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Carla Carluccio Francesco Salvatore Arianna Fornili 《Journal of biomolecular structure & dynamics》2016,34(3):497-507
The enzyme phenylalanine hydroxylase (PAH) is defective in the inherited disorder phenylketonuria. PAH, a tetrameric enzyme, is highly regulated and displays positive cooperativity for its substrate, Phe. Whether Phe binds to an allosteric site is a matter of debate, despite several studies worldwide. To address this issue, we generated a dimeric model for Phe–PAH interactions, by performing molecular docking combined with molecular dynamics simulations on human and rat wild-type sequences and also on a human G46S mutant. Our results suggest that the allosteric Phe-binding site lies at the dimeric interface between the regulatory and the catalytic domains of two adjacent subunits. The structural and dynamical features of the site were characterized in depth and described. Interestingly, our findings provide evidence for lower allosteric Phe-binding ability of the G46S mutant than the human wild-type enzyme. This also explains the disease-causing nature of this mutant. 相似文献
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Tobacco smoking is associated with numerous pathological conditions. Compelling experimental evidence associates smoking to the degeneration of the intervertebral disc (IVD). In particular, it has been shown that nicotine down-regulates both the proliferation rate and glycosaminoglycan (GAG) biosynthesis of disc cells. Moreover, tobacco smoking causes the constriction of the vascular network surrounding the IVD, thus reducing the exchange of nutrients and anabolic agents from the blood vessels to the disc. It has been hypothesized that both nicotine presence in the IVD and the reduced solute exchange are responsible for the degeneration of the disc due to tobacco smoking, but their effects on tissue homeostasis have never been quantified. In this study, a previously presented computational model describing the homeostasis of the IVD was deployed to investigate the effects of impaired solute supply and nicotine-mediated down-regulation of cell proliferation and biosynthetic activity on the health of the disc. We found that the nicotine-mediated down-regulation of cell anabolism mostly affected the GAG concentration at the cartilage endplate, reducing it up to 65% of the value attained in normal physiological conditions. In contrast, the reduction of solutes exchange between blood vessels and disc tissue mostly affected the nucleus pulposus, whose cell density and GAG levels were reduced up to 50% of their normal physiological levels. The effectiveness of quitting smoking on the regeneration of a degenerated IVD was also investigated, and showed to have limited benefit on the health of the disc. A cell-based therapy in conjunction with smoke cessation provided significant improvements in disc health, suggesting that, besides quitting smoking, additional treatments should be implemented in the attempt to recover the health of an IVD degenerated by tobacco smoking. 相似文献
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Mario Stampanoni Bassi Tommaso Nuzzo Luana Gilio Mattia Miroballo Alessia Casamassa Fabio Buttari Paolo Bellantonio Roberta Fantozzi Giovanni Galifi Roberto Furlan Annamaria Finardi Arianna De Rosa Anna Di Maio Francesco Errico Diego Centonze Alessandro Usiello 《Journal of neurochemistry》2021,159(5):857-866
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Francesca Pecori‐Giraldi Giuseppina Manzoni Jorgo Michailidis Massimo Scacchi Marco Stramba‐Badiale Francesco Cavagnini 《Obesity (Silver Spring, Md.)》2011,19(10):2015-2018
Obese subjects show several electrocardiographic alterations, including prolonged QT interval, a marker for fatal cardiac arrhythmias. Prolonged QT interval has recently been linked to low testosterone levels, a frequent occurrence in male obese patients but no study has yet assessed whether hypoandrogenism contributes to QT interval prolongation in this population. Aim of this study was to evaluate whether prolonged QT interval is linked to hypogonadism in male obese subjects. QT interval corrected for heart rate (QTc) was measured from standard electrocardiogram recordings in 136 obese men (BMI 30 >kg/m2, range 30.1–75.4 kg/m2). Obese men were classified as eugonadal or hypogonadal according to serum total testosterone levels (i.e., greater or less than 9.9 nmol/l). Our study showed that QTc measurements corrected by either Bazett (419 ± 3.2 vs. 408 ± 3.4 ms, P < 0.05), Fridericia (406.3 ± 3.39 vs. 396.4 ± 3.03 ms, P < 0.05) or Hodges (407.0 ± 3.12 vs. 397.3 ± 2.84 ms, P < 0.05) were longer in hypogonadal compared with eugonadal obese men; further, prolonged QTc interval (i.e., >440 ms) was more frequent among hypogonadal compared with eugonadal obese men (23% vs. 10%, P < 0.05). The degree of weight excess, diabetes, sleep apnoea and potassium levels were not associated with prolonged QTc. In conclusion, obese hypogonadal men show a greater prevalence of prolonged QT interval compared with their eugonadal counterparts. It appears therefore that low levels of testosterone in obese men may contribute to the arrhythmogenic profile of these patients, a heretofore unknown link which warrants further clinical attention. 相似文献
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Dario Cova Leonardo DE Angelis Elena Monti Francesco Piccinini 《Free radical research》1992,15(6):353-360
Previous investigations, performed on isolated rat atria, showed that the lipophylic spin-trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) is able to prevent the acute cardiotoxic effects produced by doxorubicin (DXR), whereas the hydrophylic compound 5,5-dimethyl-pyrroline-N-oxide (DMPO) is inactive. The present study was designed to ascertain whether differences in the pharmacological effects of the two spin traps are related to their different subcellular distribution. Langendorff rat hearts were perfused for 60 minutes with [I4C]-DXR and either PBN or DMPO. The subcellular mapping of the three compounds was performed by measuring DXR by liquid scintillation counting, PBN by GC/MS, and DMPO by HPLC in the following isolated fractions: nuclei, mitochondria, sarcoplasmic reticulum, sarcolemma, cytosol. DMPO was shown to accumulate in the cytosolic compartment; both PBM and DXR are taken up by nuclei and mitochondria, while only trace amounts of DXR were detected in the sarcoplasmic reticulum. These results suggest that mitochondrial (and not sarcoplasmic) enzymes are mainly involved in DXR-induced free radical production, which is thought to cause the acute cardiotoxic effects of DXR. An involvement of DXR-induced free radical generation in the nuclear compartment seems unlikely in the short-term “in vitro” effects observed with the experimental model adopted for these studies, although it may play a role in the delayed pathology. 相似文献
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Translational research using evidence-based and comparative effectiveness research continues to evolve, becoming a useful tool in improving informed
consent and decision-making in the clinical setting. While in development, emerging technologies, including cellular and molecular biology, are leading to
establishing evidence-based dental practices. One emerging technology, which conjoins bench proteomic findings to clinical decision-making for
treatment intervention, is the Translational Evidence Mechanism. This mechanism was developed to be a foundation for a compact between researcher,
translational researcher, clinician, and patient. The output of such a mechanism is the clinical practice guideline (CPG), an interactive tool for dentists and
patients to game evidence in reaching optimum clinical decisions that correspond to individual patient preferences and values. As such, the clinical
practice guideline requires the vesting of decision, utility, and cost best evidence. Evidence-based research provides decision data, a first attempt at
supporting decision-making by providing best outcome data. Since then comparative effectiveness research has emerged, using systematic review analysis
to compare similar treatments or procedures in maximizing the choice of the most effective cost/benefit option within the context of best evidence. With
innovation in the clinical practice guideline for optimizing efficacy and comparative effectiveness research, evidence-based practices will shape a new
approach to health-based systems that adhere to shared decision-making between bench scientists, healthcare providers and patients. 相似文献
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