全文获取类型
收费全文 | 865篇 |
免费 | 62篇 |
国内免费 | 7篇 |
专业分类
耳鼻咽喉 | 24篇 |
儿科学 | 11篇 |
妇产科学 | 24篇 |
基础医学 | 122篇 |
口腔科学 | 27篇 |
临床医学 | 76篇 |
内科学 | 277篇 |
皮肤病学 | 8篇 |
神经病学 | 48篇 |
特种医学 | 19篇 |
外科学 | 111篇 |
综合类 | 4篇 |
一般理论 | 1篇 |
预防医学 | 31篇 |
眼科学 | 11篇 |
药学 | 68篇 |
肿瘤学 | 72篇 |
出版年
2023年 | 7篇 |
2022年 | 9篇 |
2021年 | 54篇 |
2020年 | 24篇 |
2019年 | 29篇 |
2018年 | 36篇 |
2017年 | 39篇 |
2016年 | 21篇 |
2015年 | 39篇 |
2014年 | 45篇 |
2013年 | 43篇 |
2012年 | 85篇 |
2011年 | 84篇 |
2010年 | 36篇 |
2009年 | 39篇 |
2008年 | 62篇 |
2007年 | 68篇 |
2006年 | 53篇 |
2005年 | 50篇 |
2004年 | 42篇 |
2003年 | 17篇 |
2002年 | 12篇 |
2001年 | 4篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1997年 | 1篇 |
1996年 | 4篇 |
1995年 | 1篇 |
1993年 | 1篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
排序方式: 共有934条查询结果,搜索用时 31 毫秒
1.
2.
Numerical study of the influence of pulsed laser deposited TiN thin films’ microstructure morphologies on strain heterogeneities during loading was the goal of this research. The investigation was based on the digital material representation (DMR) concept applied to replicate an investigated thin film’s microstructure morphology. The physically based pulsed laser deposited model was implemented to recreate characteristic features of a thin film microstructure. The kinetic Monte Carlo (kMC) approach was the basis of the model in the first part of the work. The developed kMC algorithm was used to generate thin film’s three-dimensional representation with its columnar morphology. Such a digital model was then validated with the experimental data from metallographic analysis of laboratory deposited TiN(100)/Si. In the second part of the research, the kMC generated DMR model of thin film was incorporated into the finite element (FE) simulation. The 3D film’s morphology was discretized with conforming finite element mesh, and then incorporated as a microscale model into the macroscale finite element simulation of nanoindentation test. Such a multiscale model was finally used to evaluate the development of local deformation heterogeneities associated with the underlying microstructure morphology. In this part, the capabilities of the proposed approach were clearly highlighted. 相似文献
3.
Maciej Tomaszewski James Eales Matthew Denniff Stephen Myers Guat Siew Chew Christopher P. Nelson Paraskevi Christofidou Aishwarya Desai Cara Büsst Lukasz Wojnar Katarzyna Musialik Jacek Jozwiak Radoslaw Debiec Anna F. Dominiczak Gerjan Navis Wiek H. van Gilst Pim van der Harst Nilesh J. Samani Stephen Harrap Pawel Bogdanski Ewa Zukowska-Szczechowska Fadi J. Charchar 《Journal of the American Society of Nephrology : JASN》2015,26(12):3151-3160
The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65×10−5) and diastolic BP (P=7.61×10−3) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0×10−3). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP. 相似文献
4.
Soluble B7‐H4 blood serum levels are elevated in women at high risk for preeclampsia in the first trimester,as well as in patients with confirmed preeclampsia 下载免费PDF全文
Pawel Mach Luisa Nolte‐Boenigk Leonie Droste Laura Fox Mirjam Frank Boerge Schmidt Florian Herse Stefan Verlohren Lukasz Wicherek Antonella Iannaccone Cahit Birdir Dimitrios Andrikos Rainer Kimmig Alexandra Gellhaus Angela Köninger 《American journal of reproductive immunology (New York, N.Y. : 1989)》2018,80(3)
5.
