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141.
LepA is a translational GTPase highly conserved in bacterial lineages. While it has been shown that LepA can catalyze reverse ribosomal translocation in vitro, the role of LepA in the cell remains unclear. Here, we show that deletion of the lepA gene (ΔlepA) in Escherichia coli causes hypersensitivity to potassium tellurite and penicillin G, but has no appreciable effect on growth under many other conditions. ΔlepA does not increase miscoding or frameshifting errors under normal or stress conditions, indicating that LepA does not contribute to the fidelity of translation. Overexpression of LepA interferes with tmRNA-mediated peptide tagging and A-site mRNA cleavage, suggesting that LepA is a bona fide translation factor that can act on stalled ribosomes with a vacant A site in vivo. Together these results lead us to hypothesize that LepA is involved in co-translational folding of proteins that are otherwise vulnerable to tellurite oxidation. 相似文献
142.
Myxococcus xanthus is a Gram‐negative bacterium capable of complex developmental processes involving vegetative swarming and fruiting body formation. Social (S‐) gliding motility, one of the two motility systems used by M. xanthus, requires at least two cell surface structures: type IV pili (TFP) and extracellular polysaccharides (EPS). Extended TFP that are composed of thousands of copies of PilA retract upon binding to EPS and thereby pull the cell forward. TFP also act as external sensor to regulate EPS production. In this study, we generated a random PilA mutant library and identified one derivative, SW1066, which completely failed to undergo developmental processes. Detailed characterization revealed that SW1066 produced very little EPS but wild‐type amounts of PilA. These mutated PilA subunits, however, are unable to assemble into functional TFP despite their ability to localize to the membrane. By preventing the mutated PilA of SW1066 to translocate from the cytoplasm to the membrane, fruiting body formation and EPS production were restored to the levels observed in mutant strains lacking PilA. This apparent connection between PilA membrane accumulation and reduction in surface EPS implies that specific cellular PilA localization are required to maintain the EPS level necessary to sustain normal S‐motility in M. xanthus. 相似文献
143.
Melandri Vlok Marc Fredrick Oxenham Kate Domett Hiep Hoang Trinh Tran Thi Minh Nguyen Thi Mai Huong Hirofumi Matsumura Nghia Truong Huu Lan Cuong Nguyen Anna Willis Hallie Buckley 《American journal of physical anthropology》2023,180(4):715-732
Objective
Scurvy in non-adults was assessed at the Pre-Neolithic site of Con Co Ngua and the Neolithic site of Man Bac in northern Vietnam to investigate nutritional stress during the agricultural transition in Mainland Southeast Asia (MSEA).Materials
One hundred and four human skeletons under the age of 20 years old were assessed.Methods
Lesions were recorded macroscopically and radiographically. Differential diagnosis using prior established paleopathological diagnostic criteria for scurvy was conducted.Results
There was no clear evidence for scurvy at Con Co Ngua and a high burden of scurvy was present at Man Bac (>79% diagnosed with probable scurvy). Scurvy levels were high across all non-adult ages at Man Bac indicating significant burden throughout childhood and adolescence.Conclusions
No scurvy at Con Co Ngua is consistent with widely available food sources at the peak of the Holocene thermal maximum. High levels of scurvy at Man Bac corresponds with decreased dietary diversity, high pathogen load, and increased population stress with the transition to agriculture around the time of the 4.2 ka desertification event.Significance
This is the first systematic population-level non-adult investigation of specific nutritional disease in MSEA and demonstrates an increase in nutritional stress during the Neolithic transition in northern Vietnam.Limitations
Subperiosteal new bone deposits can be due to normal growth in infants and young children, therefore, identification of scurvy in children under the age of 4 years needs to be considered critically.Suggestions for Further Research
Further work in diagnosing specific nutritional disease in other non-adult cohorts throughout MSEA is required. 相似文献144.
