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81.
Batool Shannan Quan Chen Andrea Watters Michela Perego Clemens Krepler Rakhee Thombre Ling Li Geena Rajan Scott Peterson Phyllis A. Gimotty Melissa Wilson Katherine L. Nathanson Tara C. Gangadhar Lynn M. Schuchter Ashani T. Weeraratna Meenhard Herlyn Adina Vultur 《Pigment cell & melanoma research》2016,29(3):317-328
Targeted therapies for mutant BRAF metastatic melanoma are effective but not curative due to acquisition of resistance. PI3K signaling is a common mediator of therapy resistance in melanoma; thus, the need for effective PI3K inhibitors is critical. However, testing PI3K inhibitors in adherent cultures is not always reflective of their potential in vivo. To emphasize this, we compared PI3K inhibitors of different specificity in two‐ and three‐dimensional (2D, 3D) melanoma models and show that drug response predictions gain from evaluation using 3D models. Our results in 3D demonstrate the anti‐invasive potential of PI3K inhibitors and that drugs such as PX‐866 have beneficial activity in physiological models alone and when combined with BRAF inhibition. These assays finally help highlight pathway effectors that could be involved in drug response in different environments (e.g. p4E‐BP1). Our findings show the advantages of 3D melanoma models to enhance our understanding of PI3K inhibitors. 相似文献
82.
Kirsten S. Evonuk Carson E. Moseley Ryan E. Doyle Casey T. Weaver Tara M. DeSilva 《Journal of visualized experiments : JoVE》2016,(115)
A major hallmark of the autoimmune demyelinating disease multiple sclerosis (MS) is immune cell infiltration into the brain and spinal cord resulting in myelin destruction, which not only slows conduction of nerve impulses, but causes axonal injury resulting in motor and cognitive decline. Current treatments for MS focus on attenuating immune cell infiltration into the central nervous system (CNS). These treatments decrease the number of relapses, improving quality of life, but do not completely eliminate relapses so long-term disability is not improved. Therefore, therapeutic agents that protect the CNS are warranted. In both animal models as well as human patients with MS, T cell entry into the CNS is generally considered the initiating inflammatory event. In order to assess if a drug protects the CNS, any potential effects on immune cell infiltration or proliferation in the periphery must be ruled out. This protocol describes how to determine whether CNS protection observed after drug intervention is a consequence of attenuating CNS-infiltrating immune cells or blocking death of CNS cells during inflammatory insults. The ability to examine MS treatments that are protective to the CNS during inflammatory insults is highly critical for the advancement of therapeutic strategies since current treatments reduce, but do not completely eliminate, relapses (i.e., immune cell infiltration), leaving the CNS vulnerable to degeneration. 相似文献
83.
Platon Eliseev Grigory Balantcev Elena Nikishova Anastasia Gaida Elena Bogdanova Donald Enarson Tara Ornstein Anne Detjen Russell Dacombe Elena Gospodarevskaya Patrick P. J. Phillips Gillian Mann Stephen Bertel Squire Andrei Mariandyshev 《PloS one》2016,11(4)
BackgroundIn the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy.MethodsA culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm.ResultsAmong smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms.ConclusionThe results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics. 相似文献
84.
Relationships Between Adult Male and Maturing Mountain Gorillas (Gorilla beringei beringei) Persist Across Developmental Stages and Social Upheaval 下载免费PDF全文
Stacy Rosenbaum Jean Paul Hirwa Joan B. Silk Tara S. Stoinski 《Ethology : formerly Zeitschrift fur Tierpsychologie》2016,122(2):134-150
Across the animal kingdom, long‐term social relationships outside the context of reproductive pair bonds are rare. However, they have been demonstrated in some mammals including primates, cetaceans, and social carnivores. The ontogeny of such relationships is likely to depend on the benefits individuals can gain by cultivating them. Previous studies demonstrated that young mountain gorillas (Gorilla beringei beringei) have strong relationships with adult males, but little is known about the longevity of these bonds. Here, we examine the temporal stability of proximity relationships between coresident adult male and maturing gorillas in the habituated population monitored by the Dian Fossey Gorilla Fund International's Karisoke Research Center in Volcanoes National Park, Rwanda. We used spatial proximity data to assess the strength of relationships between adult males and juveniles, and tracked these relationships as the juveniles matured into subadults (3–4 yr later; n = 229 dyads) and then young adults (7 yr later; n = 42 dyads). The proximity relationships of juveniles of both sexes predicted their proximity relationships with adult males in both subadulthood and young adulthood. However some young adult males who had lost their top adult male proximity partner from juvenilehood developed new relationships with older males that had risen in the dominance hierarchy. These data suggest that (1) kin selection may play a more important role in social relationships between potential fathers and adult female offspring than previously suspected, and (2) when maturing males' foremost adult male social partners remain available to them, their relationships can be stable past the age at which younger males become reproductive competitors. 相似文献
85.
