全文获取类型
收费全文 | 4133篇 |
免费 | 283篇 |
国内免费 | 1篇 |
出版年
2021年 | 34篇 |
2019年 | 31篇 |
2018年 | 38篇 |
2017年 | 23篇 |
2016年 | 72篇 |
2015年 | 94篇 |
2014年 | 109篇 |
2013年 | 184篇 |
2012年 | 220篇 |
2011年 | 195篇 |
2010年 | 121篇 |
2009年 | 99篇 |
2008年 | 198篇 |
2007年 | 184篇 |
2006年 | 178篇 |
2005年 | 153篇 |
2004年 | 151篇 |
2003年 | 165篇 |
2002年 | 153篇 |
2001年 | 64篇 |
2000年 | 60篇 |
1999年 | 49篇 |
1998年 | 40篇 |
1997年 | 42篇 |
1996年 | 45篇 |
1995年 | 62篇 |
1994年 | 38篇 |
1993年 | 50篇 |
1992年 | 42篇 |
1991年 | 39篇 |
1990年 | 41篇 |
1989年 | 36篇 |
1988年 | 36篇 |
1987年 | 38篇 |
1986年 | 34篇 |
1985年 | 38篇 |
1984年 | 39篇 |
1983年 | 43篇 |
1982年 | 33篇 |
1981年 | 45篇 |
1980年 | 28篇 |
1979年 | 31篇 |
1978年 | 54篇 |
1977年 | 27篇 |
1973年 | 33篇 |
1971年 | 24篇 |
1966年 | 28篇 |
1965年 | 26篇 |
1964年 | 22篇 |
1956年 | 24篇 |
排序方式: 共有4417条查询结果,搜索用时 15 毫秒
1.
In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response
to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in
different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders.
We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with
carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory
illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug
responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug
efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced
endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced
adaptations dissipate (the “time-off seizure” effect), leading to the re-emergence of seizures, a re-induction of a new, but
diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats,
an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance.
We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous
adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression
and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can
be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive
(decreasing the stimulation current.), increasing drug dosage, switching to a new drug that does not show crosstolerance to
the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal.
Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression
of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined
that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity
can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted
by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the
neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the
biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent
illness emergence and progression and its associated accumulating neurobiological, vulnerability factors. 相似文献
2.
Minh H. Dinh Meegan R. Anderson Michael D. McRaven Gianguido C. Cianci Scott G. McCoombe Z. L. Kelley Casey J. Gioia Angela J. Fought Alfred W. Rademaker Ronald S. Veazey Thomas J. Hope 《PLoS pathogens》2015,11(3)
To gain insight into female-to-male HIV sexual transmission and how male circumcision protects against this mode of transmission, we visualized HIV-1 interactions with foreskin and penile tissues in ex vivo tissue culture and in vivo rhesus macaque models utilizing epifluorescent microscopy. 12 foreskin and 14 cadaveric penile specimens were cultured with R5-tropic photoactivatable (PA)-GFP HIV-1 for 4 or 24 hours. Tissue cryosections were immunofluorescently imaged for epithelial and immune cell markers. Images were analyzed for total virions, proportion of penetrators, depth of virion penetration, as well as immune cell counts and depths in the tissue. We visualized individual PA virions breaching penile epithelial surfaces in the explant and macaque model. Using kernel density estimated probabilities of localizing a virion or immune cell at certain tissue depths revealed that interactions between virions and cells were more likely to occur in the inner foreskin or glans penis (from local or cadaveric donors, respectively). Using statistical models to account for repeated measures and zero-inflated datasets, we found no difference in total virions visualized at 4 hours between inner and outer foreskins from local donors. At 24 hours, there were more virions in inner as compared to outer foreskin (0.0495 +/− 0.0154 and 0.0171 +/− 0.0038 virions/image, p = 0.001). In the cadaveric specimens, we observed more virions in inner foreskin (0.0507 +/− 0.0079 virions/image) than glans tissue (0.0167 +/− 0.0033 virions/image, p<0.001), but a greater proportion was seen penetrating uncircumcised glans tissue (0.0458 +/− 0.0188 vs. 0.0151 +/− 0.0100 virions/image, p = 0.099) and to significantly greater mean depths (29.162 +/− 3.908 vs. 12.466 +/− 2.985 μm). Our in vivo macaque model confirmed that virions can breach penile squamous epithelia in a living model. In summary, these results suggest that the inner foreskin and glans epithelia may be important sites for HIV transmission in uncircumcised men. 相似文献
3.
