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251.
Amir Alexander 《Foundations of Science》2018,23(2):393-398
In “The Jesuits and the Method of Indivisibles” David Sherry criticizes a central thesis of my book Infinitesimal: that in the seventeenth century the Jesuits sought to suppress the method of indivisibles because it undermined their efforts to establish a perfect rational and hierarchical order in the world, modeled on Euclidean Geometry. Sherry accepts that the Jesuits did indeed suppress the method, but offers two objections. First, that the book does not distinguish between indivisibles and infinitesimals, and that whereas the Jesuits might have reason to object to the first, the second posed no problem for them. Second, seeking an alternative explanation for the Jesuits’ hostility to the method, he proposes that its implicit atomism conflicted with the Catholic doctrine of the sacrament of the Eucharist, and was therefore heretical. In response to Sherry’s first criticism I point out that the Jesuits objected to all forms of the method of indivisibles, and that the distinction between indivisibles and infinitesimals consequently cannot explain the fight over the method in the seventeenth century. With regards to the Eucharist, I agree with Sherry that the Jesuits were indeed concerned about the method’s affinity to atomism and materialism, though for a different reason: these doctrines were antithetical to their efforts to impose divine hierarchy and order on the world. In as much as the technical details of the miracle of the Eucharist mattered, they provided no grounds for objecting to a mathematical (rather than physical) doctrine. 相似文献
252.
Logan CV Lucke B Pottinger C Abdelhamed ZA Parry DA Szymanska K Diggle CP van Riesen A Morgan JE Markham G Ellis I Manzur AY Markham AF Shires M Helliwell T Scoto M Hübner C Bonthron DT Taylor GR Sheridan E Muntoni F Carr IM Schuelke M Johnson CA 《Nature genetics》2011,43(12):1189-1192
Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia. 相似文献
253.
Lieberman TD Michel JB Aingaran M Potter-Bynoe G Roux D Davis MR Skurnik D Leiby N LiPuma JJ Goldberg JB McAdam AJ Priebe GP Kishony R 《Nature genetics》2011,43(12):1275-1280
Bacterial pathogens evolve during the infection of their human host(1-8), but separating adaptive and neutral mutations remains challenging(9-11). Here we identify bacterial genes under adaptive evolution by tracking recurrent patterns of mutations in the same pathogenic strain during the infection of multiple individuals. We conducted a retrospective study of a Burkholderia dolosa outbreak among subjects with cystic fibrosis, sequencing the genomes of 112 isolates collected from 14 individuals over 16 years. We find that 17 bacterial genes acquired nonsynonymous mutations in multiple individuals, which indicates parallel adaptive evolution. Mutations in these genes affect important pathogenic phenotypes, including antibiotic resistance and bacterial membrane composition and implicate oxygen-dependent regulation as paramount in lung infections. Several genes have not previously been implicated in pathogenesis and may represent new therapeutic targets. The identification of parallel molecular evolution as a pathogen spreads among multiple individuals points to the key selection forces it experiences within human hosts. 相似文献
254.
MicroRNAs can generate thresholds in target gene expression 总被引:2,自引:0,他引:2
Mukherji S Ebert MS Zheng GX Tsang JS Sharp PA van Oudenaarden A 《Nature genetics》2011,43(9):854-859
MicroRNAs (miRNAs) are short, highly conserved noncoding RNA molecules that repress gene expression in a sequence-dependent manner. We performed single-cell measurements using quantitative fluorescence microscopy and flow cytometry to monitor a target gene's protein expression in the presence and absence of regulation by miRNA. We find that although the average level of repression is modest, in agreement with previous population-based measurements, the repression among individual cells varies dramatically. In particular, we show that regulation by miRNAs establishes a threshold level of target mRNA below which protein production is highly repressed. Near this threshold, protein expression responds sensitively to target mRNA input, consistent with a mathematical model of molecular titration. These results show that miRNAs can act both as a switch and as a fine-tuner of gene expression. 相似文献
255.
Suhre K Wallaschofski H Raffler J Friedrich N Haring R Michael K Wasner C Krebs A Kronenberg F Chang D Meisinger C Wichmann HE Hoffmann W Völzke H Völker U Teumer A Biffar R Kocher T Felix SB Illig T Kroemer HK Gieger C Römisch-Margl W Nauck M 《Nature genetics》2011,43(6):565-569
We present a genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body. Using NMR spectroscopy, we tested for associations between 59 metabolites in urine from 862 male participants in the population-based SHIP study. We replicated the results using 1,039 additional samples of the same study, including a 5-year follow-up, and 992 samples from the independent KORA study. We report five loci with joint P values of association from 3.2 × 10(-19) to 2.1 × 10(-182). Variants at three of these loci have previously been linked with important clinical outcomes: SLC7A9 is a risk locus for chronic kidney disease, NAT2 for coronary artery disease and genotype-dependent response to drug toxicity, and SLC6A20 for iminoglycinuria. Moreover, we identify rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria. 相似文献
256.
