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141.
Gloria Omosa-Manyonyi Juliet Mpendo Eugene Ruzagira William Kilembe Elwyn Chomba Fran?ois Roman Patricia Bourguignon Marguerite Koutsoukos Alix Collard Gerald Voss Dagna Laufer Gwynn Stevens Peter Hayes Lorna Clark Emmanuel Cormier Len Dally Burc Barin Jim Ackland Kristen Syvertsen Devika Zachariah Kamaal Anas Eddy Sayeed Angela Lombardo Jill Gilmour Josephine Cox Patricia Fast Frances Priddy 《PloS one》2015,10(5)
Background
Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses.Methods
In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured.Results
The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration.Conclusion
Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses.Trial Registration
ClinicalTrials.gov NCT01264445 相似文献142.
Andrea L. Ciaranello Landon Myer Kathleen Kelly Sarah Christensen Kristen Daskilewicz Katie Doherty Linda-Gail Bekker Taige Hou Robin Wood Jordan A. Francke Kara Wools-Kaloustian Kenneth A. Freedberg Rochelle P. Walensky 《PloS one》2015,10(3)
Background
Many prevention of mother-to-child HIV transmission (PMTCT) programs currently prioritize antiretroviral therapy (ART) for women with advanced HIV. Point-of-care (POC) CD4 assays may expedite the selection of three-drug ART instead of zidovudine, but are costlier than traditional laboratory assays.Methods
We used validated models of HIV infection to simulate pregnant, HIV-infected women (mean age 26 years, gestational age 26 weeks) in a general antenatal clinic in South Africa, and their infants. We examined two strategies for CD4 testing after HIV diagnosis: laboratory (test rate: 96%, result-return rate: 87%, cost: $14) and POC (test rate: 99%, result-return rate: 95%, cost: $26). We modeled South African PMTCT guidelines during the study period (WHO “Option A”): antenatal zidovudine (CD4 ≤350/μL) or ART (CD4>350/μL). Outcomes included MTCT risk at weaning (age 6 months), maternal and pediatric life expectancy (LE), maternal and pediatric lifetime healthcare costs (2013 USD), and cost-effectiveness ($/life-year saved).Results
In the base case, laboratory led to projected MTCT risks of 5.7%, undiscounted pediatric LE of 53.2 years, and undiscounted PMTCT plus pediatric lifetime costs of $1,070/infant. POC led to lower modeled MTCT risk (5.3%), greater pediatric LE (53.4 years) and lower PMTCT plus pediatric lifetime costs ($1,040/infant). Maternal outcomes following laboratory were similar to POC (LE: 21.2 years; lifetime costs: $23,860/person). Compared to laboratory, POC improved clinical outcomes and reduced healthcare costs.Conclusions
In antenatal clinics implementing Option A, the higher initial cost of a one-time POC CD4 assay will be offset by cost-savings from prevention of pediatric HIV infection. 相似文献143.
144.
Kristen E. Rennoll-Bankert M. Sayeedur Rahman Joseph J. Gillespie Mark L. Guillotte Simran J. Kaur Stephanie S. Lehman Magda Beier-Sexton Abdu F. Azad 《PLoS pathogens》2015,11(8)
Bacterial Sec7-domain-containing proteins (RalF) are known only from species of Legionella and Rickettsia, which have facultative and obligate intracellular lifestyles, respectively. L. pneumophila RalF, a type IV secretion system (T4SS) effector, is a guanine nucleotide exchange factor (GEF) of ADP-ribosylation factors (Arfs), activating and recruiting host Arf1 to the Legionella-containing vacuole. In contrast, previous in vitro studies showed R. prowazekii (Typhus Group) RalF is a functional Arf-GEF that localizes to the host plasma membrane and interacts with the actin cytoskeleton via a unique C-terminal domain. As RalF is differentially encoded across Rickettsia species (e.g., pseudogenized in all Spotted Fever Group species), it may function in lineage-specific biology and pathogenicity. Herein, we demonstrate RalF of R. typhi (Typhus Group) interacts with the Rickettsia T4SS coupling protein (RvhD4) via its proximal C-terminal sequence. RalF is expressed early during infection, with its inactivation via antibody blocking significantly reducing R. typhi host cell invasion. For R. typhi and R. felis (Transitional Group), RalF ectopic expression revealed subcellular localization with the host plasma membrane and actin cytoskeleton. Remarkably, R. bellii (Ancestral Group) RalF showed perinuclear localization reminiscent of ectopically expressed Legionella RalF, for which it shares several structural features. For R. typhi, RalF co-localization with Arf6 and PI(4,5)P2 at entry foci on the host plasma membrane was determined to be critical for invasion. Thus, we propose recruitment of PI(4,5)P2 at entry foci, mediated by RalF activation of Arf6, initiates actin remodeling and ultimately facilitates bacterial invasion. Collectively, our characterization of RalF as an invasin suggests that, despite carrying a similar Arf-GEF unknown from other bacteria, different intracellular lifestyles across Rickettsia and Legionella species have driven divergent roles for RalF during infection. Furthermore, our identification of lineage-specific Arf-GEF utilization across some rickettsial species illustrates different pathogenicity factors that define diverse agents of rickettsial diseases. 相似文献
145.
