide antibi-otics in bacteria.A putative ortholog of thePlasmodium chloroquine resistance–linkedgene Pf CRT(17)was also identified,althoughthe parasite does not possess a food vacuole likethe one seen in Plasmodium.Unlike Plasmodium,C.parvum does notpossess extensive subtelomeric clusters of anti-genically variant proteins(exemplified by thelarge families of var and rif/stevor genes)thatare involved in immune evasion.In contrast,more than20genes were identified that encodemucin-like proteins(18,19)having hallmarksof extensive Thr or Ser stretches suggestive ofglycosylation and signal peptide sequences sug-gesting secretion(table S2).One notable exam-ple is an11,700–amino acid protein with anuninterrupted stretch of308Thr residues(cgd3_720).Although large families of secretedproteins analogous to the Plasmodium multi-gene families were not found,several smallermultigene clusters were observed that encodepredicted secreted proteins,with no detectablesimilarity to proteins from other organisms(Fig.1,A and B).Within this group,at leastfour distinct families appear to have emergedthrough gene expansions specific to the Cryp-R E P O R T S SCIENCE VOL30416APRIL2004443o n O c t o b e r 7 , 2 0 0 9 w w w . s c i e n c e m a g . o r g D o w n l o a d e d f r o mtosporidium clade.These families —SKSR,MEDLE,WYLE,FGLN,and GGC —were named after well-conserved sequence motifs (table S2).Reverse transcription polymerase chain reaction (RT-PCR)expression analysis (20)of one cluster,a locus of seven adjacent CpLSP genes (Fig.1B),shows coexpression during the course of in vitro development (Fig.1C).An additional eight genes were identified that encode proteins having a periodic cysteine structure similar to the Cryptosporidium oocyst wall protein;these eight genes are similarly expressed during the onset of oocyst formation and likely participate in the formation of the coccidian rigid oocyst wall in both Cryptospo-ridium and Toxoplasma (21).Whereas the extracellular proteins described above are of apparent apicomplexan or lineage-specific in-vention,Cryptosporidium possesses many genesencodingsecretedproteinshavinglineage-specific multidomain architectures composed of animal-and bacterial-like extracellular adhe-sive domains (fig.S1).Lineage-specific expansions were ob-served for several proteases (table S2),in-cluding an aspartyl protease (six genes),a subtilisin-like protease,a cryptopain-like cys-teine protease (five genes),and a Plas-modium falcilysin-like (insulin degrading enzyme –like)protease (19genes).Nine of the Cryptosporidium falcilysin genes lack the Zn-chelating “HXXEH ”active site motif and are likely to be catalytically inactive copies that may have been reused for specific protein-protein interactions on the cell sur-face.In contrast to the Plasmodium falcilysin,the Cryptosporidium genes possess signal peptide sequences and are likely trafficked to a secretory pathway.The expansion of this family suggests either that the proteins have distinct cleavage specificities or that their diversity may be related to evasion of a host immune response.Completion of the C.parvum genome se-quence has highlighted the lack of conven-tional drug targets currently pursued for the control and treatment of other parasitic protists.On the basis of molecular and bio-chemical studies and drug screening of other apicomplexans,several putative Cryptospo-ridium metabolic pathways or enzymes have been erroneously proposed to be potential drug targets (22),including the apicoplast and its associated metabolic pathways,the shikimate pathway,the mannitol cycle,the electron transport chain,and HXGPRT.Nonetheless,complete genome sequence analysis identifies a number of classic and novel molecular candidates for