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Soft Systems Methodology (SSM) has been criticized for its interpretivistic stance by, among others, Critical systems thinkers. By locating problems inherent in the techniques of SSM, this paper proposes an expanded theoretical framework, concerning measure of performance in the conceptual models. The expansion is based on the theories behind Multi-Modal Methodology and has resulted in a new model of performance indicators for the design. 相似文献
23.
Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin 总被引:14,自引:0,他引:14
Otto EA Loeys B Khanna H Hellemans J Sudbrak R Fan S Muerb U O'Toole JF Helou J Attanasio M Utsch B Sayer JA Lillo C Jimeno D Coucke P De Paepe A Reinhardt R Klages S Tsuda M Kawakami I Kusakabe T Omran H Imm A Tippens M Raymond PA Hill J Beales P He S Kispert A Margolis B Williams DS Swaroop A Hildebrandt F 《Nature genetics》2005,37(3):282-288
Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN. 相似文献
24.
Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret 总被引:10,自引:0,他引:10
Batourina E Choi C Paragas N Bello N Hensle T Costantini FD Schuchardt A Bacallao RL Mendelsohn CL 《Nature genetics》2002,32(1):109-115
Almost 1% of human infants are born with urogenital abnormalities, many of which are linked to irregular connections between the distal ureters and the bladder. During development, ureters migrate by an unknown mechanism from their initial integration site in the Wolffian ducts up to the base of the bladder in a process that we call ureter maturation. Rara(-/-) Rarb2(-/-) mice display impaired vitamin A signaling and develop syndromic urogenital malformations similar to those that occur in humans, including renal hypoplasia, hydronephrosis and mega-ureter, abnormalities also seen in mice with mutations in the proto-oncogene Ret. Here we show that ureter maturation depends on formation of the 'trigonal wedge', a newly identified epithelial outgrowth from the base of the Wolffian ducts, and that the distal ureter abnormalities seen in Rara(-/-) Rarb2(-/-) and Ret(-/-) mutant mice are probably caused by a failure of this process. Our studies indicate that formation of the trigonal wedge may be essential for correct insertion of the distal ureters into the bladder, and that these events are mediated by the vitamin A and Ret signaling pathways. 相似文献
25.
Anita Fetzer 《Foundations of Science》2002,7(3):255-291
This contribution investigates the role ofcontext in natural-language communication bydifferentiating between linguistic andsociocultural contexts. It is firmly anchoredto a dialogue framework and based on arelational conception of context as astructured and interactionally organisedphenomenon. However, context is not onlyexamined from this bottom-up or microperspective, but also from a top-down or macroviewpoint as pre- and co-supposed socioculturalcontext. Here, context is not solely seen as aninteractionally organised phenomenon, butrather as a sociocultural apparatus whichstrongly influences the interpretation of microsituations.The section, micro building blocks andlocal meaning, argues for a sociopragmaticapproach to natural-language communication thusaccommodating both speech act theory andconversation analysis. It examines the questionof how linguistic and sociocultural contextsare accommodated by the micro building blocksof speech act and turn, and speaker and hearer.The results obtained are systematised in thesection, micro meets macro, and adaptedto the requirements of the dialogue act ofa plus/minus-validity claimbased on thecontextualisation of Jürgen Habermas'sconception of ratification of validityclaimadopted from this theory ofcommunicative action(1987). The definition ofa plus/minus-validity claim is furthersupplemented by the Gricean CooperativePrinciple, the ethnomethodological premise ofaccountability of social action, theconversation-analytic notion of sequentialorganisation and the interpersonal concepts offace and participation format. Validity claimsare discussed from both bottom-up and top-downperspectives stressing the dynamics of contextwith regard to both process and product, andselection and construction.In conclusion, the relational status of contextrequires an interactive frame of referenceaccounting for context, contextualisation,decontextualisation and recontextualisation. 相似文献
26.
When N-methylformamide is administered to rats on the 11th day of pregnancy approximately 50% of the fetuses are resorbed and a reduced weight of the developed animals is found in comparison to the controls on the 21th day (delivery by Caesarian section). The toxic effect is increased by using nicotinamide and methionine. If a combination of these substances is employed practically all fetuses are resorbed. Tryptophan, however, has a considerably protective influence. N-Methylformamide has no influence on the NAD-synthesis induced by nicotinamide or tryptophan. It does, however, inhibits the activity of the ADPR transferase. 相似文献
27.
Zusammenfassung In der Pylorusschleimhaut der Ratte wurde ein Gastrin ähnlicher Stoff nachgewiesen. 相似文献
28.
Anita Pruzan L. Ehrman Ira Perelle Joan Probber 《Cellular and molecular life sciences : CMLS》1979,35(8):1023-1025
Summary
Drosophila females modify their choice of mates after an initial mating experience. The altered choices correspond to selective pressures within strains (D. pseudoobscura), semispecies (D. paulistorum), and full species (D. melanogaster andD. simulans) and indicate a learned component in sexual selection. 相似文献
29.
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities 总被引:2,自引:0,他引:2
Boyden LM Choi M Choate KA Nelson-Williams CJ Farhi A Toka HR Tikhonova IR Bjornson R Mane SM Colussi G Lebel M Gordon RD Semmekrot BA Poujol A Välimäki MJ De Ferrari ME Sanjad SA Gutkin M Karet FE Tucci JR Stockigt JR Keppler-Noreuil KM Porter CC Anand SK Whiteford ML Davis ID Dewar SB Bettinelli A Fadrowski JJ Belsha CW Hunley TE Nelson RD Trachtman H Cole TR Pinsk M Bockenhauer D Shenoy M Vaidyanathan P Foreman JW Rasoulpour M Thameem F Al-Shahrouri HZ Radhakrishnan J Gharavi AG Goilav B 《Nature》2012,482(7383):98-102
Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis. 相似文献
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