Ami A Shah Elena Schiopu Laura K Hummers Michael Wade Kristine Phillips Cynthia Anderson Robert Wise Francesco Boin James R Seibold Fredrick Wigley Kristan D Rollins 《Arthritis research & therapy》2013,15(2)
Introduction
Treprostinil diethanolamine is an innovative salt form of the prostacyclin analogue, treprostinil sodium, developed as an oral sustained release (SR) osmotic tablet. The availability of a formulation permitting convenient systemic delivery might have applicability to scleroderma vascular complications. We evaluated pharmacokinetics and perfusion in scleroderma patients with digital ischemia following escalating twice-daily doses of treprostinil diethanolamine SR.Methods
Scleroderma patients with digital ulcers were enrolled in this dual-center, open-label, phase I pharmacokinetic study. Drug concentrations and perfusion, quantified by laser Doppler imaging, were measured over 12 hours at the 2 mg and 4 mg (or maximally tolerated) doses. Pharmacokinetic parameters were determined from individual plasma concentration versus time profiles using non-compartmental analysis methods. Digital perfusion and skin temperature were modeled as a function of log-transformed drug concentration and other covariates by performing repeated measures analyses using random effects models.Results
Nineteen scleroderma patients (84% female, 53% limited scleroderma) received treprostinil diethanolamine SR with dose titration up to 4 mg twice daily as tolerated. Peak concentrations (mean maximum plasma concentration (Cmax) = 1,176 and 2,107 pg/mL) occurred approximately 3.6 hours after dose administration, and overall exposure (under the plasma concentration-time curve from time 0 to 12 hours post dose (AUC0-12) = 7,187 and 12,992 hr*pg/mL) was linear between the 2 mg and 4 mg doses. Perfusion and digital skin temperature were positively associated with log-transformed plasma concentration at the 4 mg dose (P = 0.015 and P = 0.013, respectively). The most frequent adverse events were similar to those seen with prostacyclin analogues.Conclusions
Oral treprostinil diethanolamine was effectively absorbed in patients with scleroderma. Drug administration was temporally associated with improved cutaneous perfusion and temperature. Treprostinil diethanolamine may provide a new therapeutic option for Raynaud''s phenomenon and the peripheral vascular disease of scleroderma.Trial Registration
ClinicalTrials.gov . NCT00848939Electronic supplementary material
The online version of this article (doi:10.1186/ar4216) contains supplementary material, which is available to authorized users. 相似文献145.
Neil D. Fredrick John A. Berges Benjamin S. Twining Daliangelis Nu?ez-Milland Ferdi L. Hellweger 《Applied and environmental microbiology》2013,79(14):4359-4368
There can be significant intraspecific individual-level heterogeneity in the intracellular P of phytoplankton, which can affect the population-level growth rate. Several mechanisms can create this heterogeneity, including phenotypic variability in various physiological functions (e.g., nutrient uptake rate). Here, we use modeling to explore the contribution of various mechanisms to the heterogeneity in phytoplankton grown in a laboratory culture. An agent-based model simulates individual cells and their intracellular P. Heterogeneity is introduced by randomizing parameters (e.g., maximum uptake rate) of daughter cells at division. The model was calibrated to observations of the P quota of individual cells of the centric diatom Thalassiosira pseudonana, which were obtained using synchrotron X-ray fluorescence (SXRF). A number of simulations, with individual mechanisms of heterogeneity turned off, then were performed. Comparison of the coefficient of variation (CV) of these and the baseline simulation (i.e., all mechanisms turned on) provides an estimate of the relative contribution of these mechanisms. The results show that the mechanism with the largest contribution to variability is the parameter characterizing the maximum intracellular P, which, when removed, results in a CV of 0.21 compared to a CV of 0.37 with all mechanisms turned on. This suggests that nutrient/element storage capabilities/mechanisms are important determinants of intrapopulation heterogeneity. 相似文献
146.
Hong Yu Ren Diane E. Grove Oxana De La Rosa Scott A. Houck Pattarawut Sopha Fredrick Van Goor Beth J. Hoffman Douglas M. Cyr 《Molecular biology of the cell》2013,24(19):3016-3024
Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR. 相似文献
147.
