全文获取类型
收费全文 | 712篇 |
免费 | 55篇 |
出版年
2023年 | 5篇 |
2022年 | 8篇 |
2021年 | 16篇 |
2020年 | 10篇 |
2019年 | 15篇 |
2018年 | 20篇 |
2017年 | 26篇 |
2016年 | 25篇 |
2015年 | 23篇 |
2014年 | 32篇 |
2013年 | 53篇 |
2012年 | 49篇 |
2011年 | 41篇 |
2010年 | 37篇 |
2009年 | 26篇 |
2008年 | 40篇 |
2007年 | 30篇 |
2006年 | 40篇 |
2005年 | 37篇 |
2004年 | 31篇 |
2003年 | 22篇 |
2002年 | 15篇 |
2001年 | 10篇 |
2000年 | 14篇 |
1999年 | 16篇 |
1998年 | 9篇 |
1997年 | 9篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1993年 | 3篇 |
1992年 | 9篇 |
1991年 | 5篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1983年 | 7篇 |
1981年 | 5篇 |
1980年 | 3篇 |
1979年 | 3篇 |
1978年 | 4篇 |
1977年 | 3篇 |
1975年 | 4篇 |
1974年 | 2篇 |
1972年 | 2篇 |
1971年 | 2篇 |
1970年 | 3篇 |
1967年 | 2篇 |
排序方式: 共有767条查询结果,搜索用时 15 毫秒
151.
Barbara A. Miller Nicholas E. Hoffman Salim Merali Xue-Qian Zhang JuFang Wang Sudarsan Rajan Santhanam Shanmughapriya Erhe Gao Carlos A. Barrero Karthik Mallilankaraman Jianliang Song Tongda Gu Iwona Hirschler-Laszkiewicz Walter J. Koch Arthur M. Feldman Muniswamy Madesh Joseph Y. Cheung 《The Journal of biological chemistry》2014,289(11):7615-7629
Cardiac TRPM2 channels were activated by intracellular adenosine diphosphate-ribose and blocked by flufenamic acid. In adult cardiac myocytes the ratio of GCa to GNa of TRPM2 channels was 0.56 ± 0.02. To explore the cellular mechanisms by which TRPM2 channels protect against cardiac ischemia/reperfusion (I/R) injury, we analyzed proteomes from WT and TRPM2 KO hearts subjected to I/R. The canonical pathways that exhibited the largest difference between WT-I/R and KO-I/R hearts were mitochondrial dysfunction and the tricarboxylic acid cycle. Complexes I, III, and IV were down-regulated, whereas complexes II and V were up-regulated in KO-I/R compared with WT-I/R hearts. Western blots confirmed reduced expression of the Complex I subunit and other mitochondria-associated proteins in KO-I/R hearts. Bioenergetic analyses revealed that KO myocytes had a lower mitochondrial membrane potential, mitochondrial Ca2+ uptake, ATP levels, and O2 consumption but higher mitochondrial superoxide levels. Additionally, mitochondrial Ca2+ uniporter (MCU) currents were lower in KO myocytes, indicating reduced mitochondrial Ca2+ uptake was likely due to both lower ψm and MCU activity. Similar to isolated myocytes, O2 consumption and ATP levels were also reduced in KO hearts. Under a simulated I/R model, aberrant mitochondrial bioenergetics was exacerbated in KO myocytes. Reactive oxygen species levels were also significantly higher in KO-I/R compared with WT-I/R heart slices, consistent with mitochondrial dysfunction in KO-I/R hearts. We conclude that TRPM2 channels protect the heart from I/R injury by ameliorating mitochondrial dysfunction and reducing reactive oxygen species levels. 相似文献
152.
Namthip Witayavanitkul Younss Ait Mou Diederik W. D. Kuster Ramzi J. Khairallah Jason Sarkey Suresh Govindan Xin Chen Ying Ge Sudarsan Rajan David F. Wieczorek Thomas Irving Margaret V. Westfall Pieter P. de Tombe Sakthivel Sadayappan 《The Journal of biological chemistry》2014,289(13):8818-8827
Myocardial infarction (MI) is associated with depressed cardiac contractile function and progression to heart failure. Cardiac myosin-binding protein C, a cardiac-specific myofilament protein, is proteolyzed post-MI in humans, which results in an N-terminal fragment, C0-C1f. The presence of C0-C1f in cultured cardiomyocytes results in decreased Ca2+ transients and cell shortening, abnormalities sufficient for the induction of heart failure in a mouse model. However, the underlying mechanisms remain unclear. Here, we investigate the association between C0-C1f and altered contractility in human cardiac myofilaments in vitro. To accomplish this, we generated recombinant human C0-C1f (hC0C1f) and incorporated it into permeabilized human left ventricular myocardium. Mechanical properties were studied at short (2 μm) and long (2.3 μm) sarcomere length (SL). Our data demonstrate that the presence of hC0C1f in the sarcomere had the greatest effect at short, but not long, SL, decreasing maximal force and myofilament Ca2+ sensitivity. Moreover, hC0C1f led to increased cooperative activation, cross-bridge cycling kinetics, and tension cost, with greater effects at short SL. We further established that the effects of hC0C1f occur through direct interaction with actin and α-tropomyosin. Our data demonstrate that the presence of hC0C1f in the sarcomere is sufficient to induce depressed myofilament function and Ca2+ sensitivity in otherwise healthy human donor myocardium. Decreased cardiac function post-MI may result, in part, from the ability of hC0C1f to bind actin and α-tropomyosin, suggesting that cleaved C0-C1f could act as a poison polypeptide and disrupt the interaction of native cardiac myosin-binding protein C with the thin filament. 相似文献
153.
