全文获取类型
收费全文 | 1562篇 |
免费 | 119篇 |
国内免费 | 1篇 |
专业分类
耳鼻咽喉 | 4篇 |
儿科学 | 44篇 |
妇产科学 | 22篇 |
基础医学 | 236篇 |
口腔科学 | 34篇 |
临床医学 | 181篇 |
内科学 | 225篇 |
皮肤病学 | 15篇 |
神经病学 | 259篇 |
特种医学 | 32篇 |
外科学 | 217篇 |
综合类 | 47篇 |
预防医学 | 131篇 |
眼科学 | 14篇 |
药学 | 130篇 |
中国医学 | 2篇 |
肿瘤学 | 89篇 |
出版年
2023年 | 20篇 |
2022年 | 22篇 |
2021年 | 35篇 |
2020年 | 25篇 |
2019年 | 39篇 |
2018年 | 44篇 |
2017年 | 37篇 |
2016年 | 36篇 |
2015年 | 41篇 |
2014年 | 62篇 |
2013年 | 80篇 |
2012年 | 102篇 |
2011年 | 88篇 |
2010年 | 63篇 |
2009年 | 46篇 |
2008年 | 68篇 |
2007年 | 57篇 |
2006年 | 77篇 |
2005年 | 56篇 |
2004年 | 69篇 |
2003年 | 55篇 |
2002年 | 43篇 |
2001年 | 38篇 |
2000年 | 43篇 |
1999年 | 25篇 |
1998年 | 10篇 |
1997年 | 10篇 |
1995年 | 8篇 |
1994年 | 9篇 |
1993年 | 11篇 |
1992年 | 32篇 |
1991年 | 26篇 |
1990年 | 25篇 |
1989年 | 18篇 |
1988年 | 22篇 |
1987年 | 26篇 |
1986年 | 22篇 |
1985年 | 17篇 |
1984年 | 15篇 |
1983年 | 12篇 |
1980年 | 15篇 |
1979年 | 12篇 |
1978年 | 10篇 |
1977年 | 9篇 |
1976年 | 11篇 |
1975年 | 13篇 |
1974年 | 10篇 |
1973年 | 9篇 |
1971年 | 6篇 |
1966年 | 5篇 |
排序方式: 共有1682条查询结果,搜索用时 0 毫秒
51.
Leslie I. Grad Justin J. Yerbury Bradley J. Turner William C. Guest Edward Pokrishevsky Megan A. O’Neill Anat Yanai Judith M. Silverman Rafaa Zeineddine Lisa Corcoran Janet R. Kumita Leila M. Luheshi Masoud Yousefi Bradley M. Coleman Andrew F. Hill Steven S. Plotkin Ian R. Mackenzie Neil R. Cashman 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(9):3620-3625
Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5–10% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWtSOD1 propagation has been established, misfolding of HuWtSOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates. Conditioned media transmission of HuWtSOD1 misfolding in HEK293 cells is blocked by HuWtSOD1 siRNA knockdown, consistent with human SOD1 being a substrate for conversion, and attenuated by ultracentrifugation or incubation with SOD1 misfolding-specific antibodies, indicating a relatively massive transmission particle which possesses antibody-accessible SOD1. Finally, misfolded and protease-sensitive HuWtSOD1 comprises up to 4% of total SOD1 in spinal cords of patients with sporadic ALS (SALS). Propagation of HuWtSOD1 misfolding, and its subsequent cell-to-cell transmission, is thus a candidate process for the molecular pathogenesis of SALS, which may provide novel treatment and biomarker targets for this devastating disease.Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular condition that afflicts as many as 1 of 350 males and 420 females over the age of 18 (1). In ALS, degeneration of upper and lower motor neurons causes progressive muscle paralysis and spasticity, affecting mobility, speech, swallowing, and respiration (2). Half of affected individuals die within 3 y, and less than 20% survive for more than 5 y (3); 90–95% of ALS cases are sporadic (SALS) in which some apparently facilitating gene mutations, such as repeat expansions in the gene that encodes ataxin-2 (4), have been identified. The remaining 5–10% of ALS cases are familial (FALS) and predominantly associated with Mendelian-inherited mutations in the genes encoding Cu/Zn superoxide dismutase (SOD1), TAR-DNA–binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), C9ORF72, and other genes (reviewed in ref. 3).Despite the profusion of functionally diverse genes implicated in FALS and SALS, clinical and pathological similarities between all forms of ALS suggest the existence of a common pathogenic pathway that could be united by a single gene/protein (5). One of the mechanisms by which a mutant or wild-type (WT) protein can dominate pathogenesis of phenotypically diverse diseases is by propagated protein misfolding, such as that underpinning the prion diseases, which has been increasingly implicated in other neurodegenerative