Michael R. Sawaya Duilio Cascio Mari Gingery Jose Rodriguez Lukasz Goldschmidt Jacques-Philippe Colletier Marc M. Messerschmidt Sébastien Boutet Jason E. Koglin Garth J. Williams Aaron S. Brewster Karol Nass Johan Hattne Sabine Botha R. Bruce Doak Robert L. Shoeman Daniel P. DePonte Hyun-Woo Park Brian A. Federici Nicholas K. Sauter Ilme Schlichting David S. Eisenberg 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(35):12769-12774
It has long been known that toxins produced by Bacillus thuringiensis (Bt) are stored in the bacterial cells in crystalline form. Here we describe the structure determination of the Cry3A toxin found naturally crystallized within Bt cells. When whole Bt cells were streamed into an X-ray free-electron laser beam we found that scattering from other cell components did not obscure diffraction from the crystals. The resolution limits of the best diffraction images collected from cells were the same as from isolated crystals. The integrity of the cells at the moment of diffraction is unclear; however, given the short time (∼5 µs) between exiting the injector to intersecting with the X-ray beam, our result is a 2.9-Å-resolution structure of a crystalline protein as it exists in a living cell. The study suggests that authentic in vivo diffraction studies can produce atomic-level structural information.The advent of X-ray free-electron lasers (XFELs) has made it possible to obtain atomic resolution macromolecular structures from crystals with sizes approximating only 1/60th of the volume of a single red blood cell. Brief, intense pulses of coherent X-rays, focused on a spot of 3-μm diameter, have produced 1.9-Å-resolution diffraction data from a stream of lysozyme crystals, each crystal no bigger than 3 μm3 (1). A stream of crystals, not just one crystal, is required to collect the many tens of thousands of diffraction patterns that compose a complete data set. No single crystal can contribute more than one diffraction pattern because the XFEL beam is so intense and the crystals so small that the crystals are typically vaporized after a single pulse. Impressively, a photosystem I crystal no bigger than 10 unit cells (300 nm) on an edge produced observable subsidiary diffraction peaks between Bragg reflections, details which would be unobservable from conventionally sized crystals (2). With this new ability to collect diffraction patterns from crystals of unprecedentedly small dimensions, it is conceivable that high-resolution diffraction data could be collected from crystals in vivo. The structure obtained in this manner would be unaltered from that occurring naturally in a living cell, free from distortion that might otherwise potentially arise from nonphysiological conditions imposed by recrystallization. A practical advantage would also be gained by eliminating the need for a protein purification step, whether the in vivo grown crystals were naturally, or heterologously expressed (3).The nascent field of serial femtosecond crystallography (SFX) has published results on nine different macromolecular systems since its inception in 2009 (3, 9). The crystals for this study were not grown in artificial crystallization chambers as has been the protocol of conventional macromolecular crystallography since the 1950s. Instead, crystals were grown in cells. Specifically, they were grown in Sf9 insect cells, heterologously expressing Trypanosoma brucei cathepsin B. These in vivo-grown crystals were used for the XFEL diffraction experiment. To this end, the cells were lysed and the crystals were extracted before injecting them in the XFEL beam for data collection. This last purification step seems to be the only major departure from our goal of obtaining high-resolution structural information from crystal inclusions in vivo, without requiring the crystal to be extracted from the cell that assembled it. Here we attempt to go one step further than previous studies—to record diffraction from crystals within living cells.
