全文获取类型
收费全文 | 299篇 |
免费 | 29篇 |
出版年
2022年 | 2篇 |
2021年 | 7篇 |
2018年 | 2篇 |
2017年 | 3篇 |
2016年 | 8篇 |
2015年 | 9篇 |
2014年 | 8篇 |
2013年 | 15篇 |
2012年 | 26篇 |
2011年 | 27篇 |
2010年 | 19篇 |
2009年 | 6篇 |
2008年 | 12篇 |
2007年 | 8篇 |
2006年 | 14篇 |
2005年 | 9篇 |
2004年 | 9篇 |
2003年 | 12篇 |
2002年 | 6篇 |
2001年 | 7篇 |
2000年 | 8篇 |
1999年 | 10篇 |
1998年 | 2篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1986年 | 7篇 |
1983年 | 2篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 4篇 |
1977年 | 2篇 |
1975年 | 2篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1969年 | 2篇 |
1968年 | 4篇 |
1966年 | 3篇 |
1955年 | 2篇 |
1952年 | 2篇 |
1944年 | 2篇 |
1924年 | 3篇 |
1916年 | 1篇 |
1915年 | 3篇 |
1912年 | 1篇 |
排序方式: 共有328条查询结果,搜索用时 31 毫秒
151.
Cheshire J Mateos P Longley PA 《Human biology; an international record of research》2011,83(5):573-598
Surnames (family names) show distinctive geographical patterning and in many disciplines remain an underutilized source of information about population origins, migration and identity. This paper investigates the geographical structure of surnames, using a unique individual level database assembled from registers and telephone directories from 16 European countries. We develop a novel combination of methods for exhaustively analyzing this multinational data set, based upon the Lasker Distance, consensus clustering and multidimensional scaling. Our analysis is both data rich and computationally intensive, entailing as it does the aggregation, clustering and mapping of 8 million surnames collected from 152 million individuals. The resulting regionalization has applications in developing our understanding of the social and cultural complexion of Europe, and offers potential insights into the long and short-term dynamics of migration and residential mobility. The research also contributes a range of methodological insights for future studies concerning spatial clustering of surnames and population data more widely. In short, this paper further demonstrates the value of surnames in multinational population studies and also the increasing sophistication of techniques available to analyze them. 相似文献
152.
153.
Jared Klarquist Shilpak Chatterjee Jeffrey A. Mosenson Michael I. Nishimura Elizabeth Garrett‐Mayer B. Jack Longley Victor H. Engelhard Shikhar Mehrotra I. Caroline Le Poole 《Pigment cell & melanoma research》2014,27(6):1075-1085
To generate a mouse model of spontaneous epidermal depigmentation, parental h3TA2 mice, expressing both a human‐derived, tyrosinase‐reactive T‐cell receptor on T cells and the matching HLA‐A2 transgene, were crossed to keratin 14‐promoter driven, stem cell factor transgenic (K14‐SCF) mice with intra‐epidermal melanocytes. In resulting Vitesse mice, spontaneous skin depigmentation precedes symmetrical and sharply demarcated patches of graying hair. Whereas the SCF transgene alone dictates a greater retinoic acid receptor‐related orphan receptor gamma (RORγt)+ T‐cell compartment, these cells displayed markedly increased IL‐17 expression within Vitesse mice. Similar to patient skin, regulatory T cells were less abundant compared with K14‐SCF mice, with the exception of gradually appearing patches of repigmenting skin. The subtle repigmentation observed likely reflects resilient melanocytes that coexist with skin‐infiltrating, melanocyte‐reactive T cells. Similar repigmenting lesions were found in a different TCR transgenic model of vitiligo developed on an SCF transgenic background, supporting a role for SCF in repigmentation. 相似文献
154.
Crawford N Chacko AD Savage KI McCoy F Redmond K Longley DB Fennell DA 《Apoptosis : an international journal on programmed cell death》2011,16(3):311-320
Resistance to cisplatin chemotherapy remains a major hurdle preventing effective treatment of many solid cancers. BAX and
BAK are pivotal regulators of the mitochondrial apoptosis pathway, however little is known regarding their regulation in cisplatin
resistant cells. Cisplatin induces DNA damage in both sensitive and resistant cells, however the latter exhibits a failure
to initiate N-terminal exposure of mitochondrial BAK or mitochondrial SMAC release. Both phenotypes are highly sensitive to
mitochondrial permeabilisation induced by exogenous BH3 domain peptides derived from BID, BIM, NOXA (which targets MCL-1 and
A1), and there is no significant change in their prosurvival BCL2 protein expression profiles. Obatoclax, a small molecule
inhibitor of pro-survival BCL-2 family proteins including MCL-1, decreases cell viability irrespective of platinum resistance
status across a panel of cell lines selected for oxaliplatin resistance. In summary, selection for platinum resistance is
associated with a block of mitochondrial death signalling upstream of BAX/BAK activation. Conservation of sensitivity to BH3
domain induced apoptosis can be exploited by agents such as obatoclax, which directly target the mitochondria and BCL-2 family. 相似文献
155.
