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PURPOSE OF REVIEW: To appraise a new approach to laparoscopic surgery for infertility caused by advanced endometriosis. RECENT FINDINGS: Endometriosis is a common systemic and local disease with altered peritoneal function, which requires both systemic and local treatment. Medication alone cannot improve infertility, and laparoscopic treatment, particularly in severe endometriosis, has a high recurrence rate and is often limited by technical difficulties. Novel treatment strategies have therefore to be sought, especially in women who do not want in-vitro fertilization as a first option, either because they suffer from pain in addition to infertility or want to enhance their fertility over many cycles. SUMMARY: Two-step operative laparoscopy with interval pituitary suppression by means of gonadotrophin-releasing hormone analogues reduces the extent of endometriosis, as classified by the American Fertility Association, and appears to be a promising method of achieving optimal cytoreduction and facilitating complicated surgery in severe endometriosis, while protecting the ovary from unnecessary trauma. A large-scale well-designed study is needed to confirm that this treatment leads to improved pregnancy rates. 相似文献
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Alessio Alfieri Juraj Koudelka Mosi Li Sanny Scheffer Jessica Duncombe Andrea Caporali Rajesh N Kalaria Colin Smith Ajay M Shah Karen Horsburgh 《Journal of cerebral blood flow and metabolism》2022,42(7):1176
Chronic microvascular inflammation and oxidative stress are inter-related mechanisms underpinning white matter disease and vascular cognitive impairment (VCI). A proposed mediator is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), a major source of reactive oxygen species (ROS) in the brain. To assess the role of Nox2 in VCI, we studied a tractable model with white matter pathology and cognitive impairment induced by bilateral carotid artery stenosis (BCAS). Mice with genetic deletion of Nox2 (Nox2 KO) were compared to wild-type (WT) following BCAS. Sustained BCAS over 12 weeks in WT mice induced Nox2 expression, indices of microvascular inflammation and oxidative damage, along with white matter pathology culminating in a marked cognitive impairment, which were all protected by Nox2 genetic deletion. Neurovascular coupling was impaired in WT mice post-BCAS and restored in Nox2 KO mice. Increased vascular expression of chemoattractant mediators, cell-adhesion molecules and endothelial activation factors in WT mice post-BCAS were ameliorated by Nox2 deficiency. The clinical relevance was confirmed by increased vascular Nox2 and indices of microvascular inflammation in human post-mortem subjects with cerebral vascular disease. Our results support Nox2 activity as a critical determinant of VCI, whose targeting may be of therapeutic benefit in cerebral vascular disease. 相似文献
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Ravi Mahalingam Brittany Feia Colin Coleman Kusala Anupindi Pratush Saravanan Amalia Luthens Amalia Bustillos Arpita Das Eileen de Haro Lara Doyle-Meyers Jayme Looper Andrew N. Bubak Christy S. Niemeyer Brent Palmer Maria A. Nagel Vicki Traina-Dorge 《Viruses》2022,14(6)
Primary simian varicella virus (SVV) infection and reactivation in nonhuman primates is a valuable animal model in the study of varicella zoster virus disease [varicella (chickenpox) and herpes zoster (shingles)]. To understand SVV pathogenesis in skin, we inoculated 10 rhesus macaques with SVV, resulting in varicella rash. After the establishment of latency, eight of the monkeys were immunosuppressed using tacrolimus with or without irradiation and prednisone and two monkeys were not immunosuppressed. Zoster rash developed in all immunosuppressed monkeys and in one non-immunosuppressed monkey. Five monkeys had recurrent zoster. During varicella and zoster, SVV DNA in skin scrapings ranged from 50 to 107 copies/100 ng of total DNA and 2–127 copies/100 ng of total DNA, respectively. Detection of SVV DNA in blood during varicella was more frequent and abundant compared to that of zoster. During varicella and zoster, SVV antigens colocalized with neurons expressing β-III tubulin in epidermis, hair follicles, and sweat glands, suggesting axonal transport of the virus. Together, we have demonstrated that both SVV DNA and antigens can be detected in skin lesions during varicella and zoster, providing the basis for further studies on SVV skin pathogenesis, including immune responses and mechanisms of peripheral spread. 相似文献
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Dorothee M. Kottmeier Abdesslam Chrachri Gerald Langer Katherine E. Helliwell Glen L. Wheeler Colin Brownlee 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(19)