Schmidt T Ben-Batalla I Schultze A Loges S 《Cellular and molecular life sciences : CMLS》2012,69(9):1391-1414
Ample clinical and preclinical evidence indicates that macrophages interact with tumor cells as well as with virtually all
populations of host cells present in the tumor microenvironment. This crosstalk can strongly promote malignancy, but also
has in principle the potential to inhibit tumor growth. Thus, it is of the utmost importance to improve our understanding
of the mechanisms driving the pro- and antimalignant behavior of tumor-associated macrophages (TAMs) in order to develop better
anticancer therapies. In this review, we discuss the biological consequences of reciprocal interactions between TAMs, cancer
cells, endothelial cells, fibroblasts and other leukocyte subfractions within tumors. It was recently elucidated that tumors
specifically educate macrophages to secrete growth arrest-specific gene 6 (Gas6), the common ligand of the Tyro3, Axl, Mer
receptor (TAMR) family. In turn, Gas6 fosters tumor growth by promoting cancer cell proliferation. Therefore, the Gas6–TAMR
axis might represent a novel target for disrupting tumor–macrophage crosstalk. We summarize here what is known about TAMR
and their ligands in (human) cancer biology. In order to shed more light on the role of macrophages in human cancer, we additionally
provide an overview of what is currently known about the prognostic impact of TAMs in human cancer. 相似文献
257.
Parameshwaran K Buabeid MA Karuppagounder SS Uthayathas S Thiruchelvam K Shonesy B Dityatev A Escobar MC Dhanasekaran M Suppiramaniam V 《Cellular and molecular life sciences : CMLS》2012,69(5):829-841
In the developing brain, nicotinic acetylcholine receptors (nAChRs) are involved in cell survival, targeting, formation of
neural and sensory circuits, and development and maturation of other neurotransmitter systems. This regulatory role is disrupted
when the developing brain is exposed to nicotine, which occurs with tobacco use during pregnancy. Prenatal nicotine exposure
has been shown to be a strong risk factor for memory deficits and other behavioral aberrations in the offspring. The molecular
mechanisms underlying these neurobehavioral outcomes are not clearly elucidated. We used a rodent model to assess behavioral,
neurophysiological, and neurochemical consequences of prenatal nicotine exposure in rat offspring with specific emphasis on
the hippocampal glutamatergic system. Pregnant dams were infused with nicotine (6 mg/kg/day) subcutaneously from the third
day of pregnancy until birth. Results indicate that prenatal nicotine exposure leads to increased anxiety and depressive-like
effects and impaired spatial memory. Synaptic plasticity in the form of long-term potentiation (LTP), basal synaptic transmission,
and AMPA receptor-mediated synaptic currents were reduced. The deficit in synaptic plasticity was paralleled by declines in
protein levels of vesicular glutamate transporter 1 (VGLUT1), synaptophysin, AMPA receptor subunit GluR1, phospho(Ser845)
GluR1, and postsynaptic density 95 (PSD-95). These results suggest that prenatal nicotine exposure by maternal smoking could
result in alterations in the glutamatergic system in the hippocampus contributing to the abnormal neurobehavioral outcomes. 相似文献
258.
Challen GA Sun D Jeong M Luo M Jelinek J Berg JS Bock C Vasanthakumar A Gu H Xi Y Liang S Lu Y Darlington GJ Meissner A Issa JP Godley LA Li W Goodell MA 《Nature genetics》2012,44(1):23-31
Loss of the de novo DNA methyltransferases Dnmt3a and Dnmt3b in embryonic stem cells obstructs differentiation; however, the role of these enzymes in somatic stem cells is largely unknown. Using conditional ablation, we show that Dnmt3a loss progressively impairs hematopoietic stem cell (HSC) differentiation over serial transplantation, while simultaneously expanding HSC numbers in the bone marrow. Dnmt3a-null HSCs show both increased and decreased methylation at distinct loci, including substantial CpG island hypermethylation. Dnmt3a-null HSCs upregulate HSC multipotency genes and downregulate differentiation factors, and their progeny exhibit global hypomethylation and incomplete repression of HSC-specific genes. These data establish Dnmt3a as a critical participant in the epigenetic silencing of HSC regulatory genes, thereby enabling efficient differentiation. 相似文献
259.
Fairfax BP Makino S Radhakrishnan J Plant K Leslie S Dilthey A Ellis P Langford C Vannberg FO Knight JC 《Nature genetics》2012,44(5):502-510
Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10(-15)), PRIC285 (P = 3.0 × 10(-10)) and an upstream region of CDKN1A (P = 2 × 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility. 相似文献
260.
TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome 总被引:1,自引:0,他引:1
C Boileau DC Guo N Hanna ES Regalado D Detaint L Gong M Varret SK Prakash AH Li H d'Indy AC Braverman B Grandchamp CS Kwartler L Gouya RL Santos-Cortez M Abifadel SM Leal C Muti J Shendure MS Gross MJ Rieder A Vahanian DA Nickerson JB Michel;National Heart Lung Blood Institute 《Nature genetics》2012,44(8):916-921
A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta. 相似文献