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71.
72.
Christoph Jüschke Yunli Xie Maria Pia Postiglione Juergen A. Knoblich 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(3):1014-1019
The orientation of the mitotic spindle determines the relative size and position of the daughter cells and influences the asymmetric inheritance of localized cell fate determinants. The onset of mammalian neurogenesis, for example, coincides with changes in spindle orientation. To address the functional implications of this and related phenomena, precise methods for determining the orientation of the mitotic spindle in complex tissues are needed. Here, we present methodology for the analysis of spindle orientation in 3D. Our method allows statistical analysis and modeling of spindle orientation and involves two parameters for horizontal and vertical bias that can unambiguously describe the distribution of spindle orientations in an experimental sample. We find that 3D analysis leads to systematically different results from 2D analysis and, surprisingly, truly random spindle orientations do not result in equal numbers of horizontal and vertical orientations. We show that our method can describe the distribution of spindle orientation angles under different biological conditions. As an example of biological application we demonstrate that the adapter protein Inscuteable (mInsc) can actively promote vertical spindle orientation in apical progenitors during mouse neurogenesis.Controlling the orientation of mitotic spindles is an important aspect of tissue development and homeostasis. The position of the mitotic spindle is regulated by pulling forces acting between the spindle poles and cortical microtubule attachment sites (1, 2). The spindle position determines the cleavage plane and thereby influences the size and position of the newly forming daughter cells (3, 4). A defined spatial organization of newly generated cells is crucial for creating complex 3D structures such as tubes, ducts, and vessels (5, 6). Multicellular organisms therefore use spindle orientation for various purposes, for example to regulate planar expansion and tissue stratification in epithelia.In stem cells, spindle orientation can regulate the ratio between proliferating and differentiating divisions (7). Because the maintenance of stem cell populations often depends on contact with a signaling niche, spindle orientation determines whether daughter cells maintain niche contact and stem cell fate or lose contact and differentiate. Alternatively, spindle orientation can ensure the reliable inheritance of localized cell-fate determinants by the correct daughter cells in stem cell populations that are regulated by cell-intrinsic signals. The early development of the mammalian neocortex, for example, starts with symmetric divisions of neural progenitor cells to expand the progenitor pool. At later stages, asymmetric divisions of the same progenitor cells generate both self-renewing daughter cells and also cells that give rise to transit-amplifying cells or neurons (8–13). The precise control of spindle orientation is vital for determining the different cell fate decisions during the course of cortical development (14–16).Here, we describe a mathematical method for the analysis of spindle orientation that takes into account the 3D structure of the dividing cell and the variability of the reference plane and its effect on angle determination. We identify and quantify potential sources of error that can occur when mitotic figures are analyzed in 2D. Currently, terms such as “randomized spindle orientation” are not unambiguously defined, but this would be necessary to describe mutant phenotypes in a way that allows mechanistic interpretation. We therefore establish a mathematical definition of randomness for spindle orientation in 3D and use this to calculate the expected frequencies for various spindle orientation angles. We establish statistics allowing us to determine how far experimental data deviate from true randomness and introduce two parameters called λh and λv that describe the degree of horizontal and vertical spindle enrichment, respectively, in an experimental dataset. Finally, we apply our method to biological data from mice overexpressing the mouse Inscuteable (mInsc) gene and show that these data are consistent with a role of mInsc in promoting vertical spindle orientations during mouse corticogenesis but not with simply inhibiting horizontal orientation. 相似文献
73.
Hematopoietic chimerism can be used as a tool for patient management after allogeneic hematopoietic stem cell transplantation (HSCT). An increase in the proportion of recipient cells after transplantation is strongly associated with relapse in chronic myeloid leukemia. However, in acute myeloid leukemia (AML) the significance of increasing mixed chimerism (MC) as a predictive marker for relapse is less clear. Several mutations frequently found in AML have been employed for minimal residual disease detection and relapse prediction. Therefore, a combined analysis of hematopoietic chimerism and of the molecular aberrations found in AML could be used to improve MC characterization. We developed a multiplex PCR for use in the simultaneous detection of hematopoietic chimerism and mutations in nucleophosmin (NPM1) and fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD). A total of 303 samples from 20 AML patients were analyzed after HSCT. The microsatellite markers used for hematopoietic chimerism detection were D1S80, D7S1517, D4S2366, THO1, and SE33. A total of 149 samples from 18 patients showed MC with a mean detection time of 9.7 months. From the 18 patients with MC, in 6 of the patients, no FLT3-ITD or NPM1 mutation was found at any time point tested, and these patients remained in complete hematological remission. In 12 patients with MC, FLT3-ITD and NPM1 mutations were found, and these patients showed signs of hematological relapse. Our combined analysis of NPM1/FLT3-ITD mutations and hematopoietic chimerism improved the characterization of patients with MC after HSCT. The present approach may be further expanded by combining additional mutations found in AML with hematopoietic chimerism detection. 相似文献
74.
Maria Strauss Roland Mergl Juergen Kratzsch Mathias Brügel Erik Strauss Ulrich Hegerl Peter Schoenknecht 《Psychiatry research》2014
The relationship between leptin and affective disorders is still unknown. We measured free and bound leptin in 13 drug naïve subjects. Leptin did not significantly differ between patients and controls. As part of future studies, it also appears useful to distinguish between free and bound leptin. 相似文献
75.
