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61.
Erica S. Rinella Yongzhao Shao Lauren Yackowski Sreemanta Pramanik Ruth Oratz Freya Schnabel Saurav Guha Charles LeDuc Christopher L. Campbell Susan D. Klugman Mary Beth Terry Ruby T. Senie Irene L. Andrulis Mary Daly Esther M. John Daniel Roses Wendy K. Chung Harry Ostrer 《Human genetics》2013,132(5):523-536
The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations. 相似文献
62.
Background and aims
The roots of tussock-forming plants contribute to the formation of microtopographic features in many ecosystems, but the dynamics of such roots are poorly understood. We examined the spatial heterogeneity of tussock fine root dynamics to investigate allocation patterns and the role of root productivity in the persistence of tussock structures.Methods
We compared the spatial variability of fine root (<1 mm, 1–2 mm) density, biomass, % live, allocation, turnover rate (using bomb 14C), and productivity of four Carex stricta Lam.-dominated tussock meadows in the upper Midwest, USA (3 reference, 1 restored site).Results
Relative to underlying microsites, tussocks were warm, dry, and high in root density, productivity, % live biomass, and turnover. Root productivity averaged 649 g?m?2 yr?1 (±208) in reference sites, comprised 57 % (±10) of total net production, and was concentrated in tussocks (70 %?±?4). Root turnover rate averaged 0.63 yr?1 (±0.08), but tussocks had ~50 % faster root turnover than the underlying soil, and <1 mm roots turned over ~40 % faster than 1–2 mm roots.Conclusions
Our detailed analysis of the spatial heterogeneity of tussock root dynamics suggests that high allocation and elevated turnover of tussock roots facilitates organic matter accumulation and tussock persistence over time. 相似文献63.
Seongah Han Taro E. Akiyama Stephen F. Previs Kithsiri Herath Thomas P. Roddy Kristian K. Jensen Hong-Ping Guan Beth A. Murphy Lesley A. McNamara Xun Shen Walter Strapps Brian K. Hubbard Shirly Pinto Cai Li Jing Li 《Journal of lipid research》2013,54(10):2615-2622
Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is a key regulator for glucose homeostasis, antagonizing the glucagon receptor (GCGR) is a possible therapeutic strategy for the treatment of diabetes mellitus. To study the effect of hepatic GCGR inhibition on the regulation of lipid metabolism, we generated siRNA-mediated GCGR knockdown (si-GCGR) in the db/db mouse. The hepatic knockdown of GCGR markedly reduced plasma glucose levels; however, total plasma cholesterol was increased. The detailed lipid analysis showed an increase in the LDL fraction, and no change in VLDL HDL fractions. Further studies showed that the increase in LDL was the result of over-expression of hepatic lipogenic genes and elevated de novo lipid synthesis. Inhibition of hepatic glucagon signaling via siRNA-mediated GCGR knockdown had an effect on both glucose and lipid metabolism in db/db mice. 相似文献
64.
E-Ching Ong Vasyl Nesin Courtney L. Long Chang-Xi Bai Jan L. Guz Ivaylo P. Ivanov Joel Abramowitz Lutz Birnbaumer Mary Beth Humphrey Leonidas Tsiokas 《The Journal of biological chemistry》2013,288(31):22219-22232
Ca2+ signaling is essential for bone homeostasis and skeletal development. Here, we show that the transient receptor potential canonical 1 (TRPC1) channel and the inhibitor of MyoD family, I-mfa, function antagonistically in the regulation of osteoclastogenesis. I-mfa null mice have an osteopenic phenotype characterized by increased osteoclast numbers and surface, which are normalized in mice lacking both Trpc1 and I-mfa. In vitro differentiation of pre-osteoclasts derived from I-mfa-deficient mice leads to an increased number of mature osteoclasts and higher bone resorption per osteoclast. These parameters return to normal levels in osteoclasts derived from double mutant mice. Consistently, whole cell currents activated in response to the depletion of intracellular Ca2+ stores are larger in pre-osteoclasts derived from I-mfa knock-out mice compared with currents in wild type mice and normalized in cells derived from double mutant mice, suggesting a cell-autonomous effect of I-mfa on TRPC1 in these cells. A new splice variant of TRPC1 (TRPC1ϵ) was identified in early pre-osteoclasts. Heterologous expression of TRPC1ϵ in HEK293 cells revealed that it is unique among all known TRPC1 isoforms in its ability to amplify the activity of the Ca2+ release-activated Ca2+ (CRAC) channel, mediating store-operated currents. TRPC1ϵ physically interacts with Orai1, the pore-forming subunit of the CRAC channel, and I-mfa is recruited to the TRPC1ϵ-Orai1 complex through TRPC1ϵ suppressing CRAC channel activity. We propose that the positive and negative modulation of the CRAC channel by TRPC1ϵ and I-mfa, respectively, fine-tunes the dynamic range of the CRAC channel regulating osteoclastogenesis. 相似文献
65.