drug explora-tion,including numerous plant-like and bacterial-like enzymes (tables S3and S4).Although the C.parvum genome lacks HXGPRT,a potent drug target in other api-complexans,it has only the single pathway dependent on IMPDH to convert AMP to GMP.The bacterial-type IMPDH may be a promising target because it differs substan-tially from that of eukaryotic enzymes (15).Because of the lack of de novo biosynthetic capacity for purines,pyrimidines,and amino acids,C.parvum relies solely on scavenge from the host via a series of transporters,which may be exploited for chemotherapy.C.parvum possesses a bacterial-type thymidine kinase,and the role of this enzyme in pyrim-idine metabolism and its drug target candida-cy should be pursued.The presence of an alternative oxidase,likely targeted to the remnant mitochondrion,gives promise to the study of salicylhydroxamic acid (SHAM),as-cofuranone,and their analogs as inhibitors of energy metabolism in the parasite (23).Cryptosporidium possesses at least 15“plant-like ”enzymes that are either absent in or highly divergent from those typically found in mammals (table S3).Within the glycolytic pathway,the plant-like PPi-PFK has been shown to be a potential target in other parasites including T.gondii ,and PEPCL and PGI ap-pear to be plant-type enzymes in C.parvum .Another example is a trehalose-6-phosphate synthase/phosphatase catalyzing trehalose bio-synthesis from glucose-6-phosphate and uridine diphosphate –glucose.Trehalose may serve as a sugar storage source or may function as an antidesiccant,antioxidant,or protein stability agent in oocysts,playing a role similar to that of mannitol in Eimeria oocysts (24).Orthologs of putative Eimeria mannitol synthesis enzymes were not found.However,two oxidoreductases (table S2)were identified in C.parvum ,one of which belongs to the same families as the plant mannose dehydrogenases (25)and the other to the plant cinnamyl alcohol dehydrogenases.In principle,these enzymes could synthesize protective polyol compounds,and the former enzyme could use host-derived mannose to syn-thesize mannitol.References and Notes1.D.G.Korich et al .,Appl.Environ.Microbiol.56,1423(1990).2.See supportingdata on Science Online.3.M.J.Gardner et al .,Nature 419,498(2002).4.A.T.Bankier et al .,Genome Res.13,1787(2003).5.J.C.Wootton,Comput.Chem.18,269(1994).Fig.1.(A )Schematic showing the chromosomal locations of clusters of potentially secreted proteins.Numbers of adjacent genes are indicated in paren-theses.Arrows indicate direc-tion of clusters containinguni-directional genes (encoded on the same strand);squares indi-cate clusters containingg enes encoded on both strands.Non-paralogous genes are indicated by solid gray squares or direc-tional triangles;SKSR (green triangles),FGLN (red trian-gles),and MEDLE (blue trian-gles)indicate three C.parvum –specific families of paralogous genes predominantly located at telomeres.Insl (yellow tri-angles)indicates an insulinase/falcilysin-like paralogous gene family.Cp LSP (white square)indicates the location of a clus-ter of adjacent large secreted proteins (table S2)that are cotranscriptionally regulated.Identified anchored telomeric repeat sequences are indicated by circles.(B )Schematic show-inga select locus containinga cluster of coexpressed large secreted proteins (Cp LSP).Genes and intergenic regions (regions between identified genes)are drawn to scale at the nucleotide level.The length of the intergenic re-gions is indicated above or be-low the locus.(C )Relative ex-pression levels of CpLSP (red lines)and,as a control,C.parvum Hedgehog-type HINT domain gene (blue line)duringin vitro development,as determined by semiquantitative RT-PCR usingg ene-specific primers correspondingto the seven adjacent g enes within the CpLSP locus as shown in (B).Expression levels from three independent time-course experiments are represented as the ratio of the expression of each gene to that of C.parvum 18S rRNA present in each of the infected samples (20).R E P O R T S16APRIL 2004VOL 304SCIENCE 444 o n O c t o b e r 7, 2009w w w .s c i e n c e m a g .o r g D o w n l o a d e d f r o m。