Kumar Abhiram Jha Tapas C Nag Shashi Wadhwa Tara Sankar Roy 《Journal of biosciences》2016,41(4):667-676
Light causes damage to the retina, which is one of the supposed factors for age-related macular degeneration in human. Some animal species show drastic retinal changes when exposed to intense light (e.g. albino rats). Although birds have a pigmented retina, few reports indicated its susceptibility to light damage. To know how light influences a cone-dominated retina (as is the case with human), we examined the effects of moderate light intensity on the retina of white Leghorn chicks (Gallus g. domesticus). The newly hatched chicks were initially acclimatized at 500 lux for 7 days in 12 h light: 12 h dark cycles (12L:12D). From posthatch day (PH) 8 until PH 30, they were exposed to 2000 lux at 12L:12D, 18L:6D (prolonged light) and 24L:0D (constant light) conditions. The retinas were processed for transmission electron microscopy and the level of expressions of rhodopsin, S- and L/M cone opsins, and synaptic proteins (Synaptophysin and PSD-95) were determined by immunohistochemistry and Western blotting. Rearing in 24L:0D condition caused disorganization of photoreceptor outer segments. Consequently, there were significantly decreased expressions of opsins and synaptic proteins, compared to those seen in 12L:12D and 18L:6D conditions. Also, there were ultrastructural changes in outer and inner plexiform layer (OPL, IPL) of the retinas exposed to 24L:0D condition. Our data indicate that the cone-dominated chick retina is affected in constant light condition, with changes (decreased) in opsin levels. Also, photoreceptor alterations lead to an overall decrease in synaptic protein expressions in OPL and IPL and death of degenerated axonal processes in IPL. 相似文献
86.
During 1999 through 2014, retained placenta was the most common cause of clinical admission for reproductive complications in breeding colonies of baboons (approximate colony size, 2000 animals), cynomolgus macaques (approximately 1000), and rhesus macaques (approximately 500) at the Southwest National Primate Research Center. Retained placentas occurred in 2.7% of baboons, 3.3% of cynomolgus macaques, and 1.0% of rhesus macaques. Apparent risk factors for retained placenta included stillbirth or abortion and at least one prior cesarean section. There was a significant association between stillbirth and retained placenta in all species. Cesarean sections were performed routinely for baboons to meet research objectives but occurred only as needed for cynomolgus and rhesus macaques. Having had at least one prior cesarean section was an incidence factor for retained placenta in 37.0% of baboons and 4.7% of cynomolgus macaques; none of the rhesus macaques with retained placentas had undergone cesarean section previously. More than 90% of dams with retained placenta returned to a successful reproductive life or assignment to a nonbreeding research protocol. Advances in reproductive management will benefit from prospective studies that capture additional data from all members of a breeding group prior to reproductive complications.Abbreviations: Southwest National Primate Research Center (SNPRC), retained placenta (RP), cesarean section (C-section)Retained placentas and other reproductive problems are unavoidable complications encountered in association with NHP production colonies and are difficult to diagnose, because most births occur at night, when human observation is minimal, and because the dams routinely consume the placenta.41,44,45 There is extensive information regarding retained placentas in dairy cattle,7,25,20 and humans,3,13,24,35,36,40 but little is documented about this problem''s health hazard and effect on future reproduction in NHP,16,17,23,49 with 3 documented cases reported as isolated reports between 1991 and 2009.16,17,23 The first documented case of a retained placenta in a NHP was that of a female chimpanzee (Pan troglodytes).17 Clinical signs for that case included depression, poor maternal care, and vaginal hemorrhage 1 wk after delivery. The chimpanzee was treated successfully, and the infant was returned to the dam with no further complications. Another documented case involved a golden lion tamarin (Leontopithecus rosalia),16 which had experienced prolonged labor resulting in a stillbirth. After continued placental retention, the tamarin was hysterectomized. Histopathologic evaluation revealed that placental infiltration into the myometrium was the cause of retention.16 The third documented case occurred in a bonobo (Pan paniscus) housed in a sanctuary in the Democratic Republic of Congo.23 The animal was treated with oxytocin injections; after manual removal of the placenta, the dam and infant were reunited, and maternal recovery was uneventful.In addition, in an unpublished case, one of the current authors (TH) treated a mandrill (Mandrillus sphinx) by using oxytocin injection and manual removal of the placenta, after which the dam and infant were reunited, and maternal recovery was uneventful. Several other unpublished cases documented in the medical records of the breeding colonies at the Southwest National Primate Research Center (SNPRC) involved species baboons (Papio spp.), cynomolgus macaques (Macaca fascicularis), and rhesus macaques (Macaca mulatta). Clinical veterinarians had deemed all of these animals to be healthy prior to their placement into breeding groups and were rechecked semiannually concurrent with tuberculin testing. Body condition varied from lean to obese, but body condition score was not recorded. We retrospectively reviewed these records to determine the risk factors and incidence of retained placenta within the 3 NHP colonies over 15 y. 相似文献
87.
