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排序方式: 共有483条查询结果,搜索用时 15 毫秒
351.
Service S DeYoung J Karayiorgou M Roos JL Pretorious H Bedoya G Ospina J Ruiz-Linares A Macedo A Palha JA Heutink P Aulchenko Y Oostra B van Duijn C Jarvelin MR Varilo T Peddle L Rahman P Piras G Monne M Murray S Galver L Peltonen L Sabatti C Collins A Freimer N 《Nature genetics》2006,38(5):556-560
The genome-wide distribution of linkage disequilibrium (LD) determines the strategy for selecting markers for association studies, but it varies between populations. We assayed LD in large samples (200 individuals) from each of 11 well-described population isolates and an outbred European-derived sample, using SNP markers spaced across chromosome 22. Most isolates show substantially higher levels of LD than the outbred sample and many fewer regions of very low LD (termed 'holes'). Young isolates known to have had relatively few founders show particularly extensive LD with very few holes; these populations offer substantial advantages for genome-wide association mapping. 相似文献
352.
Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8 总被引:7,自引:0,他引:7
Moseley ML Zu T Ikeda Y Gao W Mosemiller AK Daughters RS Chen G Weatherspoon MR Clark HB Ebner TJ Day JW Ranum LP 《Nature genetics》2006,38(7):758-769
353.
Chromatin immunoprecipitation (ChIP) defines the genomic distribution of proteins and their modifications but is limited by the cell numbers required (ideally >10(7)). Here we describe a protocol that uses carrier chromatin and PCR, 'carrier' ChIP (CChIP), to permit analysis of as few as 100 cells. We assayed histone modifications at key regulator genes (such as Nanog, Pou5f1 (also known as Oct4) and Cdx2) by CChIP in mouse embryonic stem (ES) cells and in inner cell mass (ICM) and trophectoderm of cultured blastocysts. Activating and silencing modifications (H4 acetylation and H3K9 methylation) mark active and silent promoters as predicted, and we find close correlation between values derived from CChIP (1,000 ES cells) and conventional ChIP (5 x 10(7) ES cells). Studies on genes silenced in both ICM and ES cells (Cdx2, Cfc1, Hhex and Nkx2-2, also known as Nkx) show that the intensity of silencing marks is relatively diminished in ES cells, indicating a possible relaxation of some components of silencing on adaptation to culture. 相似文献
354.
Tarpey P Thomas S Sarvananthan N Mallya U Lisgo S Talbot CJ Roberts EO Awan M Surendran M McLean RJ Reinecke RD Langmann A Lindner S Koch M Jain S Woodruff G Gale RP Bastawrous A Degg C Droutsas K Asproudis I Zubcov AA Pieh C Veal CD Machado RD Backhouse OC Baumber L Constantinescu CS Brodsky MC Hunter DG Hertle RW Read RJ Edkins S O'Meara S Parker A Stevens C Teague J Wooster R Futreal PA Trembath RC Stratton MR Raymond FL Gottlob I 《Nature genetics》2006,38(11):1242-1244
Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability. 相似文献
355.
356.
Protein-protein interactions: Interactome under construction 总被引:1,自引:0,他引:1
357.
Akiyoshi B Sarangapani KK Powers AF Nelson CR Reichow SL Arellano-Santoyo H Gonen T Ranish JA Asbury CL Biggins S 《Nature》2010,468(7323):576-579
Kinetochores are macromolecular machines that couple chromosomes to dynamic microtubule tips during cell division, thereby generating force to segregate the chromosomes. Accurate segregation depends on selective stabilization of correct 'bi-oriented' kinetochore-microtubule attachments, which come under tension as the result of opposing forces exerted by microtubules. Tension is thought to stabilize these bi-oriented attachments indirectly, by suppressing the destabilizing activity of a kinase, Aurora B. However, a complete mechanistic understanding of the role of tension requires reconstitution of kinetochore-microtubule attachments for biochemical and biophysical analyses in vitro. Here we show that native kinetochore particles retaining the majority of kinetochore proteins can be purified from budding yeast and used to reconstitute dynamic microtubule attachments. Individual kinetochore particles maintain load-bearing associations with assembling and disassembling ends of single microtubules for >30?min, providing a close match to the persistent coupling seen in vivo between budding yeast kinetochores and single microtubules. Moreover, tension increases the lifetimes of the reconstituted attachments directly, through a catch bond-like mechanism that does not require Aurora B. On the basis of these findings, we propose that tension selectively stabilizes proper kinetochore-microtubule attachments in vivo through a combination of direct mechanical stabilization and tension-dependent phosphoregulation. 相似文献
358.
Bevilacqua L Doly S Kaprio J Yuan Q Tikkanen R Paunio T Zhou Z Wedenoja J Maroteaux L Diaz S Belmer A Hodgkinson CA Dell'osso L Suvisaari J Coccaro E Rose RJ Peltonen L Virkkunen M Goldman D 《Nature》2010,468(7327):1061-1066
Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency >?1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity. 相似文献
359.
DT Jones N Jäger M Kool T Zichner B Hutter M Sultan YJ Cho TJ Pugh V Hovestadt AM Stütz T Rausch HJ Warnatz M Ryzhova S Bender D Sturm S Pleier H Cin E Pfaff L Sieber A Wittmann M Remke H Witt S Hutter T Tzaridis J Weischenfeldt B Raeder M Avci V Amstislavskiy M Zapatka UD Weber Q Wang B Lasitschka CC Bartholomae M Schmidt C von Kalle V Ast C Lawerenz J Eils R Kabbe V Benes P van Sluis J Koster R Volckmann D Shih MJ Betts RB Russell S Coco GP Tonini U Schüller V Hans N Graf YJ Kim C Monoranu 《Nature》2012,488(7409):100-105
Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients. 相似文献
360.
Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy 总被引:1,自引:0,他引:1
P Koppikar N Bhagwat O Kilpivaara T Manshouri M Adli T Hricik F Liu LM Saunders A Mullally O Abdel-Wahab L Leung A Weinstein S Marubayashi A Goel M Gönen Z Estrov BL Ebert G Chiosis SD Nimer BE Bernstein S Verstovsek RL Levine 《Nature》2012,489(7414):155-159
The identification of somatic activating mutations in JAK2 (refs?1–4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors. 相似文献