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51.
A. Tchirkov Jacques-Olivier Bay David Pernin Yves-Jean Bignon Pascale Rio Maria Grancho Fabrice Kwiatkowski Michel Giollant Paul Malet Pierre Verrelle 《Human genetics》1997,101(3):312-316
In ataxia-telangiectasia (A-T) patients, mutations in a single gene, ATM, result in an autosomal recessive syndrome that embraces a variety of clinical features and manifests extreme radiosensitivity
and a strong predisposition to malignancy. Heterozygotes for the ATM gene have no clinical expression of A-T but may be cancer prone with a moderate increase in in vitro radiosensitivity. We
performed a blind chromosomal analysis on G2-phase lymphocytes from 7 unrelated A-T patients, 13 obligate A-T heterozygotes (parents of the patients), and 14 normal controls
following X-irradiation with 1 Gy in order to evaluate this cytogenetic method as a tool for detection of ATM carriers. Both A-T homozygotes and heterozygotes showed significantly increased levels of radiation-induced chromatid damage
relative to that of normal controls. These results show that the G2-phase chromosomal radiosensitivity assay can be used for the detection of A-T heterozygotes. In combination with molecular
genetic analyses, this test may be of value in studies of familial and sporadic cancers aimed at determination of the potential
involvement of ATM mutations in tumor risk or development.
Received: 5 May 1997 / Accepted: 26 August 1997 相似文献
52.
Akram Khan Mansour Qurashi Kim Kwiatkowski Don Cates Henrique Rigatto 《Journal of applied physiology》2005,98(4):1171-1176
We measured the PCO2 apneic threshold in preterm and term infants. We hypothesized that, compared with adult subjects, the PCO2 apneic threshold in neonates is very close to the eupneic PCO2, likely facilitating the appearance of periodic breathing and apnea. In contrast with adults, who need to be artificially hyperventilated to switch from regular to periodic breathing, neonates do this spontaneously. We therefore measured the apneic threshold as the average alveolar PCO2 (PaCO2) of the last three breaths of regular breathing preceding the first apnea of an epoch of periodic breathing. We also measured the PaCO2 of the first three breaths of regular breathing after the last apnea of the same periodic breathing epoch. In preterm infants, eupneic PaCO2 was 38.6 +/- 1.4 Torr, the preperiodic PaCO2 apneic threshold was 37.3 +/- 1.4 Torr, and the postperiodic PaCO2 was 37.2 +/- 1.4 Torr. In term infants, the eupneic PaCO2 was 39.7 +/- 1.1 Torr, the preperiodic PaCO2 apneic threshold was 38.7 +/- 1.0 Torr, and the postperiodic value was 37.9 +/- 1.2 Torr. This means that the PaCO2 apneic thresholds were 1.3 +/- 0.1 and 1.0 +/- 0.2 Torr below eupneic PaCO2 in preterm and term infants, respectively. The transition from eupneic PaCO2 to PaCO2 apneic threshold preceding periodic breathing was accompanied by a minor and nonsignificant increase in ventilation, primarily related to a slight increase in frequency. The findings suggest that neonates breathe very close to their PCO2 apneic threshold, the overall average eupneic PCO2 being only 1.15 +/- 0.2 Torr (0.95-1.79, 95% confidence interval) above the apneic threshold. This value is much lower than that reported for adult subjects (3.5 +/- 0.4 Torr). We speculate that this closeness of eupneic and apneic PCO2 thresholds confers great vulnerability to the respiratory control system in neonates, because minor oscillations in breathing may bring eupneic PCO2 below threshold, causing apnea. 相似文献
53.
Traykova-Brauch M Schönig K Greiner O Miloud T Jauch A Bode M Felsher DW Glick AB Kwiatkowski DJ Bujard H Horst J von Knebel Doeberitz M Niggli FK Kriz W Gröne HJ Koesters R 《Nature medicine》2008,14(9):979-984
We describe a transgenic mouse line, Pax8-rtTA, which, under control of the mouse Pax8 promoter, directs high levels of expression of the reverse tetracycline-dependent transactivator (rtTA) to all proximal and distal tubules and the entire collecting duct system of both embryonic and adult kidneys. Using crosses of Pax8-rtTA mice with tetracycline-responsive c-MYC mice, we established a new, inducible model of polycystic kidney disease that can mimic adult onset and that shows progression to renal malignant disease. When targeting the expression of transforming growth factor beta-1 to the kidney, we avoided early lethality by discontinuous treatment and successfully established an inducible model of renal fibrosis. Finally, a conditional knockout of the gene encoding tuberous sclerosis complex-1 was achieved, which resulted in the early outgrowth of giant polycystic kidneys reminiscent of autosomal recessive polycystic kidney disease. These experiments establish Pax8-rtTA mice as a powerful tool for modeling renal diseases in transgenic mice. 相似文献
54.