Rivka Colen Ian Foster Robert Gatenby Mary Ellen Giger Robert Gillies David Gutman Matthew Heller Rajan Jain Anant Madabhushi Subha Madhavan Sandy Napel Arvind Rao Joel Saltz James Tatum Roeland Verhaak Gary Whitman 《Translational oncology》2014,7(5):556-569
The National Cancer Institute (NCI) Cancer Imaging Program organized two related workshops on June 26–27, 2013, entitled “Correlating Imaging Phenotypes with Genomics Signatures Research” and “Scalable Computational Resources as Required for Imaging-Genomics Decision Support Systems.” The first workshop focused on clinical and scientific requirements, exploring our knowledge of phenotypic characteristics of cancer biological properties to determine whether the field is sufficiently advanced to correlate with imaging phenotypes that underpin genomics and clinical outcomes, and exploring new scientific methods to extract phenotypic features from medical images and relate them to genomics analyses. The second workshop focused on computational methods that explore informatics and computational requirements to extract phenotypic features from medical images and relate them to genomics analyses and improve the accessibility and speed of dissemination of existing NIH resources. These workshops linked clinical and scientific requirements of currently known phenotypic and genotypic cancer biology characteristics with imaging phenotypes that underpin genomics and clinical outcomes. The group generated a set of recommendations to NCI leadership and the research community that encourage and support development of the emerging radiogenomics research field to address short-and longer-term goals in cancer research. 相似文献
154.
Ashna Rajan Ganesh Keshav Thirunavukkarasu Richard F. Lockey Narasaiah Kolliputi 《Journal of cell communication and signaling》2022,16(1):1
The pathophysiology of COVID-19 is an enigma with its severity often determined by the extent of coagulopathy. Several regulatory pathways targeted by the SARS-CoV-2 include the renin-angiotensin system, von Willebrand Factor, and most importantly, the complement pathway. This article discusses these pathways to help design potential future therapies. 相似文献
155.
Thiruchandurai Rajan, Julie Moore and Leonard Shultz here review the evolution of technology in murine xeno-lymphohemopoietic chimeras, produced by engraftment with xenogeneic (fetal or adult) progenitor cells or mature lymphohemopoietic tissues into immunodeficient mice, and their use as hosts for hemoprotozoan parasites. Particular attention is paid to the development of chimeras that house xenogeneic peripheral red blood cells (xeno-RBC). These chimeras are potentially invaluable models for hemoprotozoan parasites, such as Babesia and Plasmodium. There are, however, daunting limitations that have to be overcome before these models can become universally acceptable systems for the study of these parasitic agents. 相似文献
156.
Rajan Prasad Paudel Rabin Kadariya Babu Ram Lamichhane Naresh Subedi Mariko Sashika Michito Shimozuru Toshio Tsubota 《Ecology and evolution》2022,12(3)
Mammals have experienced a massive decline in their populations and geographic ranges worldwide. The sloth bear, Melursus ursinus (Shaw, 1791), is one of many species facing conservation threats. Despite being endangered in Nepal, decades of inattention to the situation have hindered their conservation and management. We assessed the distribution and patterns of habitat use by sloth bears in Chitwan National Park (CNP), Nepal. We conducted sign surveys from March to June, 2020, in 4 × 4 km grids (n = 45). We collected detection/non‐detection data along a 4‐km trail that was divided into 20 continuous segments of 200 m each. We obtained environmental, ecological, and anthropogenic covariates to understand determinants of sloth bear habitat occupancy. The data were analyzed using the single‐species single‐season occupancy method, with a spatially correlated detection. Using repeated observations, these models accounted for the imperfect detectability of the species to provide robust estimates of habitat occupancy. The model‐averaged occupancy estimate for the sloth bear was 69% and the detection probability was 0.25. The probability of habitat occupancy by sloth bears increased with the presence of termites and fruits and in rugged, dry, open, undisturbed habitats. Our results indicate that the sloth bear is elusive, functionally unique, and widespread in CNP. Future conservation interventions and action plans aimed at sloth bear management must adequately consider their habitat requirements. 相似文献
157.
