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421.
Maria Angeles Martinez-Grau Isabel C. Gonzalez Valcarcel Julie V. Early Richard Klaus Gessner Candice Soares de Melo Eva Maria Martin de la Nava Aaron Korkegian Yulia Ovechkina Lindsay Flint Anisa Gravelle Jeff W. Cramer Prashant V. Desai Leslie J. Street Joshua Odingo Thierry Masquelin Kelly Chibale Tanya Parish 《Bioorganic & medicinal chemistry letters》2018,28(10):1758-1764
Despite increased research efforts to find new treatments for tuberculosis in recent decades, compounds with novel mechanisms of action are still required. We previously identified a series of novel aryl-oxadiazoles with anti-tubercular activity specific for bacteria using butyrate as a carbon source. We explored the structure activity relationship of this series. Structural modifications were performed in all domains to improve potency and physico-chemical properties. A number of compounds displayed sub-micromolar activity against M. tuberculosis utilizing butyrate, but not glucose as the carbon source. Compounds showed no or low cytotoxicity against eukaryotic cells. Three compounds were profiled in mouse pharmacokinetic studies. Plasma clearance was low to moderate but oral exposure suggested solubility-limited drug absorption in addition to first pass metabolism. The presence of a basic nitrogen in the linker slightly increased solubility, and salt formation optimized aqueous solubility. Our findings suggest that the 1,3,4-oxadiazoles are useful tools and warrant further investigation. 相似文献
422.
423.
Shomu Bohora Amit Vora Aditya Kapoor Vanita Arora Nitish Naik Raja Selvaraj Narayan Namboodiri Anil Saxena Ajay Naik Balbir Singh C. Narsimhan Mohan Nair T.S. Kler 《Indian pacing and electrophysiology journal》2018,18(6):188-192
Cardiac implantable electronic device (CIED) procedures are being done by many operators/centers and it is projected that this therapy will remarkably increase in India in the coming years. This document by IHRS, aims at guiding the Indian medical community in the appropriate use and method of implantation with emphasis on implanter training and center preparedness to deliver a safe and effective therapy to patients with cardiac rhythm disorders and heart failure. 相似文献
424.
425.
Brian J. Booth Boopathy Ramakrishnan Kristin Narayan Andrew M. Wollacott Gregory J. Babcock Zachary Shriver 《MABS-AUSTIN》2018,10(7):1098-1110
Engineering of antibodies for improved pharmacokinetics through enhanced binding to the neonatal Fc receptor (FcRn) has been demonstrated in transgenic mice, non-human primates and humans. Traditionally, such approaches have largely relied on random mutagenesis and display formats, which fail to address related critical attributes of the antibody, such as effector functions or biophysical stability. We have developed a structure- and network-based framework to interrogate the engagement of IgG with multiple Fc receptors (FcRn, C1q, TRIM21, FcγRI, FcγRIIa/b, FcγRIIIa) simultaneously. Using this framework, we identified features that govern Fc-FcRn interactions and identified multiple distinct pathways for enhancing FcRn binding in a pH-specific manner. Network analysis provided a novel lens to study the allosteric impact of half-life-enhancing Fc mutations on FcγR engagement, which occurs distal to the FcRn binding site. Applying these principles, we engineered a panel of unique Fc variants that enhance FcRn binding while maintaining robust biophysical properties and wild type-like binding to activating receptors. An antibody harboring representative Fc designs demonstrates a half-life improvement of > 9 fold in transgenic mice and > 3.5 fold in cynomolgus monkeys, and maintains robust effector functions such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. 相似文献
426.
Genetic Map of Diploid Wheat, Triticum Monococcum L., and Its Comparison with Maps of Hordeum Vulgare L 总被引:6,自引:0,他引:6 下载免费PDF全文
J. Dubcovsky M. C. Luo G. Y. Zhong R. Bransteitter A. Desai A. Kilian A. Kleinhofs J. Dvorak 《Genetics》1996,143(2):983-999
A genetic map of diploid wheat, Triticum monococcum L., involving 335 markers, including RFLP DNA markers, isozymes, seed storage proteins, rRNA, and morphological loci, is reported. T. monococcum and barley linkage groups are remarkably conserved. They differ by a reciprocal translocation involving the long arms of chromosomes 4 and 5, and paracentric inversions in the long arm of chromosomes 1 and 4; the latter is in a segment of chromosome arm 4L translocated to 5L in T. monococcum. The order of the markers in the inverted segments in the T. monococcum genome is the same as in the B and D genomes of T. aestivum L. The T. monococcum map differs from the barley maps in the distribution of recombination within chromosomes. The major 5S rRNA loci were mapped on the short arms of T. monococcum chromosomes 1 and 5 and the long arms of barley chromosomes 2 and 3. Since these chromosome arms are colinear, the major 5S rRNA loci must be subjected to positional changes in the evolving Triticeae genome that do not perturb chromosome colinearity. The positional changes of the major 5S rRNA loci in Triticeae genomes are analogous to those of the 18S-5.8S-26S rRNA loci. 相似文献
427.