Bernhard Sehm Marco Taubert Virginia Conde David Weise Joseph Classen Juergen Dukart Bogdan Draganski Arno Villringer Patrick Ragert 《Neurobiology of aging》2014
We investigated morphometric brain changes in patients with Parkinson's disease (PD) that are associated with balance training. A total of 20 patients and 16 healthy matched controls learned a balance task over a period of 6 weeks. Balance testing and structural magnetic resonance imaging were performed before and after 2, 4, and 6 training weeks. Balance performance was re-evaluated after ∼20 months. Balance training resulted in performance improvements in both groups. Voxel-based morphometry revealed learning-dependent gray matter changes in the left hippocampus in healthy controls. In PD patients, performance improvements were correlated with gray matter changes in the right anterior precuneus, left inferior parietal cortex, left ventral premotor cortex, bilateral anterior cingulate cortex, and left middle temporal gyrus. Furthermore, a TIME × GROUP interaction analysis revealed time-dependent gray matter changes in the right cerebellum. Our results highlight training-induced balance improvements in PD patients that may be associated with specific patterns of structural brain plasticity. In summary, we provide novel evidence for the capacity of the human brain to undergo learning-related structural plasticity even in a pathophysiological disease state such as in PD. 相似文献
76.
Ekaterina Krauss Abbas Agaimy Angelina Gottfried Juergen Maiss Thomas Weidinger Heinz Albrecht Arndt Hartmann Werner Hohenberger Markus F Neurath Hermann Kessler Jonas Mudter 《International journal of clinical and experimental pathology》2014,7(11):7419-7431
Background & aims: Ileo-colonic strictures are common complication of Crohn’s disease (CD), and may result in repeated endoscopic or surgical therapy with a risk of further complications, such as perforation or short bowel syndrome. Strictures develop as a consequence of tissue remodelling and fibrosis due to chronic inflammation. This study compares the outcome of CD patients undergoing primarily endoscopic treatment with those undergoing surgery at an university hospital. Methods: In this study we retrospectively included 88 CD patients with intestinal strictures (37 males, 51 females, mean age 40 years, range 19-65 years) of both our medical and our surgical department, who underwent either surgical or endoscopic therapy between January 2002 and January 2006 with prospective, controlled follow-up, extended till January 2010 (mean follow-up period: 5 years; range 4-8 years). The primary end-point was operation- and symptom-free time. Patients were primarily divided into four groups: only surgical therapy, only endoscopic therapy, endoscopy with subsequent surgery, and initial surgical therapy followed by endoscopic dilations. Results: 53% of all patients remained surgery-free with mean follow-up of 49 months; a single endoscopic dilation was sufficient enough in 9 patients to achieve a surgery-free time of 51 months, other patients required up to 5 dilations. The average interval between first and second dilation was 6.5 months, between second and third 10.5 months. In the group of patients with only endoscopic therapy, surgery- and symptom-free time was shorter, as compared to the group of only surgical therapy. We found that stenoses in the surgical group with an average length of 6.5 cm were as expected longer, as compared to the endoscopic group (3 cm, ranging from 2-4 cm). The surgery-free time was 49 months (42-71 months, P = 0.723) with a symptom-free time of 12 months (4.5-46 months, P = 0.921). In the group of only surgically treated patients, 68.4% of the patients had only one stenosis, 18.4% had 2-3 stenoses and 13.2% more than 3 stenoses. In all patients the surgery- and symptoms- free time was 69 months (57-83 months, P = 0.850 and 0.908). The other two groups showed similar results. We found no significant effect of characteristic of stenosis (length, inflammation, the number of stenoses), injection of prednisolone, disease activity at the time of dilation and medication at the time of dilation on the long-term outcome. Importantly, the success of symptom free time correlated with the diameter of the balloon. Conclusions: Endoscopic dilation should be considered as a first-line therapy for short, accessible, fibrotic strictures. Careful patient selection and proper diagnostic imaging pre-procedure are essential requirements for safe and successful treatment. The balloon diameter seems to correlate positively with the long term outcome of dilation. However, at ever shorter intervals between endoscopic interventions, surgery should be discussed as an option for further treatment. 相似文献
77.
78.
Fabian Falkenstein Marco Gessi Daniela Kandels Ho-Keung Ng René Schmidt Monika Warmuth-Metz Brigitte Bison Juergen Krauss Rolf-Dieter Kortmann Beate Timmermann Ulrich-Wilhelm Thomale Michael H. Albert Arnulf Pekrun Eberhard Maaß Astrid K. Gnekow Torsten Pietsch 《International journal of cancer. Journal international du cancer》2020,147(8):2159-2175
Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment. 相似文献
79.
Bhim M. Adhikari Juergen Dukart Joerg F. Hipp Anna Forsyth Rebecca McMillan Suresh D. Muthukumaraswamy Meghann C. Ryan L. Elliot Hong Simon B. Eickhoff Neda Jahandshad Paul M. Thompson Laura M. Rowland Peter Kochunov 《Human brain mapping》2020,41(3):767-778
Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10?3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = ?.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug. 相似文献
80.
Daniele Roberto Giacobbe Juergen Prattes Joost Wauters Silvia Dettori Alessio Signori Jon Salmanton-García Johan Maertens Marc Bourgeois Marijke Reynders Lynn Rutsaert Niels Van Regenmortel Piet Lormans Simon Feys Nikolay Klimko Olga Shadrivova Oliver A. Cornely Riina Rautemaa-Richardson Philipp Koehler Katrien Lagrou Matteo Bassetti Martin Hoenigl 《Journal of clinical microbiology》2022,60(4)