Open in a separate window*The available XFEL energy was limited to 2 keV (6.2 Å wavelength) when these experiments were conducted.Our target for in vivo crystal structure determination is the insecticidal Cry3A toxin from Bacillus thuringiensis (Bt). The bacterium naturally produces crystals of toxin during sporulation (16). Presumably, the capacity for in vivo crystallization evolved in Bt as a mechanism to store the toxin in a concentrated, space-efficient manner. Since the 1920s, farmers have used the crystalline insecticidal proteins to control insect pests; its production as a natural pesticide is now a commercial enterprise. Attempts to structurally characterize the toxins date back to more than 40 y ago with the first report of diffraction from isolated crystals that were packed together in powder form to obtain a measurable signal; X-ray sources available at the time were relatively weak (17). More than 20 y later, the structure was determined at 2.5-Å resolution by single crystal diffraction using a synchrotron X-ray source (18). However, to achieve this result, the authors dissolved the naturally occurring microcrystals and recrystallized the toxin using the hanging drop vapor diffusion method. To date, more than a dozen Bt toxin structures have been reported from various strains [Protein Data Bank (PDB) ID codes 1cby, 1ciy, 1i5p, 1ji6, 1w99, 2d42, 2c9k, 2rci, 3eb7, 2ztb, 3ron, 4d8m, 4ato, 4ary, and 4arx], but none using naturally occurring crystals, and all of the crystals had lost their native context.In pursuit of in vivo diffraction, we took advantage of the Bt subsp. israelensis strain 4Q7/pPFT3As to produce the largest in vivo crystals achievable. This strain contains the plasmid pPFT3As, which increases expression of Cry3A by 12.7-fold over wild type by using strong promoters and an mRNA stabilizing sequence (19). The level of Cry3A production is such that the cell essentially distorts to take on the shape of the enclosed crystal. The calculated average crystal volume is 0.7 µm3 (19), almost accounting for the volume of the cell. To explore the possibilities for in situ data collection of in vivo microcrystals, we injected both the crystals in cells and crystals that we isolated from cells in the XFEL beam and collected SFX diffraction data. Our experiments revealed that the cell wall and other cellular components are not an obstacle to achieving 2.9-Å-resolution diffraction, and analogous studies in other systems might be similarly successful. 相似文献
Table 1.
SFX publications from XFEL sources to datePublication date | System | Product | Resolution (Å) | Title of publication | Authors | Reference |
Feb 2011* | Photosystem I | Structure | 8.7 | Femtosecond X-ray protein nanocrystallography | Chapman et al. | 2 |
Dec 2011* | Lysozyme | Structure | 8.7 | Radiation damage in protein serial femtosecond crystallography using an X-ray free-electron laser | Lomb et al. | 4 |
Jan 2012* | Photosystem I-Ferredoxin | Data | 11 | Time-resolved protein nanocrystallography using an X-ray free-electron laser | Aquila et al. | 5 |
Jan 2012* | Cathepsin B | Data | 7.5 | In vivo protein crystallization opens new routes in structural biology | Koopman et al. | 3 |
Jan 2012* | Photosynthetic Reaction Center | Structure | 7.4 | Lipidic phase membrane protein serial femtosecond crystallography | Johansson et al. | 6 |
Jun 2012 | Photosystem II | Structure | 6.6 | Room temperature femtosecond X-ray diffraction of photosystem II microcrystals | Kern et al. | 7 |
Jul 2012 | Lysozyme | Structure | 1.9 | High-resolution protein structure determination by serial femtosecond crystallography | Boutet et al. | 1 |
Nov 2012 | Thermolysin | Data | 4.0 | Nanoflow electrospinning serial femtosecond crystallography | Sierra et al. | 8 |
Jan 2013 | Cathepsin B | Structure | 2.1 | Natively inhibited Trypsanosoma brucei cathepsin B structure determined by using an X-ray laser | Redecke et al. | 9 |
Apr 2013 | Photosystem II | Structure | 5.7 | Simultaneous femtosecond X-ray spectroscopy and diffraction of photosystem II at room temperature | Kern et al. | 10 |
May 2013 | Lysozyme | Structure | 3.2 | Anomalous signal from S atoms in protein crystallographic data from an X-ray free-electron laser | Barends et al. | 11 |
Sept 2013 | Ribosome | Data | <6 | Serial femtosecond X-ray diffraction of 30S ribosomal subunit microcrystals in liquid suspension at ambient temperature using an X-ray free-electron laser | Demirci et al. | 12 |
Dec 2013 | Photosynthetic Reaction Center | Structure | 3.5 | Structure of a photosynthetic reaction center determined by serial femtosecond crystallography | Johansson et al. | 13 |
Dec 2013 | Serotonin receptor | Structure | 2.8 | Serial femtosecond crystallography of G protein-coupled receptors | Liu et al. | 14 |
Jan 2014 | Lysozyme + Gd | Structure | 2.1 | De novo protein crystal structure determination from XFEL data | Barends et al. | 15 |
This study | Cry3A toxin, isolated crystals and whole cells | Structure | 2.8, 2.9 | 2.9 Å-Resolution protein crystal structure obtained from injecting bacterial cells into an X-ray free-electron laser beam | Sawaya et al. | This study |
6.
