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131.
132.
The presence of a novel receptor for the neurotransmitter gamma-aminobutyric acid (GABA) on peripheral autonomic nerve terminals and in mammalian brain slices has been described recently. This receptor differs from the classical GABA site as it is unaffected by recognized GABA antagonists such as bicuculline and is not sensitive to the majority of accepted GABA-mimetics such as 3-aminopropanesulphonic acid (3-APS) or isoguvacine. We propose to designate the classical site as the GABA A and the novel site as the GABA B receptor. The beta-p-chlorophenyl derivative of GABA, baclofen, is stereospecifically active at the GABA B site whereas it is devoid of activity at the classical GABA A3 site. We now report that high-affinity saturable binding of 3H-baclofen and 3H-GABA to the GABA B site can be detected in fragments of crude synaptic membranes prepared from rat brain. The results support the concept of a novel GABA receptor within the mammalian brain and show that GABA and baclofen can compete for the same recognition site. 相似文献
133.
LSD as an agonist and antagonist at central dopamine receptors 总被引:1,自引:0,他引:1
134.
Zusammenfassung Plötzliche Dehnungen oder Entspannungen während des Eigenrhythmus der Herzkammer vonBusycon canaliculatum wurden dazu benützt, um den Verlauf des Aktivitätszustandes zu untersuchen. Sowohl Anstieg, wie auch Abfall des «active state» waren entsprechend langsam wie bei Wirbeltier-Herzmuskeln. Das tetanisierbare Schneckenherz stellt somit ein gutes Versuchsobjekt für die Aktivierung des Herzmuskels dar, da die maximale Kraft unabhängig von der Zeit ist.
Research supported by National Science Foundation grant No. GB-1001. 相似文献
Research supported by National Science Foundation grant No. GB-1001. 相似文献
135.
The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression 总被引:8,自引:0,他引:8
Kim JC Badano JL Sibold S Esmail MA Hill J Hoskins BE Leitch CC Venner K Ansley SJ Ross AJ Leroux MR Katsanis N Beales PL 《Nature genetics》2004,36(5):462-470
BBS4 is one of several proteins that cause Bardet-Biedl syndrome (BBS), a multisystemic disorder of genetic and clinical complexity. Here we show that BBS4 localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery to recruit PCM1 (pericentriolar material 1 protein) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division and apoptotic cell death. Expression of two truncated forms of BBS4 that are similar to those found in some individuals with BBS had a similar effect on PCM1 and microtubules. Our findings indicate that defective targeting or anchoring of pericentriolar proteins and microtubule disorganization contribute to the BBS phenotype and provide new insights into possible causes of familial obesity, diabetes and retinal degeneration. 相似文献
136.
Sheen VL Ganesh VS Topcu M Sebire G Bodell A Hill RS Grant PE Shugart YY Imitola J Khoury SJ Guerrini R Walsh CA 《Nature genetics》2004,36(1):69-76
Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development. 相似文献
137.
Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2 总被引:12,自引:0,他引:12
Coste SC Kesterson RA Heldwein KA Stevens SL Heard AD Hollis JH Murray SE Hill JK Pantely GA Hohimer AR Hatton DC Phillips TJ Finn DA Low MJ Rittenberg MB Stenzel P Stenzel-Poore MP 《Nature genetics》2000,24(4):403-409
The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2. 相似文献
138.
Malaria susceptibility and CD36 mutation 总被引:1,自引:0,他引:1
Aitman TJ Cooper LD Norsworthy PJ Wahid FN Gray JK Curtis BR McKeigue PM Kwiatkowski D Greenwood BM Snow RW Hill AV Scott J 《Nature》2000,405(6790):1015-1016
139.
Xia B Dorsman JC Ameziane N de Vries Y Rooimans MA Sheng Q Pals G Errami A Gluckman E Llera J Wang W Livingston DM Joenje H de Winter JP 《Nature genetics》2007,39(2):159-161
The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2-interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2-deficient cells showed hypersensitivity to cross-linking agents and lacked chromatin-bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion. 相似文献
140.
Caffau E Bonifacio P François P Sbordone L Monaco L Spite M Spite F Ludwig HG Cayrel R Zaggia S Hammer F Randich S Molaro P Hill V 《Nature》2011,477(7362):67-69
The early Universe had a chemical composition consisting of hydrogen, helium and traces of lithium; almost all other elements were subsequently created in stars and supernovae. The mass fraction of elements more massive than helium, Z, is known as 'metallicity'. A number of very metal-poor stars has been found, some of which have a low iron abundance but are rich in carbon, nitrogen and oxygen. For theoretical reasons and because of an observed absence of stars with Z?1.5?×?10(-5), it has been suggested that low-mass stars cannot form from the primitive interstellar medium until it has been enriched above a critical value of Z, estimated to lie in the range 1.5?×?10(-8) to 1.5?×?10(-6) (ref. 8), although competing theories claiming the contrary do exist. (We use 'low-mass' here to mean a stellar mass of less than 0.8 solar masses, the stars that survive to the present day.) Here we report the chemical composition of a star in the Galactic halo with a very low Z (≤?6.9?×?10(-7), which is 4.5?×?10(-5) times that of the Sun) and a chemical pattern typical of classical extremely metal-poor stars--that is, without enrichment of carbon, nitrogen and oxygen. This shows that low-mass stars can be formed at very low metallicity, that is, below the critical value of Z. Lithium is not detected, suggesting a low-metallicity extension of the previously observed trend in lithium depletion. Such lithium depletion implies that the stellar material must have experienced temperatures above two million kelvin in its history, given that this is necessary to destroy lithium. 相似文献