and systemic disorders (6, 7). A role for propagated protein misfolding in ALS is supported by the prion-like spatiotemporal progression of disease through the neuroaxis (8, 9). However, given the disparity in protein inclusion pathology between subtypes of ALS, a single unifying prion-like protein that could explain such a progression remains obscure.Whereas it is generally accepted SOD1 is not found in large perikaryal cytoplasmic inclusions outside of SOD1 FALS cases, misfolded SOD1 has been increasingly identified in SALS and non-SOD1 FALS (5, 10, 11). Indeed, we have reported that misfolded human wild-type SOD1 (HuWtSOD1) can be detected by spinal cord immunohistochemistry (IHC) in FALS secondary to FUS mutation, and in SALS patients with cytosolic WT TDP-43 accumulation (11). Moreover, in cell models, overexpression of WTTDP-43, or expression of mutant FUS or TDP-43, is associated with HuWtSOD1 misfolding (11). Collectively, these data are consistent with SOD1 being a molecular common denominator for all types of ALS. Furthermore, prion-like activity has been described for the cell-to-cell transmission of misfolding of mutant SOD1 (12), and we have reported that mutant SOD1 can confer its misfold on HuWtSOD1 (13). However, mutant SOD1 cannot explain propagation in SALS.To test if HuWtSOD1 participates in cell-to-cell transmission of protein misfolding, we make use of previously developed mouse mAb probes for misfolded/oxidized SOD1, recognizing either full-length human mutant or WT SOD1, generated against regions that are antibody-inaccessible in natively folded SOD1 (13–15). Misfolded SOD1 mAbs used in this work are 10E11C11 and 3H1, directed against an unstructured electrostatic loop [disease-specific epitope-2 (DSE2)], and 10C12, directed against a C-terminal dimer interface peptide in which the cysteine at position 146 is substituted by a cysteic acid residue to mimic oxidation of this residue (DSE1a) (13). The use of such antibody probes have enabled us to unambiguously determine the role of misfolded mutant G127X in the induced misfolding of HuWtSOD1, which upon misfolding acquires a marked increase in sensitivity to protease digestion, consistent with global loosening of structure (13). The finding that misfolded endogenous HuWtSOD1 was observed long after transfected G127X-SOD1 was degraded suggested that HuWtSOD1, once misfolded, is capable of triggering an intracellular propagated misfolding reaction (13). We now report for the first time that misfolded HuWtSOD1 can transit cell to cell both via exosomes, and release of protein aggregates and subsequent uptake in neuronal cells. In addition, misfolded HuWtSOD1 can sustain intercellular propagated misfolding in vitro and is detectable in the spinal cord of all ALS patients tested, regardless of the genetic etiology of the disease. Collectively, these data indicate that HuWtSOD1 is competent to participate in propagated misfolding, suggesting a common pathogenic mechanism linking FALS and SALS. 相似文献
52.
Loss of Gsα Early in the Osteoblast Lineage Favors Adipogenic Differentiation of Mesenchymal Progenitors and Committed Osteoblast Precursors 下载免费PDF全文
Partha Sinha Piia Aarnisalo Rhiannon Chubb Noriaki Ono Keertik Fulzele Martin Selig Hamid Saeed Min Chen Lee S Weinstein Paola Divieti Pajevic Henry M Kronenberg Joy Y Wu 《Journal of bone and mineral research》2014,29(11):2414-2426
In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit Gsα activates protein kinase A signaling downstream of several G protein‐coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of Gsα in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage. © 2014 American Society for Bone and Mineral Research 相似文献
53.
