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1.
Dasgupta (2015) has recently put forward a novel argument, which he calls the ‘curvature argument’, that aims to show that Galilean spacetime is not an ideal setting for our classical theory of motion. This paper examines the curvature argument and argues that it is not sound. The discussion yields a remark about the conditions under which a ‘symmetry argument’ demonstrates that a particular spacetime is a non-ideal setting for our theory of motion. 相似文献
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William Boos 《Archive for History of Exact Sciences》1985,34(1-2):141-192
In this essay, I examine the metaphysical and metalogical ramifications of Gottlob Frege's controversy with David Hilbert and Alwin Korselt, over Hilbert's
Grundlagen der Geometrie. These ramifications include(1) Korselt's original appeals to general metatheoretic Deutungen (interpretations);(2) Hilbert's puzzling belief that whatever is consistent in some sense exists; and(3) Frege's semantic monist conviction that theoretical sense and reference (mathematical and other) must be eindeutig lösbar (uniquely solvable).My principal conclusions are(4) that Frege's position in (3) represented a pervasively dogmatic presumption that his newly discovered quantification theory must have a propositional metatheory (the True; the False); and(5) that this needless assumption adversely affected not only his polemic against the moderate semantic relativism of Hilbert and Korselt, but also his reception of type-theoretic ideas, and greatly facilitated his vulnerability to the sort of self-referential inconsistency Russell discovered in Grundgesetz V.These conclusions also seem to me to provide a conceptual framework for several of Frege's other arguments and reactions which might seem more particular and disparate. These include(6) his arbitrary restrictions on the range of second-order quantification, which undercut his own tentative attempts to give accounts of independence and semantic consequence;(7) his uncharacteristic hesitation, even dismay, at the prospect that such accounts might eventuate in a genuinely quantificational metamathematics, whose Gegenstände (objects) might themselves be Gedanken (thoughts); and, perhaps most revealingly(8) his otherwise quite enigmatic, quasi-stoic doctrine that genuine formal deduction must be from premises that are true.A deep reluctance to pluralize or iterate the transition from theory to meta-theory would also be consonant, of course, with Frege's vigorous insistence that there can be only one level each of linguistic Begriffe (concepts) and Gegenstände (objects). With hindsight, such an assumption may seem more gratuitous in the philosophy of language (where it contributed, I would argue, to Wittgenstein's famous transition to the mystical in 6.45 and 6.522 of the Tractatus); but its more implausible implications in this wider context seemed to emerge more slowly.In the mathematical test-case discussed here, however, such strains were immediately and painfully apparent; the first models of hyperbolic geometry were described some thirty years before Frege drafted his polemic against Hilbert's pioneering exposition. It is my hope that a careful study of Frege's lines of argument in this relatively straightforward mathematical controversy may suggest other, parallel approaches to the richer and more ambiguous problems of his philosophy of language.Niemand kann zwei Herren dienen. Man kann nicht der Wahrheit dienen und der Unwahrheit. Wenn die euklidische Geometrie wahr ist, so ist die nichteuklidische Geometrie falsch, und wenn die nichteuklidische wahr ist, so ist die euklidische Geometrie falsch.No one can serve two masters. One cannot serve truth and untruth. If Euclidean geometry is true, non-Euclidean geometry is false, and if non-Euclidean [geometry] is true, Euclidean geometry is false. Über Euklidische Geometrie [Frege 1969], p. 183. 相似文献
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PTC124 targets genetic disorders caused by nonsense mutations 总被引:1,自引:0,他引:1
Welch EM Barton ER Zhuo J Tomizawa Y Friesen WJ Trifillis P Paushkin S Patel M Trotta CR Hwang S Wilde RG Karp G Takasugi J Chen G Jones S Ren H Moon YC Corson D Turpoff AA Campbell JA Conn MM Khan A Almstead NG Hedrick J Mollin A Risher N Weetall M Yeh S Branstrom AA Colacino JM Babiak J Ju WD Hirawat S Northcutt VJ Miller LL Spatrick P He F Kawana M Feng H Jacobson A Peltz SW Sweeney HL 《Nature》2007,447(7140):87-91
Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options. 相似文献
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Koebel CM Vermi W Swann JB Zerafa N Rodig SJ Old LJ Smyth MJ Schreiber RD 《Nature》2007,450(7171):903-907
The capacity of immunity to control and shape cancer, that is, cancer immunoediting, is the result of three processes that function either independently or in sequence: elimination (cancer immunosurveillance, in which immunity functions as an extrinsic tumour suppressor in naive hosts); equilibrium (expansion of transformed cells is held in check by immunity); and escape (tumour cell variants with dampened immunogenicity or the capacity to attenuate immune responses grow into clinically apparent cancers). Extensive experimental support now exists for the elimination and escape processes because immunodeficient mice develop more carcinogen-induced and spontaneous cancers than wild-type mice, and tumour cells from immunodeficient mice are more immunogenic than those from immunocompetent mice. In contrast, the equilibrium process was inferred largely from clinical observations, including reports of transplantation of undetected (occult) cancer from organ donor into immunosuppressed recipients. Herein we use a mouse model of primary chemical carcinogenesis and demonstrate that equilibrium occurs, is mechanistically distinguishable from elimination and escape, and that neoplastic cells in equilibrium are transformed but proliferate poorly in vivo. We also show that tumour cells in equilibrium are unedited but become edited when they spontaneously escape immune control and grow into clinically apparent tumours. These results reveal that, in addition to destroying tumour cells and sculpting tumour immunogenicity, the immune system of a naive mouse can also restrain cancer growth for extended time periods. 相似文献
9.
Mullighan CG Goorha S Radtke I Miller CB Coustan-Smith E Dalton JD Girtman K Mathew S Ma J Pounds SB Su X Pui CH Relling MV Evans WE Shurtleff SA Downing JR 《Nature》2007,446(7137):758-764
Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer. 相似文献
10.
Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia. Here we show that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment that cause hypokalaemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle Na(V)1.4 channel. This 'gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na+, K+ and Cs+, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations Ba2+, Ca2+ and Zn2+ are not detectably permeant and block the gating pore at millimolar concentrations. Our results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalaemic periodic paralysis. This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis and cytopathology that are characteristic of hypokalaemic periodic paralysis. A survey of other ion channelopathies reveals numerous examples of mutations that would be expected to cause gating pore current, raising the possibility of a broader impact of gating pore current in ion channelopathies. 相似文献