In recent years, the process of selective autophagy has received much attention with respect to the clearance of protein aggregates, damaged mitochondria and bacteria. However, until recently, there have been virtually no studies on the selective autophagy of viruses, although they are perhaps one of the most ubiquitous unwanted constituents in human cells. Recently, we have shown that the ability of neuronal Atg5 to protect against lethal Sindbis virus central nervous system (CNS) infection in mice is associated with impaired viral capsid clearance, increased p62 accumulation and increased neuronal cell death. In vitro, we showed that p62 interacts with the Sindbis capsid protein and targets it for degradation in autophagosomes. Herein, we review these findings and broadly speculate about potential roles of selective viral autophagy in the regulation of host immunity and viral pathogenesis. 相似文献
156.
Stevenson L Allen WL Proutski I Stewart G Johnston L McCloskey K Wilson PM Longley DB Johnston PG 《PloS one》2011,6(5):e20276
The role of the calcium binding protein, Calbindin 2 (CALB2), in regulating the response of colorectal cancer (CRC) cells to 5-Fluorouracil (5-FU) was investigated. Real-time RT-PCR and Western blot analysis revealed that CALB2 mRNA and protein expression were down-regulated in p53 wild-type and p53 null isogenic HCT116 CRC cell lines following 48 h and 72 h 5-FU treatment. Moreover, 5-FU-induced apoptosis was significantly reduced in HCT116 and LS174T CRC cell lines in which CALB2 expression had been silenced. Further investigation revealed that CALB2 translocated to the mitochondria following 5-FU treatment and that 5-FU-induced loss of mitochondrial membrane potential (Δψ(m)) was abrogated in CALB2-silenced cells. Furthermore, CALB2 silencing decreased 5-FU-induced cytochrome c and smac release from the mitochondria and also decreased 5-FU-induced activation of caspases 9 and 3/7. Of note, co-silencing of XIAP overcame 5-FU resistance in CALB2-silenced cells. Collectively, these results suggest that following 5-FU treatment in CRC cell lines, CALB2 is involved in apoptosis induction through the intrinsic mitochondrial pathway. This indicates that CALB2 may be an important mediator of 5-FU-induced cell death. Moreover, down-regulation of CALB2 in response to 5-FU may represent an intrinsic mechanism of resistance to this anti-cancer drug. 相似文献
157.
158.
Baldwin SL Bertholet S Reese VA Ching LK Reed SG Coler RN 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(5):2189-2197
An effective protein-based vaccine for tuberculosis will require a safe and effective adjuvant. There are few adjuvants in approved human vaccines, including alum and the oil-in-water-based emulsions MF59 (Novartis Vaccines and Diagnostics), AS03 and AS04 (GlaxoSmithKline Biologics), AF03 (Sanofi), and liposomes (Crucell). When used with pure, defined proteins, both alum and emulsion adjuvants are effective at inducing primarily humoral responses. One of the newest adjuvants in approved products is AS04, which combines monophosphoryl lipid A, a TLR-4 agonist, with alum. In this study, we compared two adjuvants: a stable oil-in-water emulsion (SE) and a stable oil-in-water emulsion incorporating glucopyranosyl lipid adjuvant, a synthetic TLR-4 agonist (GLA-SE), each together with a recombinant protein, ID93. Both the emulsion SE and GLA-SE adjuvants induce potent cellular responses in combination with ID93 in mice. ID93/SE induced Th2-biased immune responses, whereas ID93/GLA-SE induced multifunctional CD4(+) Th1 cell responses (IFN-γ, TNF-α, and IL-2). The ID93/GLA-SE vaccine candidate induced significant protection in mice and guinea pigs, whereas no protection was observed with ID93/SE, as assessed by reductions in bacterial burden, survival, and pathology. These results highlight the importance of properly formulating subunit vaccines with effective adjuvants for use against tuberculosis. 相似文献
159.
Rhea van de Bospoort Margherita Farina Sabine K. Schmitz Arthur de Jong Heidi de Wit Matthijs Verhage Ruud F. Toonen 《The Journal of cell biology》2012,199(6):883-891
Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2–null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically. 相似文献
160.
Kevin M. Potter Robert M. Jetton William S. Dvorak Valerie D. Hipkins Rusty Rhea W. Andrew Whittier 《Conservation Genetics》2012,13(2):475-498
Eastern hemlock (Tsuga canadensis [L.] Carr.) is an ecologically important tree species experiencing severe mortality across much of its eastern North American
distribution, caused by infestation of the exotic hemlock woolly adelgid (Adelges tsugae Annand). To guide gene conservation strategies for this imperiled conifer, we conducted a range-wide genetic variation study
for eastern hemlock, amplifying 13 highly polymorphic nuclear microsatellite loci in 1,180 trees across 60 populations. The
results demonstrate that eastern hemlock exhibits moderate inbreeding, possibly a signature of a prehistoric decline associated
with a widespread insect outbreak. Contrary to expectations, populations in formerly glaciated regions are not less genetically
diverse than in the putative southern refugial region. As expected, peripheral disjunct populations are less genetically diverse
than main-range populations, but some are highly genetically differentiated or contain unique alleles. Spatially explicit
Bayesian clustering analyses suggest that three or four Pleistocene glacial refuges may have existed in the Southeastern United
States, with a main post-glacial movement into the Northeast and the Great Lakes region. Efforts to conserve eastern hemlock
genetic material should emphasize the capture of broad adaptability that occurs across the geographic range of the species,
as well as genetic variability within regions with the highest allelic richness and heterozygosity, such as the Southern Appalachians
and New England, and within disjunct populations that are genetically distinct. Much genetic variation exists in areas both
infested and uninfested by the adelgid. 相似文献