Advances in Psychology 心理学进展, 2019, 9(10), 1767-1777Published Online October 2019 in Hans. /journal/aphttps:///10.12677/ap.2019.910214Effect of Somatostatin-ExpressingInterneuron Deficits in DepressionChen GuoSchool of Psychology, The Key Lab of Cognition and Personality of the Ministry of Education, The Southwest University, ChongqingReceived: Oct. 3rd, 2019; accepted: Oct. 18th, 2019; published: Oct. 25th, 2019AbstractMajor depressive disorder is a common mental illness, but its pathological mechanism is still unclear.In recent years, studies have found that imbalance of neural network excitability and inhibition may be one of the important factors leading to depression, which is mainly caused by the incoordination between excitatory glutamatergic pyramidal neurons and inhibitory gamma-aminobutyric acid neu-rons. Somatostatin-expressing interneurons, the main inhibitory neurons, regulate pyramidal neu-ronal activity, participate in stress response, and have a high susceptibility to stress. In the dorsal ventral frontal lobes (dlPFC), cingulate gyrus (ACC), hippocampus and other brain regions in pa-tients with depression, researchers have found a decrease in SST mRNA and protein levels. This ar-ticle will review the function of somatostatin-expressing interneuron and how its functional reduc-tion impacts depression, including causes and performance.KeywordsMajor Depressive Disorder, Gabaergic Interneurons, Somatostatin Interneurons, Prefrontal Cortex, Drug DevelopmentSST中间神经元功能降低对抑郁症的影响郭沉西南大学心理学部教育部认知与人格重点实验室,重庆收稿日期:2019年10月3日;录用日期:2019年10月18日;发布日期:2019年10月25日摘要抑郁症(major depressive disorder)是一种常见的精神疾病,但其病理机制尚不清楚。
· 93 ·中国疼痛医学杂志Chinese Journal of Pain Medicine 2021, 27 (2)[49] Teodor, Goroszeniuk. The effect of peripheral neuro-modulation on pain from the sacroiliac joint: A retro-spective cohort study[J]. Neuromodulation: Journal of the International Neuromodulation Society, 2019, 22(5):661-666.[50] Kim YH, Moon DE. Sacral nerve stimulation for thetreatment of sacroiliac joint dysfunction: A case re-port[J]. Neuromodulation, 2010, 13(4):306-310. [51] Dengler J, Kools D, Pflugmacher R, et al. Randomizedtrial of sacroiliac joint arthrodesis compared with con-servative management for chronic low back pain at-tributed to the sacroiliac joint[J]. J Bone Joint Surg Am, 2019, 101(5): 400-411.[52] Sachs D, Capobianco R. One year successful outcomesfor novel sacroiliac joint arthrodesis system[J]. Ann Surg Innovat Res, 2012, 6(1):13.[53] Smith AG, Capobianco R, Cher D, et al. Open versusminimally invasive sacroiliac joint fusion: A multi-center comparison of perioperative measures and clinical outcomes[J]. Ann Surg Innovat Res, 2013, 7(1):14.[54] Capobianco R, Cher D. Safety and effectiveness ofminimally invasive sacroiliac joint fusion in women with persistent post-partum posterior pelvic girdle pain: 12-month outcomes from a prospective, multi-center trial[J]. SpringerPlus, 2015, 4:570.•国际译文•杏仁核-海马环路参与抑郁症的发病机制慢性应激常可引发抑郁症。
当你上课感觉就像打酱油时,当你对研究生很迷茫时,当你坐在电脑前孜孜不倦时,请看下面的文章,很受用,至少我心里现在没有以前浮躁。
好的文章有时能改变一个人的精神状态,下面就是其中之一。
首先,我们要知道标题的结构是什么。
英文题名多以短语为主要形式,尤以名词短语( noun phrase)最为常见,即题名基本上由一个或几个名词或名词短语加上其前置和(或)后置定语构成。
例如:Example 1 Catheter a blation for superventricular tachycardia in clcongenital heart diseases.Example 2 Antioxidant property of ginsenoside Re in cardiomyocytes.Example 3 Molecular physiology of cardiac repolarization.Example 4 Pharmacological differentiation between intracellular calcium pumpisoforms现以“ Example1, Example2”为例加以分析。