Antonia L. Dow Tiffany V. Lin Elena H. Chartoff David Potter Donna L. McPhie Ashlee V. Van’t Veer Allison T. Knoll Kristen N. Lee Rachael L. Neve Tarun B. Patel Dost Ongur Bruce M. Cohen William A. Carlezon Jr 《PloS one》2015,10(3)
Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders. 相似文献
146.
Kristen N. Pollizzi Adam T. Waickman Chirag H. Patel Im Hong Sun Jonathan D. Powell 《PloS one》2015,10(4)
mTOR is a central integrator of metabolic and immunological stimuli, dictating immune cell activation, proliferation and differentiation. In this study, we demonstrate that within a clonal population of activated T cells, there exist both mTORhi and mTORlo cells exhibiting highly divergent metabolic and immunologic functions. By taking advantage of the role of mTOR activation in controlling cellular size, we demonstrate that upon antigen recognition, mTORhi CD4+ T cells are destined to become highly glycolytic effector cells. Conversely, mTORlo T cells preferentially develop into long-lived cells that express high levels of Bcl-2, CD25, and CD62L. Furthermore, mTORlo T cells have a greater propensity to differentiate into suppressive Foxp3+ T regulatory cells, and this paradigm was also observed in human CD4+ T cells. Overall, these studies provide the opportunity to track the development of effector and memory T cells from naïve precursors, as well as facilitate the interrogation of immunologic and metabolic programs that inform these fates. 相似文献
147.
148.
Background
Protein post-translational modifications (PTMs) are an important aspect of protein regulation. The number of PTMs discovered within the human proteome, and other proteomes, has been rapidly expanding in recent years. As a consequence of the rate in which new PTMs are identified, analysis done in one year may result in different conclusions when repeated in subsequent years. Among the various functional questions pertaining to PTMs, one important relationship to address is the interplay between modifications and mutations. Specifically, because the linear sequence surrounding a modification site often determines molecular recognition, it is hypothesized that mutations near sites of PTMs may be more likely to result in a detrimental effect on protein function, resulting in the development of disease.Methods and Results
We wrote an application programming interface (API) to make analysis of ProteomeScout, a comprehensive database of PTMs and protein information, easy and reproducible. We used this API to analyze the relationship between PTMs and human mutations associated with disease (based on the ‘Clinical Significance’ annotation from dbSNP). Proteins containing pathogenic mutations demonstrated a significant study bias which was controlled for by analyzing only well-studied proteins, based on their having at least one pathogenic mutation. We found that pathogenic mutations are significantly more likely to lie within eight amino acids of a phosphoserine, phosphotyrosine or ubiquitination site when compared to mutations in general, based on a Fisher’s Exact test. Despite the skew of pathogenic mutations occurring on positively charged arginines, we could not account for this relationship based only on residue type. Finally, we hypothesize a potential mechanism for a pathogenic mutation on RAF1, based on its proximity to a phosphorylation site, which represents a subtle regulation difference that may explain why its biochemical effect has failed to be uncovered previously. The combination of the API and a dynamically expanding PTM database will make the reanalysis of this question and other systems-level questions easier in the future. 相似文献149.
Jason P. Mooney Seung-Joo Lee Kristen L. Lokken Minelva R. Nanton Sean-Paul Nuccio Stephen J. McSorley Renée M. Tsolis 《PLoS neglected tropical diseases》2015,9(9)
In immunocompetent individuals, non-typhoidal Salmonella serovars (NTS) are associated with gastroenteritis, however, there is currently an epidemic of NTS bloodstream infections in sub-Saharan Africa. Plasmodium falciparum malaria is an important risk factor for invasive NTS bloodstream in African children. Here we investigated whether a live, attenuated Salmonella vaccine could be protective in mice, in the setting of concurrent malaria. Surprisingly, mice acutely infected with the nonlethal malaria parasite Plasmodium yoelii 17XNL exhibited a profound loss of protective immunity to NTS, but vaccine-mediated protection was restored after resolution of malaria. Absence of protective immunity during acute malaria correlated with maintenance of antibodies to NTS, but a marked reduction in effector capability of Salmonella-specific CD4 and CD8 T cells. Further, increased expression of the inhibitory molecule PD1 was identified on memory CD4 T cells induced by vaccination. Blockade of IL-10 restored protection against S. Typhimurium, without restoring CD4 T cell effector function. Simultaneous blockade of CTLA-4, LAG3, and PDL1 restored IFN-γ production by vaccine-induced memory CD4 T cells but was not sufficient to restore protection. Together, these data demonstrate that malaria parasite infection induces a temporary loss of an established adaptive immune response via multiple mechanisms, and suggest that in the setting of acute malaria, protection against NTS mediated by live vaccines may be interrupted. 相似文献
150.
Dharanesh Gangaiah Kristen M. Webb Tricia L. Humphreys Kate R. Fortney Evelyn Toh Albert Tai Samantha S. Katz Allan Pillay Cheng-Yen Chen Sally A. Roberts Robert S. Munson Jr. Stanley M. Spinola 《PLoS neglected tropical diseases》2015,9(7)