Muhammad Shahid Hussain Saleemi Afif El-Khuffash Orla Franklin John David Corcoran 《Early human development》2014
Background
Myocardial performance is impaired in the first days of life in preterm infants but improves by day 5. Tissue Doppler imaging (TDI) is a novel and reliable means of assessing myocardial performance.Objective
To investigate myocardial performance using TDI and shortening fraction (SF) in preterm infants of different gestational age groups and serial changes in these parameters in first four weeks of life.Study designInfants less than 36 weeks of gestation were divided into group 1 (24–27 weeks, n = 8), group 2 (28–31 weeks, n = 12) and group 3 (32–35 weeks, n = 13). Infants with severe congenital malformations, a hypoxic insult at birth, and those on inotropic support were excluded. Echocardiograms were performed at 36–48 hours, 2 weeks and 4 weeks of life. Left ventricular (LV) SF, systolic (S′), early diastolic (E′) and late diastolic (A′) TDI velocities were assessed. We analyzed the data using a repeated-measures ANOVA.Results
Thirty three infants underwent serial TDI and SF measurements. There was an increase in LV S′ (p = .02) and E′ (.01) velocities in group 2 , and in group 3 (p = .03 for S′ and p = .04 for E′), but no significant increase in group 1 (p = .48 for S′ and .32 for E′). At each study point, there was significant difference in myocardial performance between group 1 and 3 for each of the parameters (p < .05). There was no significant increase in SF over time in any of the groups.Conclusion
We describe a serial increase in myocardial performance in infants of 28 weeks gestation and above. While there was no change in myocardial performance among the most extremely preterm infants, this may have been the result of small sample size of the group. 相似文献54.
55.
Ashley M Blawas Kathryn E Ware Emma Schmaltz Larry Zheng Jacob Spruance Austin S Allen Nicole West Nicolas Devos David L Corcoran Douglas P Nowacek William C Eward Andreas Fahlman Jason A Somarelli 《Evolution, Medicine, and Public Health》2021,9(1):420
Background and objectivesIschemic events, such as ischemic heart disease and stroke, are the number one cause of death globally. Ischemia prevents blood, carrying essential nutrients and oxygen, from reaching tissues, leading to cell and tissue death, and eventual organ failure. While humans are relatively intolerant to ischemic events, other species, such as marine mammals, have evolved a unique tolerance to chronic ischemia/reperfusion during apneic diving. To identify possible molecular features of an increased tolerance for apnea, we examined changes in gene expression in breath-holding dolphins.MethodologyHere, we capitalized on the adaptations possesed by bottlenose dolphins (Tursiops truncatus) for diving as a comparative model of ischemic stress and hypoxia tolerance to identify molecular features associated with breath holding. Given that signals in the blood may influence physiological changes during diving, we used RNA-Seq and enzyme assays to examine time-dependent changes in gene expression in the blood of breath-holding dolphins.ResultsWe observed time-dependent upregulation of the arachidonate 5-lipoxygenase (ALOX5) gene and increased lipoxygenase activity during breath holding. ALOX5 has been shown to be activated during hypoxia in rodent models, and its metabolites, leukotrienes, induce vasoconstriction.Conclusions and implicationsThe upregulation of ALOX5 mRNA occurred within the calculated aerobic dive limit of the species, suggesting that ALOX5 may play a role in the dolphin’s physiological response to diving, particularly in a pro-inflammatory response to ischemia and in promoting vasoconstriction. These observations pinpoint a potential molecular mechanism by which dolphins, and perhaps other marine mammals, respond to the prolonged breath holds associated with diving. 相似文献
56.
Joshua L. Chan Justin G. Miller Avneesh K. Singh Keith A. Horvath Philip C. Corcoran Muhammad M. Mohiuddin 《Clinical transplantation》2018,32(8)
The field of cardiac xenotransplantation has entered an exciting era due to recent advances in the field. Although several hurdles remain, the use of rapidly evolving transgenic technology has the potential to address current allogeneic donor pool constraints and mechanical circulatory system device limitations. The success of xenotransplantation will undoubtedly be dependent on specific patient selection criteria. Defining these particular indications for xenotransplantation is important as we approach the possibility of clinical applications. 相似文献
57.
Michael J. Solomon Anand K. Deva Susan J. M. Corcoran Neil Gallagher 《ANZ journal of surgery》1996,66(12):849-851
A case of acute perforation of the terminal ileum induced by avulsion of the bowel wall in a segment of acutely inflamed Crohn's disease is presented. This case is unusual in that the avulsion developed after delivery following the rapid retraction of the uterus which had been compressing a small localized perforation and abscess. A review of the literature has failed to demonstrate a similar case report. 相似文献
58.