Rahimzadeh J Meng F Sachs F Wang J Verma D Hua SZ 《American journal of physiology. Cell physiology》2011,301(3):C646-C652
The mechanical stress due to shear flow has profound effects on cell proliferation, transport, gene expression, and apoptosis. The mechanisms for flow sensing and transduction are unclear, but it is postulated that fluid flow pulls upon the apical surface, and the resulting stress is eventually transmitted through the cytoskeleton to adhesion plaques on the basal surface. Here we report a direct observation of this flow-induced stress in the cytoskeleton in living cells using a parallel plate microfluidic chip with a fluorescence resonance energy transfer (FRET)-based mechanical stress sensor in actinin. The sensing cassette was genetically inserted into the cytoskeletal host protein and transfected into Madin-Darby canine kidney cells. A shear stress of 10 dyn/cm(2) resulted in a rapid increase in the FRET ratio indicating a decrease in stress across actinin with flow. The effect was reversible, and cells were able to respond to repeated stimulation and showed adaptive changes in the cytoskeleton. Flow-induced Ca(2+) elevation did not affect the response, suggesting that flow-induced changes in actinin stress are insensitive to intracellular Ca(2+) level. The reduction in FRET ratio suggests actin filaments are under normal compression in the presence of flow shear stress due to changes in cell shape, and/or actinin is not in series with actin. Treatment with cytochalasin-D that disrupts F-actin reduced prestress and the response to flow. The FRET/flow method is capable of resolving changes of stress in multiple proteins with optical spatial resolution and time resolution >1 Hz. This promises to provide insight into the force distribution and transduction in all cells. 相似文献
148.
The effects of short-term resistance training on endocrine function in men and women 总被引:6,自引:0,他引:6
William J. Kraemer Robert S. Staron Fredrick C. Hagerman Robert S. Hikida Andrew C. Fry Scott E. Gordon Bradley C. Nindl Lincoln A. Gothshalk Jeff S. Volek James O. Marx Robert U. Newton Keijo H?kkinen 《European journal of applied physiology and occupational physiology》1998,78(1):69-76
This investigation examined hormonal adaptations to acute resistance exercise and determined whether training adaptations
are observed within an 8-week period in untrained men and women. The protocol consisted of a 1-week pre-conditioning orientation
phase followed by 8 weeks of heavy resistance training. Three lower-limb exercises for the quadriceps femoris muscle group
(squat, leg press, knee extension) were performed twice a week (Monday and Friday) with every other Wednesday used for maximal
dynamic 1 RM strength testing. Blood samples were obtained pre-exercise (Pre-Ex), immediately post-exercise (IP), and 5 min
post-exercise (5-P) during the first week of training (T-1), after 6 weeks (T-2) and 8 weeks (T-3) of training to determine
blood concentrations of whole-blood lactate (LAC), serum total testosterone (TT), sex-hormone binding globulin (SHBG), cortisol
(CORT) and growth hormone (GH). Serum TT concentrations were significantly (P ≤ 0.05) higher for men at all time points measured. Men did not demonstrate an increase due to exercise until T-2. An increase
in pre-exercise concentrations of TT were observed both for men and women at T-2 and T-3. No differences were observed for
CORT between men and women; increases in CORT above pre-exercise values were observed for men at all training phases and at
T-2 and T-3 for women. A reduction in CORT concentrations at rest was observed both in men and women at T-3. Women demonstrated
higher pre-exercise GH values than men at all training phases; no changes with training were observed for GH concentrations.
Exercise-induced increases in GH above pre-exercise values were observed at all phases of training. Women demonstrated higher
serum concentrations of SHBG at all time points. No exercise-induced increases were observed in men over the training period
but women increased SHBG with exercise at T-3. SHBG concentrations in women were also significantly higher at T-2 and T-3
when compared to T-1 values. Increases in LAC concentrations due to exercise were observed both for men and women for all
training phases but no significant differences were observed with training. These data illustrate that untrained individuals
may exhibit early-phase endocrine adaptations during a resistance training program. These hormonal adaptations may influence
and help to mediate other adaptations in the nervous system and muscle fibers, which have been shown to be very responsive
in the early phase of strength adaptations with resistance training.
Accepted: 11 December 1997 相似文献
149.
Carole Lindblow-Kull Fredrick J. Kull Alex Shrift 《Biochemical and biophysical research communications》1980,93(2):572-576
Chemically synthesized selenobiotin is, like sulfur biotin, able to bind to avidin. This observation was used to help identify biologically synthesized selenobiotin as an excretion product of . The identification of [75Se]selenobiotin was based on the highly specific binding of biotin to avidin used as an affinity ligand to Sepharose, on its release from the complex by proteolytic treatment, and its chromatographic behavior relative to [14C]biotin standards. These results represent the first evidence of a biological synthesis of a heterocyclic ring that contains selenium in place of sulfur. 相似文献
150.