Hong F Larrea MD Doughty C Kwiatkowski DJ Squillace R Slingerland JM 《Molecular cell》2008,30(6):701-711
The cell-cycle effects of mTORC1 are not fully understood. We provide evidence that mTOR-raptor phosphorylates SGK1 to modulate p27 function. Cellular mTOR activation, by refeeding of amino acid-deprived cells or by TSC2 shRNA, activated SGK1 and p27 phosphorylation at T157, and both were inhibited by short-term rapamycin treatment and by SGK1 shRNA. mTOR overexpression activated both Akt and SGK1, causing TGF-beta resistance through impaired nuclear import and cytoplasmic accumulation of p27. Rapamycin or raptor shRNA impaired mTOR-driven p70 and SGK1 activation, but not that of Akt, and decreased cytoplasmic p27. mTOR/raptor/SGK1 complexes were detected in cells. mTOR phosphorylated SGK1, but not SGK1-S422A, in vitro. SGK1 phosphorylated p27 in vitro. These data implicate SGK1 as an mTORC1 (mTOR-raptor) substrate. mTOR may promote G1 progression in part through SGK1 activation and deregulate the cell cycle in cancers through both Akt- and SGK-mediated p27 T157 phosphorylation and cytoplasmic p27 mislocalization. 相似文献
55.
Innokentiy Maslennikov Martin Krupa Christopher Dickson Luis Esquivies Katherine Blain Georgia Kefala Senyon Choe Witek Kwiatkowski 《Journal of structural and functional genomics》2009,10(1):25-35
Abstract Bottlenecks in expression, solubilization, purification and crystallization hamper the structural study of integral membrane
proteins (IMPs). Successful crystallization is critically dependent on the purity, stability and oligomeric homogeneity of
an IMP sample. These characteristics are in turn strongly influenced by the type and concentration of the detergents used
in IMP preparation. By utilizing the techniques and analytical tools we earlier developed for the characterization of protein-detergent
complexes (PDCs) [21], we demonstrate that for successful protein extraction from E. coli membrane fractions, the solubilizing detergent associates preferentially to IMPs rather than to membrane lipids. Notably,
this result is contrary to the generally accepted mechanism of detergent-mediated IMP solubilization. We find that for one
particular member of the family of proteins studied (E. coli receptor kinases, which is purified in mixed multimeric states and oligomerizes through its transmembrane region), the protein
oligomeric composition is largely unaffected by a 10-fold increase in protein concentration, by alteration of micelle properties
through addition of other detergents to the PDC sample, or by a 20-fold variation in the detergent concentration used for
solubilization of the IMP from the membrane. We observed that the conditions used for expression of the IMP, which impact
protein density in the membrane, has the greatest influence on the IMP oligomeric structure. Finally, we argue that for concentrating
PDCs smaller than 30 kDa, stirred concentration cells are less prone to over-concentration of detergent and are therefore
more effective than centrifugal ultrafiltration devices. 相似文献
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59.
Site-directed mutations of human hemoglobin at residue 35beta: a residue at the intersection of the alpha1beta1, alpha1beta2, and alpha1alpha2 interfaces 下载免费PDF全文
Kavanaugh JS Weydert JA Rogers PH Arnone A Hui HL Wierzba AM Kwiatkowski LD Paily P Noble RW Bruno S Mozzarelli A 《Protein science : a publication of the Protein Society》2001,10(9):1847-1855
Because Tyr35beta is located at the convergence of the alpha1beta1, alpha1beta2, and alpha1alpha2 interfaces in deoxyhemoglobin, it can be argued that mutations at this position may result in large changes in the functional properties of hemoglobin. However, only small mutation-induced changes in functional and structural properties are found for the recombinant hemoglobins betaY35F and betaY35A. Oxygen equilibrium-binding studies in solution, which measure the overall oxygen affinity (the p50) and the overall cooperativity (the Hill coefficient) of a hemoglobin solution, show that removing the phenolic hydroxyl group of Tyr35beta results in small decreases in oxygen affinity and cooperativity. In contrast, removing the entire phenolic ring results in a fourfold increase in oxygen affinity and no significant change in cooperativity. The kinetics of carbon monoxide (CO) combination in solution and the oxygen-binding properties of these variants in deoxy crystals, which measure the oxygen affinity and cooperativity of just the T quaternary structure, show that the ligand affinity of the T quaternary structure decreases in betaY35F and increases in betaY35A. The kinetics of CO rebinding following flash photolysis, which provides a measure of the dissociation of the liganded hemoglobin tetramer, indicates that the stability of the liganded hemoglobin tetramer is not altered in betaY35F or betaY35A. X-ray crystal structures of deoxy betaY35F and betaY35A are highly isomorphous with the structure of wild-type deoxyhemoglobin. The betaY35F mutation repositions the carboxyl group of Asp126alpha1 so that it may form a more favorable interaction with the guanidinium group of Arg141alpha2. The betaY35A mutation results in increased mobility of the Arg141alpha side chain, implying that the interactions between Asp126alpha1 and Arg141alpha2 are weakened. Therefore, the changes in the functional properties of these 35beta mutants appear to correlate with subtle structural differences at the C terminus of the alpha-subunit. 相似文献
60.
Olivo Miotto Makoto Sekihara Shin-Ichiro Tachibana Masato Yamauchi Richard D. Pearson Roberto Amato Sonia Gonalves Somya Mehra Rintis Noviyanti Jutta Marfurt Sarah Auburn Ric N. Price Ivo Mueller Mie Ikeda Toshiyuki Mori Makoto Hirai Livingstone Tavul Manuel W. Hetzel Moses Laman Alyssa E. Barry Pascal Ringwald Jun Ohashi Francis Hombhanje Dominic P. Kwiatkowski Toshihiro Mita 《PLoS pathogens》2020,16(12)
The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants’ genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites’ drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance. 相似文献