66.
Mi Young Yang Mary Beth Hilton Steven Seaman Diana C. Haines Kunio Nagashima Christina M. Burks Lino Tessarollo Pavlina T. Ivanova H. Alex Brown Todd M. Umstead Joanna Floros Zissis C. Chroneos Brad St. Croix 《Cell reports》2013,3(5):1457-1464
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67.
Dukgyu Lee Tatsujiro Oka Beth Hunter Alison Robinson Sylvia Papp Kimitoshi Nakamura Wattamon Srisakuldee Barbara E. Nickel Peter E. Light Jason R. B. Dyck Gary D. Lopaschuk Elissavet Kardami Michal Opas Marek Michalak 《PloS one》2013,8(2)
Background
Calreticulin, a Ca2+-buffering chaperone of the endoplasmic reticulum, is highly expressed in the embryonic heart and is essential for cardiac development. After birth, the calreticulin gene is sharply down regulated in the heart, and thus, adult hearts have negligible levels of calreticulin. In this study we tested the role of calreticulin in the adult heart.Methodology/Principal Findings
We generated an inducible transgenic mouse in which calreticulin is targeted to the cardiac tissue using a Cre/loxP system and can be up-regulated in adult hearts. Echocardiography analysis of hearts from transgenic mice expressing calreticulin revealed impaired left ventricular systolic and diastolic function and impaired mitral valve function. There was altered expression of Ca2+ signaling molecules and the gap junction proteins, Connexin 43 and 45. Sarcoplasmic reticulum associated Ca2+-handling proteins (including the cardiac ryanodine receptor, sarco/endoplasmic reticulum Ca2+-ATPase, and cardiac calsequestrin) were down-regulated in the transgenic hearts with increased expression of calreticulin.Conclusions/Significance
We show that in adult heart, up-regulated expression of calreticulin induces cardiomyopathy in vivo leading to heart failure. This is due to an alternation in changes in a subset of Ca2+ handling genes, gap junction components and left ventricle remodeling. 相似文献68.
Facilitated long chain fatty acid uptake by adipocytes remains upregulated relative to BMI for more than a year after major bariatric surgical weight loss
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Fengxia Ge José L. Walewski Mehyar Hefazi Torghabeh Harrison Lobdell IV Chunguang Hu Shengli Zhou Gregory Dakin Alfons Pomp Marc Bessler Beth Schrope Aku Ude‐Welcome William B. Inabnet Tianshu Feng Elektra Carras‐Terzian Dieunine Anglade Faith E. Ebel Paul D. Berk 《Obesity (Silver Spring, Md.)》2016,24(1):113-122
69.
Sexual reproduction in plants requires development of haploid gametophytes from somatic tissues. Pollen is the male gametophyte and develops within the stamen; defects in the somatic tissues of the stamen and in the male gametophyte itself can result in male sterility. The maize fuzzy tassel (fzt) mutant has a mutation in dicer-like1 (dcl1), which encodes a key enzyme required for microRNA (miRNA) biogenesis. Many miRNAs are reduced in fzt, and fzt mutants exhibit a broad range of developmental defects, including male sterility. To gain further insight into the roles of miRNAs in maize stamen development, we conducted a detailed analysis of the male sterility defects in fzt mutants. Early development was normal in fzt mutant anthers, however fzt anthers arrested in late stages of anther maturation and did not dehisce. A minority of locules in fzt anthers also exhibited anther wall defects. At maturity, very little pollen in fzt anthers was viable or able to germinate. Normal pollen is tricellular at maturity; pollen from fzt anthers included a mixture of unicellular, bicellular, and tricellular pollen. Pollen from normal anthers is loaded with starch before dehiscence, however pollen from fzt anthers failed to accumulate starch. Our results indicate an absolute requirement for miRNAs in the final stages of anther and pollen maturation in maize. Anther wall defects also suggest that miRNAs have key roles earlier in anther development. We discuss candidate miRNAs and pathways that might underlie fzt anther defects, and also note that male sterility in fzt resembles water deficit-induced male sterility, highlighting a possible link between development and stress responses in plants. 相似文献
70.