88.
Hyojung Cha George Fish Joel Luke Ahmad Alraddadi Hyun Hwi Lee Weimin Zhang Yifan Dong Saurav Limbu Andrew Wadsworth Iuliana P. Maria Laia Francs Hou Lon Sou Tian Du Ji‐Seon Kim Martyn A. McLachlan Iain McCulloch James R. Durrant 《Liver Transplantation》2019,9(27)
Here, it is investigated whether an energetic cascade between mixed and pure regions assists in suppressing recombination losses in non‐fullerene acceptor (NFA)‐based organic solar cells. The impact of polymer‐NFA blend composition upon morphology, energetics, charge carrier recombination kinetics, and photocurrent properties are studied. By changing film composition, morphological structures are varied from consisting of highly intermixed polymer‐NFA phases to consisting of both intermixed and pure phase. Cyclic voltammetry is employed to investigate the impact of blend morphology upon NFA lowest unoccupied molecular orbital (LUMO) level energetics. Transient absorption spectroscopy reveals the importance of an energetic cascade between mixed and pure phases in the electron–hole dynamics in order to well separate spatially localized electron–hole pairs. Raman spectroscopy is used to investigate the origin of energetic shift of NFA LUMO levels. It appears that the increase in NFA electron affinity in pure phases relative to mixed phases is correlated with a transition from a relatively planar backbone structure of NFA in pure, aggregated phases, to a more twisted structure in molecularly mixed phases. The studies focus on addressing whether aggregation‐dependent acceptor LUMO level energetics are a general design requirement for both fullerene and NFAs, and quantifying the magnitude, origin, and impact of such energetic shifts upon device performance. 相似文献
89.
Jeffrey E. Stenzel Kristina J. Bartowitz Melannie D. Hartman James A. Lutz Crystal A. Kolden Alistair M. S. Smith Beverly E. Law Mark E. Swanson Andrew J. Larson William J. Parton Tara W. Hudiburg 《Global Change Biology》2019,25(11):3985-3994
Wildfire is an essential earth‐system process, impacting ecosystem processes and the carbon cycle. Forest fires are becoming more frequent and severe, yet gaps exist in the modeling of fire on vegetation and carbon dynamics. Strategies for reducing carbon dioxide (CO2) emissions from wildfires include increasing tree harvest, largely based on the public assumption that fires burn live forests to the ground, despite observations indicating that less than 5% of mature tree biomass is actually consumed. This misconception is also reflected though excessive combustion of live trees in models. Here, we show that regional emissions estimates using widely implemented combustion coefficients are 59%–83% higher than emissions based on field observations. Using unique field datasets from before and after wildfires and an improved ecosystem model, we provide strong evidence that these large overestimates can be reduced by using realistic biomass combustion factors and by accurately quantifying biomass in standing dead trees that decompose over decades to centuries after fire (“snags”). Most model development focuses on area burned; our results reveal that accurately representing combustion is also essential for quantifying fire impacts on ecosystems. Using our improvements, we find that western US forest fires have emitted 851 ± 228 Tg CO2 (~half of alternative estimates) over the last 17 years, which is minor compared to 16,200 Tg CO2 from fossil fuels across the region. 相似文献
90.
Zachariah Gompert Megan Brady Farzaneh Chalyavi Tara C. Saley Casey S. Philbin Matthew J. Tucker Matthew L. Forister Lauren K. Lucas 《Molecular ecology》2019,28(12):2967-2985
Plant–insect interactions are ubiquitous, and have been studied intensely because of their relevance to damage and pollination in agricultural plants, and to the ecology and evolution of biodiversity. Variation within species can affect the outcome of these interactions. Specific genes and chemicals that mediate these interactions have been identified, but genome‐ or metabolome‐scale studies might be necessary to better understand the ecological and evolutionary consequences of intraspecific variation for plant–insect interactions. Here, we present such a study. Specifically, we assess the consequences of genome‐wide genetic variation in the model plant Medicago truncatula for Lycaeides melissa caterpillar growth and survival (larval performance). Using a rearing experiment and a whole‐genome SNP data set (>5 million SNPs), we found that polygenic variation in M. truncatula explains 9%–41% of the observed variation in caterpillar growth and survival. Genetic correlations among caterpillar performance and other plant traits, including structural defences and some anonymous chemical features, suggest that multiple M. truncatula alleles have pleiotropic effects on plant traits and caterpillar performance (or that substantial linkage disequilibrium exists among distinct loci affecting subsets of these traits). A moderate proportion of the genetic effect of M. truncatula alleles on L. melissa performance can be explained by the effect of these alleles on the plant traits we measured, especially leaf toughness. Taken together, our results show that intraspecific genetic variation in M. truncatula has a substantial effect on the successful development of L. melissa caterpillars (i.e., on a plant–insect interaction), and further point toward traits potentially mediating this genetic effect. 相似文献