“ Catheter ablation”(导管切除)是主要的名词短语(中心词),“for superventricular tachycardia”(室上性心动过速)和“ in children and congenital heart diseases”(在儿童和先天性心脏病患者)则为两个前置词后置定语,分别修饰、说明这种导管切除技术是在什么种型的疾病,以及在什么样的患者身上施行。
又如Example2,中心词“ Antioxidant property'”是一个名词短语,“ of ginsenoside Re"和“ "in cardiomyocytes”也是两个前置词后置定语,用来修饰中心词“抗氧化特征”,说明是什么物质的“抗氧化特征”,以及对何种细胞的“抗氧化作用”。
·论著·伴有抑郁特征的首发精神分裂症患者巨噬细胞抑制因子与精神病理症状的关联性研究于健瑾,宋佳起,赵青,王晓莹,高亚伦,辛闻,李红娜,付卫红,周玲,林姿莹,王楠,陈大春摘要: 目的:探讨伴有抑郁特征的首发精神分裂症(FES)治疗前后巨噬细胞抑制因子(MIF)与精神病理症状的相关性。
方法:FES患者112例,根据汉密尔顿抑郁量表(HAMD)总分分为伴或不伴抑郁亚组,同时纳入健康对照组58例。
FES组接受利培酮单药治疗10周,采用阳性与阴性症状量表(PANSS)评定FES患者的精神病理症状。
采用化学发光法检测FES组治疗前后及健康对照组血清MIF水平。
结果:治疗前,FES组MIF水平显著高于正常对照组(P<0.01),伴抑郁组与不伴抑郁组一般精神病理分差异有统计学意义(P<0.01)。
治疗后,不伴抑郁组MIF水平显著下降(P<0.05),伴抑郁组治疗后MIF水平差异无统计学意义,两组治疗前后PANSS总分及分量表分差异均有统计学意义。
伴抑郁组基线及治疗后MIF水平与一般精神病理分均存在负相关(r1=-0.34;r2=-0.44),MIF变化值与一般精神病理分变化值存在负相关(r=-0.42)。
结论:FES患者存在血清MIF水平异常,伴有抑郁特征FES患者的MIF与一般精神病理存在一定关联。
关键词: 精神分裂症; 巨噬细胞抑制因子; 抑郁; 精神症状中图分类号: R749.4 文献标识码: A 文章编号: 1005 3220(2022)06 0442 03Relationshipbetweenmacrophageinhibitoryfactorandpsychoticsymptomsinfirst episodeschizophreniapatientswithdepressivecharacteristics YUJian jin,SONGJia qi,ZHAOQing,WANGXiao ying,GAOYa lun,XINWen,LIHong na,FUWei hong,ZHOULing,LINZi ying,WANGNan,CHENDa chun.BeijingHuilongguanHospital,Beijing100096,ChinaAbstract: Objective:Toexplorethecorrelationbetweenmacrophagemigrationinhibitoryfactor(MIF)levelsandmentalsymptomsinfirst episodeschizophrenia(FES)patientsaccompaniedwithdepressivesymp toms. Method:Atotalof112FESpatientsand58healthycontrolswereincluded.AndtheFESgroupweredividedintosubgroupsdependingonaccompaniedwithorwithoutdepressionaccordingtotheHamiltonDepressionScale(HAMD).TheFESgroupreceivedrisperidonemonotherapyfor10weeks,andthePositiveandNega tiveSymptomsScale(PANSS)wasusedtoevaluatethepsychopathologicalsymptomsofFESpatients.Chemilu minescencemethodwasusedtodetectserumMIFlevelsbeforeandaftertreatmentintheFESgroup,whileatbaselineinthehealthycontrolgroup. Results:Beforetreatment,theMIFlevelsintheFESgroupweresignifi cantlyhigherthanthoseinthecontrolgroup(P<0.01),andtherewasasignificantdifferenceinthegeneralpsychopathologicalscoresbetweenthedepressionandthenon depressiongroup(P<0.01).Aftertreatment,theMIFlevelsinthenon depressiongroupdecreased(P<0.05),whilenodifferencefoundinthedepressiongroup.ThereweresignificantdifferencesinthePANSStotalscoreandsubscalescoresbetweenbeforeandaftertreat mentinbothgroups.TheMIFlevelswerenegativelycorrelatedwithgeneralpsychopathologicalscoresinPANSSatbaselineorandaftertreatment(r1=-0.34;r2=-0.44)inthedepressiongroup.Therewasalsoanegativecorrelationbetweenthechangesofthem(r=-0.42). Conclusion:TheMIFlevelsinFESpatientsareab normal,andthereisacertaincorrelationbetweenMIFandgeneralpsychopathologyinFESpatientswithdepres sivecharacteristics.Keywords: schizophrenia; macrophageinhibitoryfactor; depression; psychiatricsymptoms基金项目:首都卫生发展科研专项项目(首发2018 2 2131)作者单位:100096 北京回龙观医院,北京大学回龙观临床医学院通信作者:陈大春,E Mail:chendachun1963@163.comDOI:10.3969/j.issn.1005 3220.2022.06.007精神分裂症(Schizophrenia,SCZ)终生患病率约占世界人口的1%。
250090-2977/14/4601-0025 © 2014 Springer Science+Business Media New York
Neurophysiology, Vol. 46, No. 1, February 2014Analysis of Long-Term Depression in the Purkinje Cell Circuit (a Model Study)
X. C. Zhang1, S. Q. Liu1, H. X. Ren1, Y. J. Zeng2, and G. X. Zhan1