Coccolithophores are major producers of ocean biogenic calcite, but this process is predicted to be negatively affected by future ocean acidification scenarios. Since coccolithophores calcify intracellularly, the mechanisms through which changes in seawater carbonate chemistry affect calcification remain unclear. Here we show that voltage-gated H+ channels in the plasma membrane of Coccolithus braarudii serve to regulate pH and maintain calcification under normal conditions but have greatly reduced activity in cells acclimated to low pH. This disrupts intracellular pH homeostasis and impairs the ability of C. braarudii to remove H+ generated by the calcification process, leading to specific coccolith malformations. These coccolith malformations can be reproduced by pharmacological inhibition of H+ channels. Heavily calcified coccolithophore species such as C. braarudii, which make the major contribution to carbonate export to the deep ocean, have a large intracellular H+ load and are likely to be most vulnerable to future decreases in ocean pH.Anthropogenic CO2 emissions and the subsequent dissolution of CO2 in seawater have resulted in substantial changes in ocean carbonate chemistry (1). The resultant decrease in seawater pH, termed ocean acidification, is predicted to be particularly detrimental for calcifying organisms (2). Mean global surface ocean pH is currently around 8.2 but is predicted to fall as low as 7.7 by 2100 (3) and is likely to continue to fall further in the following centuries. Present-day marine organisms can experience significant fluctuations in seawater pH, particularly in coastal and upwelling regions (4, 5). Ocean acidification is therefore predicted to have an important influence not only on mean surface ocean pH but also on the extremes of pH experienced by marine organisms (6, 7).Coccolithophores (Haptophyta) are a group of globally distributed unicellular phytoplankton that are characterized by their covering of intricately formed calcite scales (coccoliths). Coccolithophores account for a significant proportion of ocean productivity and are the main producers of biogenic calcite, making major contributions to global biogeochemical cycles, including the long-term export of both inorganic and organic carbon from the ocean photic zone to deep waters (8, 9). Unlike the vast majority of calcifying organisms, coccolithophore calcification occurs in an intracellular compartment, the Golgi-derived coccolith vesicle (CV), effectively isolating the calcification process from direct changes in seawater carbonate chemistry. Nevertheless, extensive laboratory observations indicate that ocean acidification may negatively impact coccolithophore calcification, albeit with significant variability of responses between species and strains (10–14). The negative impact on calcification rates occurs at calcite saturation states (Ωcalcite) >1, indicating that it results primarily from impaired cellular production rather than dissolution (10, 15). However, prediction of how natural coccolithophore populations may respond to future changes in ocean pH are hampered by lack of mechanistic understanding of pH impacts at the cellular level (10).As calcification occurs intracellularly using external HCO3− as the primary dissolved inorganic carbon (DIC) source (16–18), coccolith formation is not directly dependent on external CO32− concentrations. However, the uptake of HCO3− as a substrate for calcification results in the equimolar production of CaCO3 and H+ in the CV (18). In order to maintain saturation conditions for calcite formation, H+ produced by the calcification process must be rapidly removed from the CV, placing extraordinary demands for cellular pH regulation to prevent cellular acidosis (18).Lower calcification rates under ocean acidification conditions appear to be primarily due to decreased pH rather than other aspects of carbonate chemistry (10, 19, 20). Coccolithophores exhibit highly unusual membrane physiology, including the presence of voltage-gated H+ channels in the plasma membrane (21) and a high sensitivity of cytosolic pH (pHcyt) to changes in external pH (pHo) (21, 22). Voltage-gated H+ channels are associated with rapid H+ efflux in a number of specialized animal cell types (23) and contribute to effective pH regulation in coccolithophores (21). As H+ channel function is dependent on the electrochemical gradient of H+ across the plasma membrane, this mechanism could be impaired under lower seawater pH. However, it remains unknown whether H+ channels play a direct role in removal of calcification-derived H+ or contribute to the sensitivity of coccolithophores to ocean acidification.Coccolithophores exhibit significant diversity in their extent of calcification (SI Appendix, Fig. S1). The ratio of particulate inorganic carbon to particulate organic carbon (PIC/POC) of a coccolithophore culture is a measure of the relative rates of inorganic carbon fixation by calcification and organic carbon fixation by photosynthesis, respectively, and is commonly used as a simple metric to define the degree of calcification. The abundant bloom-forming species Emiliania huxleyi is moderately calcified (PIC/POC of around 1) and has been the focus of the vast majority of the studies into the effects of environmental change in coccolithophores (13). Coastal species belonging to the Pleurochrysidaceae and Hymenomonadaceae are lightly calcified, commonly exhibiting a PIC/POC of less than 0.5 (24–27). Species such as Coccolithus braarudii, Calcidiscus leptoporus, and Helicosphaera carteri exhibit much higher PIC/POC ratios and contribute the majority of carbonate export to the deep ocean in many areas (28–30). The physiological response of heavily calcified coccolithophores to ocean acidification is therefore of considerable biogeochemical significance. Growth and calcification rates in C. leptoporus and C. braarudii are sensitive to pH values predicted to prevail on a future decadal timescale (10, 15, 31, 32). However, a mechanistic understanding of the different sensitivity of coccolithophore species to changing ocean carbonate chemistry is lacking.The net H+ load in a cell is determined by the combination of metabolic processes that consume or produce H+. H+ fluxes in coccolithophores will be primarily determined by the balance of H+ consumed by photosynthesis and H+ generated by calcification, with uptake of different carbon sources a particularly important consideration (Fig. 1A). CO2 uptake for photosynthesis results in no net production or consumption of H+, whereas uptake of HCO3− requires the equimolar consumption of H+ in order to generate CO2. Growth at elevated CO2 causes a switch from HCO3− uptake to predominately CO2 uptake in E. huxleyi (33, 34). The associated net decrease in H+ consumption will therefore increase the H+ load in coccolithophores grown at elevated CO2, which may exacerbate the potential for cytosolic acidosis caused by lower seawater pH.Open in a separate windowFig. 1.Physiology and H+ fluxes of C. braarudii cells grown at different seawater pH. (A) Schematic indicating H+ fluxes associated with photosynthesis and calcification in a coccolithophore cell. While many metabolic processes may contribute to the cellular H+ budget, these two processes are likely to be the major contributors. In a cell taking up HCO3−, the overall H+ budget is determined by the relative rates of H+ consumed during photosynthesis and H+ generated during calcification. In a cell taking up CO2, the H+ budget is determined primarily by calcification, as 2 H+ are produced for each molecule of CaCO3 produced and H+ are no longer consumed during photosynthesis. In both scenarios, excess H+ may be removed from the cell by H+ transporters in the plasma membrane, such as voltage-gated H+ channels (Hv). Coccolithophores take up both HCO3− and CO2 across the plasma membrane, with increasing proportions of DIC taken up as CO2 as seawater CO2 increases (34). (B) Growth rate of C. braarudii cells acclimated to different seawater pH. n = 3 replicates per treatment; line represents polynomial fit to mean. (C) Cellular production of POC through photosynthesis and PIC through calcification. The optima for both processes are close to the control conditions (pH 8.15). (D) As a consequence of the unequal changes in cellular POC and PIC production across the applied pH values, cellular PIC/POC ratios are minimal at pH 7.55 (∼1.0) and maximal at pH 8.45 (∼1.8). (E) Calculated net H+ budgets under the different pH regimes, based on rates of photosynthesis and calcification shown in C (see Materials and Methods). The concentration of CO2 in seawater is also shown (dashed line). Estimates are shown for cells using taking up only HCO3− or only CO2. As C. braarudii cells will likely take up a mixture of both DIC species, with a shift toward greater CO2 usage at elevated CO2, the shaded area represents the potential range of H+ production. Regardless of DIC species used C. braarudii produces excess H+ at all applied pH values, but H+ production is much lower at pH 7.55 due to the decrease in calcification.In this study we set out to better understand the cellular mechanisms underlying the sensitivity of coccolithophore calcification to lower pH. We subjected the heavily calcified species C. braarudii, which is commonly found in temperate upwelling regions (35, 36), to conditions that reflect the range of pH values it may experience in current and future oceans. We show that acclimation to low pH leads to loss of H+ channel function and disruption of cellular pH regulation in C. braarudii. These effects are coincident with very specific defects in coccolith morphology that can be reproduced by direct inhibition of H+ channels. We conclude that H+ efflux through H+ channels is essential for maintaining both calcification rate and coccolith morphology. By providing a mechanistic insight into pH regulation during the calcification process, our results indicate that disruption of coccolithophore calcification in a future acidified ocean is likely to be most severe in heavily calcified species. 相似文献
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