E.B. Stephens S.V. Joag D. Sheffer Z.Q. Liu L. Zhao S. Mukherjee L. Foresman I. Adany Z. Li D. Pinson O. Narayan 《Journal of medical primatology》1996,25(3):175-185
Abstract: In this study, we report on the derivation of a pathogenic SIV-HIV chimeric virus (SHIV) and the initial characterization of the viral sequences from the first (macaque PPc) of a series of pig-tailed macaques that developed CD4+ T cell loss and AIDS. Viral genes were amplified by PCR from the brain, lymphoid, and kidney tissues and their sequences compared to the original SHIV used to initiate passages in macaques. Our results show that the vpu gene, which was nonfunctional in the original SHIV, now coded for functional protein in macaque PPc. The tat and rev genes had no consensus changes but the nef gene had 4–5 consensus changes, depending on the tissue examined. The gp 120 gene had the highest number of nucleotide and amino acid substitution rates that varied from 0.64% to 1.44% and 1.17% to 3.71%, respectively, again depending on the tissue examined. These results suggest that a constellation of changes accumulated at the genomic level during the derivation of a SHIV that was pathogenic for pig-tailed macaques. 相似文献
428.
Narayan Behera 《Bulletin of mathematical biology》1996,58(1):175-202
For a one-locus selection model, Svirezhev introduced an integral variational principle by defining a Lagrangian which remained
stationary on the trajectory followed by the population undergoing selection. It is shown here (i) that this principle can
be extended to multiple loci in some simple cases and (ii) that the Lagrangian is defined by a straightforward generalization
of the one-locus case, but (iii) that in two-locus or more general models there is no straightforward extension of this principle
if linkage and epistasis are present. The population trajectories can be constructed as trajectories of steepest ascent in
a Riemannian metric space. A general method is formulated to find the metric tensor and the surface in the metric space on
which the trajectories, which characterize the variations in the gene structure of the population, lie. The local optimality
principle holds good in such a space. In the special case when all possible linkage disequilibria are zero, the phase point
of then-locus genetic system moves on the surface of the product space ofn higher dimensional unit spheres in a certain Riemannian metric space of gene frequencies so that the rate of change of mean
fitness is maximum along the trajectory. In the two-locus case the corresponding surface is a hyper-torus. 相似文献
429.
Interletrkin-1beta levels are elevated in inflammatory bowel disease. In this study the mechanism by which interleukin-1beta affects electrolyte transport in the rabbit distal colon, was investigated. Interleukin-1beta caused a delayed increase in short-circuit current (I(sc)) which was attributed to protein synthesis since the effect was inhibited by cycloheximide. The interleukin-1beta induced increase in I(sc) was not affected by amiloride treatment but was completely inhibited by bumetanide or in chloride-free buffer and by indomethacin. Prostaglandin E(2) levels increased in tissue treated with interleukin-1beta, but this increase was reversed by cycloheximide. These data suggest that interleukin-1beta causes its effect via a yet to be identified second messenger, by increasing chloride secretion through a prostaglandin E(2) mediated mechanism. 相似文献
430.
Targeting of NH2-terminal–processed Microsomal Protein to Mitochondria: A Novel Pathway for the Biogenesis of Hepatic Mitochondrial P450MT2 下载免费PDF全文
Sankar Addya Hindupur K. Anandatheerthavarada Gopa Biswas Shripad V. Bhagwat Jayati Mullick Narayan G. Avadhani 《The Journal of cell biology》1997,139(3):589-599
Cytochrome P4501A1 is a hepatic, microsomal membrane–bound enzyme that is highly induced by various xenobiotic agents. Two NH2-terminal truncated forms of this P450, termed P450MT2a and MT2b, are also found localized in mitochondria from β-naphthoflavone–induced livers. In this paper, we demonstrate that P4501A1 has a chimeric NH2-terminal signal that facilitates the targeting of the protein to both the ER and mitochondria. The NH2-terminal 30–amino acid stretch of P4501A1 is thought to provide signals for ER membrane insertion and also stop transfer. The present study provides evidence that a sequence motif immediately COOH-terminal (residues 33–44) to the transmembrane domain functions as a mitochondrial targeting signal under both in vivo and in vitro conditions, and that the positively charged residues at positions 34 and 39 are critical for mitochondrial targeting. Results suggest that 25% of P4501A1 nascent chains, which escape ER membrane insertion, are processed by a liver cytosolic endoprotease. We postulate that the NH2-terminal proteolytic cleavage activates a cryptic mitochondrial targeting signal. Immunofluorescence microscopy showed that a portion of transiently expressed P4501A1 is colocalized with the mitochondrial-specific marker protein cytochrome oxidase subunit I. The mitochondrial-associated MT2a and MT2b are localized within the inner membrane compartment, as tested by resistance to limited proteolysis in both intact mitochondria and mitoplasts. Our results therefore describe a novel mechanism whereby proteins with chimeric signal sequence are targeted to the ER as well as to the mitochondria. 相似文献