Iwona Wybranska Malgorzata Malczewska-Malec Lukasz Partyka Beata Kiec-Wilk Katarzyna Kosno Iwona Leszczynska-Golabek Anna Zdzienicka Anna Gruca Malgorzata Kwasniak Aldona Dembinska-Kiec 《Clinical chemistry and laboratory medicine》2007,45(9):1124-1132
BACKGROUND: New tools to identify genotype-phenotype interactions need to be described and implemented. The aim of this study was to identify correlation between the risk originating from gene variation and diet-dependent development of insulin resistance. METHODS: Insulin output in terms of area under the curve after an oral glucose tolerance test (AUC Ins OGTT) and lipid tolerance tests (AUC Ins OLTT) were measured in 167 overweight/obese patients. Estimation of the 18 common gene polymorphisms for obesity risk and standard phenotyping were performed. RESULTS: Insulin output (AUC Ins OGTT) correlated strongly between both insulin treatments across the whole group. However, within the genotype sub-groups, correlation was lower or did not exist. Using a nutrient-induced insulin output ratio (NIOR), calculated as AUC Ins OLTT/AUC Ins OGTT, values ranged from 0.42 to 5.83 and correlated significantly with body mass index (BMI) and leptin, but not with age, gender, waist-to-hip ratio (WHR) and homeostasis model assessment of insulin resistance (HOMA-IR) or plasma adiponectin. High NIOR was found in a subgroup of carriers of rare allelic variants of genes characteristic for poorer tolerance to lipids in the diet. Low NIOR values were found within a sub-group with rare genetic variants regulating carbohydrate metabolism. Thus, the new insulin index NIOR may distinguish gene variant carriers into groups of glucose- or lipid-sensitive phenotypes. CONCLUSIONS: We suggest that the OLTT/OGTT insulin output ratio (NIOR) may be predictive for identifying individuals who are phenotypically susceptible to insulin resistance in response to high fat or carbohydrate in their habitual diet. 相似文献
7.
Pawel Gawlowski Jacek Smereka Marcin Madziala Lukasz Szarpak Michael Frass Oliver Robak 《The American journal of emergency medicine》2017,35(3):484-487
Introduction
Endotracheal intubation (ETI) using a Macintosh laryngoscope (MAC) requires the head to be positioned in a modified Jackson position, slightly reclined and elevated. Intubation of trauma patients with an injured neck or spine is therefore difficult, since the neck usually cannot be turned or is already immobilized in order to prevent further injury. The iGEL supraglottic airway seems optimal for such conditions due to its blind insertion without the need of a modified Jackson position.Methods
Prospective, randomized, crossover study in 46 paramedics. Participants performing standard intubation and blind intubation via iGEL supraglottic airway device in three airway scenarios: Scenario A – normal airway; Scenario B - manual inline cervical immobilization, performed by an independent instructor; scenario C: cervical immobilization using a standard Patriot cervical extraction collar.Results
In Scenario A, nearly all participants performed ETI successfully both with MAC and iGEL (100% vs. 95.7%). The time to intubation (TTI) using the MAC and iGEL amounted to 19 [IQR, 18–21]s vs. 12 [IQR, 11–13]s (P < 0.001). Head extension angle as well as tooth compression were significantly better with the iGEL compared to the MAC (P < 0.001). In scenario B and C, the results with the iGEL were significantly better than with MAC for all analyzed variables (TTI, success of first intubation attempt, head extension angle, tooth compression and VAS scores).Conclusion
We showed that blind intubation with the iGEL supraglottic airway was superior to ETI performed by paramedics in a simulated cervical immobilization scenario in a manikin in terms of success rate, time to definite tube placement, head extension angle, tooth compression, and rating. 相似文献8.