Received March 8, 2013In the cerebellum, long-term depression (LTD) plays a key function in sculpting neuronal circuits to store information, since motor learning and memory are thought to be associated with such long-term changes in synaptic efficacy. To better understand the principles of transmission of information in the cerebellum, we, in our model, distinguished different types of neurons (type 1- and type 2-like) to examine the neuronal excitability and analyze the interspike interval (ISI) bifurcation phenomenon in these units, and then built a Purkinje cell circuit to study the impact of external stimulation on LTD in this circuit. According to the results of computational analysis, both climbing fiber-Purkinje cell and granule cell-Purkinje cell circuits were found to manifest LTD; the external stimuli would influence LTD by changing both depression time and depression intensity. All of the simulated results showed that LTD is a very significant factor in the Purkinje circuit networks. Finally, to deliver the learning regularities, we simulated spike timing-dependent plasticity (STDP) by increasing the CaP conductance.
Keywords: long-term depression (LTD), interspike interval (ISI), ion currents, depression time, depression intensity, spike timing-dependent plasticity (STDP).
INTRODUCTION
Long-term depression (LTD) is a well-known neurophysiological phenomenon; it is manifested as activity-dependent reduction in the efficacy of neuronal synapses developing after long patterned stimulations and lasting hours or longer. LTD is observed in many areas of the CNS; its mechanisms are dissimilar in different brain regions and depend upon the developmental stage [1]. In the cerebellum, LTD occurs in synapses on cerebellar Purkinje neurons; the latter receive two forms of excitatory inputs, one from a single climbing fiber and one from hundreds of parallel fibers [2]. Ito and colleagues were the first to documente LTD in the cerebellar cortex [3, 4]. They observed that LTD results from coincident activation of parallel fiber and climbing fiber inputs onto Purkinje cells. Subsequent experiments were designed to test a hypothesis that LTD of excitatory synaptic transmission in the cerebellar cortex is caused by a rise in the postsynaptic Ca2+ concentration [5].
1 Department of Mathematics, South China University of Technology, Guangzhou, China2 Biomedical Engineering Center, Beijing University of Technology, Beijing, China Correspondence should be addressed to: X. C. Zhang (e-mail: xuchen0206@gmail.com) or S. Q. Liu (e-mail: mashqliu@scut.edu.ch).
Considering the importance of the cerebellum for motor learning, it has been widely proposed that LTD may serve as a cellular substrate of motor learning and memory in cerebellar cortical circuits [4, 6, 7]. There are numerous studies on LTD induction in the climbing fiber-Purkinje cell and parallel fiber-Purkinje cell circuits. The LTD induced from climbing fibers was not associated with changes in the input or series resistance or with alterations in the strength of action of parallel fiber synapses [8]. Chen and Thompson applied a field potential recording technique from cerebellar slices to examine temporal conditions for the LTD development. The results suggested that these conditions for LTD induction demonstrate some similarity to those of associative learning for discrete motor responses [9]. Ekerot and Kano found that climbing fibers heterosynaptically depress parallel fiber-related responses in Purkinje cells [10].According to the known pattern of the connecting system between different cells in the cerebellar cortex, we constructed a model of the Purkinje circuit network; this allowed us to separately study some dynamic properties of different types of cerebellar neuronal activity and LTD in the Purkinje circuit. Also, we analyzed some ion currents (Ca2+, K+, and Na+) in these interconnected neurons. Finally, we simulated the spike timing-dependent plasticity (STDP) phenomenon and its relation to LTD in this model network.