Jayme E. Locke Shikha Mehta Rhiannon D. Reed Paul MacLennan Allan Massie Anoma Nellore Christine Durand Dorry L. Segev 《Journal of the American Society of Nephrology : JASN》2015,26(9):2222-2229
Kidney transplantation is a viable treatment for select patients with HIV and ESRD, but data are lacking regarding long-term outcomes and comparisons with appropriately matched HIV-negative patients. We analyzed data from the Scientific Registry of Transplant Recipients (SRTR; 2002–2011): 510 adult kidney transplant recipients with HIV (median follow-up, 3.8 years) matched 1:10 to HIV-negative controls. Compared with HIV-negative controls, HIV-infected recipients had significantly lower 5-year (75.3% versus 69.2%) and 10-year (54.4% versus 49.8%) post-transplant graft survival (GS) (hazard ratio [HR], 1.37; 95% confidence interval [95% CI], 1.15 to 1.64; P<0.001) that persisted when censoring for death (HR, 1.43; 95% CI, 1.12 to 1.84; P=0.005). However, compared with HIV-negative/hepatitis C virus (HCV)–negative controls, HIV monoinfected recipients had similar 5-year and 10-year GS, whereas HIV/HCV coinfected recipients had worse GS (5-year: 64.0% versus 52.0%, P=0.02; 10-year: 36.2% versus 27.0%, P=0.004 [HR, 1.38; 95% CI, 1.08 to 1.77; P=0.01]). Patient survival (PS) among HIV-infected recipients was 83.5% at 5 years and 51.6% at 10 years and was significantly lower than PS among HIV-negative controls (HR, 1.34; 95% CI, 1.08 to 1.68; P<0.01). However, PS was similar for HIV monoinfected recipients and HIV-negative/HCV-negative controls at both times. HIV/HCV coinfected recipients had worse PS compared with HIV-negative/HCV-infected controls (5-year: 67.0% versus 78.6%, P=0.007; 10-year: 29.3% versus 56.23%, P=0.002 [HR, 1.57; 95% CI, 1.11 to 2.22; P=0.01]). In conclusion, HIV-negative and HIV monoinfected kidney transplant recipients had similar GS and PS, whereas HIV/HCV coinfected recipients had worse outcomes. Although encouraging, these results suggest caution in transplanting coinfected patients. 相似文献
59.
60.
The unbound percentage of saquinavir and indinavir remains constant throughout the dosing interval in HIV positive subjects 下载免费PDF全文
Boffito M Hoggard PG Reynolds HE Bonora S Meaden ER Sinicco A Di Perri G Back DJ 《British journal of clinical pharmacology》2002,54(3):262-268
AIMS: To measure the unbound plasma concentrations of saquinavir (SQV) and indinavir (IDV) and to relate them to the total plasma concentrations in order to establish the unbound percentage of protease inhibitors in vivo during a full dosage interval profile. METHODS: HIV-infected subjects (n = 35; median CD4 cell count = 340 x 10(6) cells l-1, range: 120-825; viral load < 50 copies ml-1 in 22/35) treated with SQV or IDV containing regimens were studied. Plasma drug samples were collected at 0, 2, 4, 8 and 12 h postdose for the twice daily regimens and 0, 1, 2, 4 and 8 h for the three times daily regimens. Ultra-filtration was used to separate unbound IDV and SQV in plasma and their respective concentrations were measured by a fully validated method using high performance liquid chromatography-mass spectometry (h.p.l.c.-MS/MS). RESULTS: Based on the ratio AUCunbound/AUCtotal, the median unbound percentage (95% CI for differences) of SQV and IDV from all the samples studied was 1.19% (0.99, 1.58%) and 36.3% (35.1, 44.2%), respectively. No significant difference was seen in the percentage binding of SQV between patients receiving SQV alone (median = 1.49%) or with ritonavir (median = 1.09%; P = 0.141; 95% CI for difference between medians = -0.145, 0.937) over the pharmacokinetic profile. Similarly, no significant difference was seen in the percentage binding of IDV in patients receiving IDV alone (median 35.2%) or with ritonavir (median = 41.3%; P = 0.069; 95% CI for difference between medians = -0.09, 15.4). The unbound concentrations of SQV (P < 0.0001; 95% CI for r(2) = 0.634, 0.815) and IDV (P < 0.0001; 95% CI for r(2) = 0.830, 0.925) remained constant as a proportion of total concentration over the full dosing profile. CONCLUSIONS: These in vivo data confirm previously published in vitro measurements of SQV and IDV protein binding. The unbound percentage of both protease inhibitors remained constant over the dosing interval. 相似文献