ABSTRACT: Large-scale sequencing of genomes has enabled the inference of phylogenies based on the evolution of genomic architecture, under such events as rearrangements, duplications, and losses. Many evolutionary models and associated algorithms have been designed over the last few years and have found use in comparative genomics and phylogenetic inference. However, the assessment of phylogenies built from such data has not been properly addressed to date. The standard method used in sequence-based phylogenetic inference is the bootstrap, but it relies on a large number of homologous characters that can be resampled; yet in the case of rearrangements, the entire genome is a single character. Alternatives such as the jackknife suffer from the same problem, while likelihood tests cannot be applied in the absence of well established probabilistic models. We present a new approach to the assessment of distance-based phylogenetic inference from whole-genome data; our approach combines features of the jackknife and the bootstrap and remains nonparametric. For each feature of our method, we give an equivalent feature in the sequence-based framework; we also present the results of extensive experimental testing, in both sequence-based and genome-based frameworks. Through the feature-by-feature comparison and the experimental results, we show that our bootstrapping approach is on par with the classic phylogenetic bootstrap used in sequence-based reconstruction, and we establish the clear superiority of the classic bootstrap for sequence data and of our corresponding new approach for rearrangement data over proposed variants. Finally, we test our approach on a small dataset of mammalian genomes, verifying that the support values match current thinking about the respective branches. Our method is the first to provide a standard of assessment to match that of the classic phylogenetic bootstrap for aligned sequences. Its support values follow a similar scale and its receiver-operating characteristics are nearly identical, indicating that it provides similar levels of sensitivity and specificity. Thus our assessment method makes it possible to conduct phylogenetic analyses on whole genomes with the same degree of confidence as for analyses on aligned sequences. Extensions to search-based inference methods such as maximum parsimony and maximum likelihood are possible, but remain to be thoroughly tested. 相似文献
158.
Cellular retinol-binding protein messenger RNA levels in normal and retinoid-deficient rats 总被引:1,自引:0,他引:1
A study was conducted to determine the levels of cellular retinol-binding protein (CRBP) mRNA and protein in various tissues of the rat, to explore relationship between CRBP mRNA and protein levels in different tissues, and to examine the effects of changes in retinol nutritional status on the tissue distribution and levels of CRBP mRNA. Previous studies have shown that tissue CRBP protein levels are reduced in totally retinoid-deficient rats, but are otherwise minimally affected by changes in retinoid status. Three groups of male rats were compared: normal controls, retinoid-deficient, and retinol-repleted deficient rats. CRBP mRNA levels were measured by RNase protection assay and CRBP protein levels by radioimmunoassay in seven tissues. High levels of both CRBP mRNA and CRBP protein were found in the proximal epididymis, kidney, and liver; lower levels were seen in lung, testis, spleen, and small intestine. Tissue CRBP mRNA and protein levels were highly correlated (P less than 0.01) with each other. Retinoid deficiency did not alter the levels of CRBP mRNA found in the proximal epididymis, kidney, and liver. In contrast, CRBP mRNA levels in the lung, testis, spleen, and small intestine were reduced substantially in retinoid-deficient rats, to values that were only 23% to 50% of the corresponding values in the tissues of control rats. After oral repletion with retinol (4-18 h earlier), CRBP mRNA levels for these latter four tissues were found to have risen to control or near-control levels. The suggestion is raised that retinol repletion may have directly induced the expression of the CRBP gene in these particular tissues.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
159.
160.
L Aguilar-Bryan C G Nichols A S Rajan C Parker J Bryan 《The Journal of biological chemistry》1992,267(21):14934-14940
Cell membranes isolated from hamster insulinoma (HIT T15) cells at passages 65-74 contain high and low affinity receptors for a sulfonylurea derivative, 5-[125I]iodo,2-hydroxyglyburide (KD values of approximately 7 nM and 16 microM). Between passages 75 and 85, the estimated B(max) for the high affinity receptor decreases approximately 10-fold from approximately 1.6 to 0.16 pmol/mg membrane protein. By contrast, the density of low affinity binding sites, 800-1000 pmol/mg, is unaltered. The drop in high affinity receptors is paralleled by a decrease in the density of KATP channels assessed using patch-clamp and 86Rb(+)-efflux techniques. These results strongly support the idea that the high affinity sulfonylurea receptor is an integral part of the KATP channel. 相似文献