Jacek Smereka Lukasz Szarpak Adam Smereka Steve Leung Kurt Ruetzler 《The American journal of emergency medicine》2017,35(4):604-609
Background
The impact of high-quality chest compressions during CPR for the patients' outcome is undisputed, as it is essential for maintaining vital organ perfusion. The aim of our study is to compare the quality of chest compression (CC) and ventilation among the two current standard techniques with our novel “nTTT” technique in infant CPR.Methods
In this randomized crossover, manikin trial, participants performed CCs using three techniques in a randomized sequence: standard two finger technique (TFT); standard two thumb technique (TTHT), and the ‘new two-thumb technique’ (nTTT). The novel method of CCs in an infant consists in using two thumbs directed at the angle of 90° to the chest while closing the fingers of both hands in a fist.Results
Median depth compression using the distinct chest compression techniques varied and amounted to 26 [IQR, 25–28] mm for TFT, and 39 [IQR, 39–39] mm for TTHT as well as for nTTT. Best percentage of fully released compressions were received using TFT (100[100 ? 100] %), then in the case of nTTT (99[98–100] %), and the worst in situation where TTHT (18[14–19] %). was used. The fastest chest compression rate was achieved with TFT (134[IQR, 129–135]/min) and the slowest when using nTTT (109 [IQR, 105–111]/min).Conclusions
We found that our new nTTT technique's performance, in terms of compression depth, hands-off time, and ventilation quality, is comparable to the current standards. Based on our findings of this initial manikin study, the nTTT technique is superior to TFT in many of parameters that are vital to a quality chest compression during pediatric CPR. 相似文献9.
Marta Pokrywczynska Marzena Anna Lewandowska Sandra Krzyzanowska Arkadiusz Jundzill Marta Rasmus Karolina Warda Maciej Gagat Aleksander Deptula Anna Helmin-Basa Marcin Holysz Maciej Nowacki Lukasz Buchholz Magdalena Bodnar Andrzej Marszalek Alina Grzanka Wojciech Jozwicki Jacek Michalkiewicz Tomasz Drewa 《Archivum immunologiae et therapiae experimentalis》2015,63(5):377-384
10.
Relationship between tumour necrosis factor‐related apoptosis inducing ligand (TRAIL) and vascular endothelial growth factor in human multiple myeloma patients 下载免费PDF全文
Lukasz Bolkun Dorota Lemancewicz Jaroslaw Piszcz Marcin Moniuszko Urszula Bolkun‐Skornicka Malgorzata Szkiladz Ewa Jablonska Janusz Kloczko Janusz Dzieciol 《Hematological oncology》2015,33(4):199-205
Tumour necrosis factor‐alfa (TNF‐α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. Tumour necrosis factor‐related apoptosis inducing ligand (TRAIL), which belongs to the TNF family of proteins, plays a role in the regulation of vascular responses, but its effect on the formation of new blood vessels (angiogenesis) is unclear. We analysed TRAIL concentrations in parallel with pro‐angiogenic cytokines in serum and their expression in trephine biopsy (TB) in 56 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of TRAIL and TNF‐α, as well as of VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. Furthermore, we observed a significant decrease in all studied pro‐angiogenic cytokines and significant increase of TRAIL concentration after anti‐angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with progression during the induction treatment. It was also established that TRAIL correlated statistically and negatively with pro‐angiogenic cytokines such as VEGF with its receptor and expression of VEGF and syndecan‐1 in TB. In summary, our data indicate that in MM patients, both clinical course and treatment responsiveness are associated with dynamic yet corresponding changes of levels of TRAIL parallel pro‐angiogenic mediators such as VEGF with its receptor and expression of VEGF and syndecan‐1 in TB. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献