Alfred G. Gilman 《Bioscience reports》1995,15(2):65-97
The function and structures of G proteins and their role in the regulation of adenylyl cyclase is reviewed.The Nobel lecture given on December 8, 1994 by Dr Alfred Gilman and published inLes Prix Nobel 1994, printed by Norstedts Tryckeri, Stockholm, Sweden, republished here with the permission of the Nobel Foundation, the copyright holder. 相似文献
4.
5.
6.
The kinetics of the electrostatically induced phase transition of dimyristoyl phosphatidic acid bilayers was followed using the stopped-flow technique. The phase transition was triggered by a fast change in the pH or the magnesium ion concentration and followed by recording the time dependence of the absorbance. When the phase transition was induced by a pH jump the time course of the absorbance could be described by two exponentials, their time constants displaying the for cooperative processes characteristic maximum at the transition midpoint. The time constants are in the 10 and 100 ms range for the H+ triggered transition from the fluid to the ordered state. A third slower process shows no appreciable temperature dependence and is probably caused by vesicle aggregation. For the OH--induced transition fron the ordered to the fluid state the time constants are in the 100 and 1000 ms range. The fluid-ordered transition could also be triggered by addition of magnesium ions. Of the several observed processes only the fastest in the 10–100 ms time range could definitely be assigned to the fluid-ordered transition while the others are due to aggregation phenomena. The experimental data were compared with results obtained from pressure jump experiments and could be interpreted on the basis of theories for non-equilibrium relaxation. 相似文献
7.
8.
9.
Donald Alfred Wellings 《International journal of peptide research and therapeutics》2010,16(3):185-189
Two novel concepts for the design and manufacture of polymer supports for solid phase synthesis of peptides are described.
The first concept involves the encapsulation of polymers within the hole of short pieces of capillary tubing often referred
to as seed beads. This provides a rigid exo-skeleton for the support of soft polymer gel and other mechanically fragile polymer
based matrices. The rigidity of the support provides a polymeric media that is particularly suited to continuous flow based
peptide synthesis. The second concept complements this by providing an inexpensive approach to the preparation of spherical
polymer particles by coating commercially available impervious hollow glass microspheres with polymer. The added advantage
of this approach lies in the buoyancy of the resultant polymer particles, which facilitates handling on a large scale. 相似文献
10.
J A Post J Leunissen-Bijvelt T J Ruigrok A J Verkleij 《Biochimica et biophysica acta》1985,845(1):119-123
Isolated rabbit hearts were perfused by the Langendorff technique, made ischemic and subsequently reperfused. It was found that ischemia results in: (i) aggregation of the intramembranous particles in the sarcolemma and (ii) extrusion of pure lipidic multilamellar structures (liposomes) from swollen mitochondria. Subsequent reperfusion resulted in further aggregation of the sarcolemmal intramembranous particles and disruption of the sarcolemma, which was attended by the formation of liposome-like structures. Intramembrane particle aggregation is explained in terms of lateral phase separation of the membrane lipids and a reduction of repulsive forces between the membrane proteins, both induced by a decrease in pH and an increase in Ca2+ concentration intracellularly. The formation and extrusion of the multilamellar structures are discussed in terms of destabilization of the bilayer which results in a structural blebbing-off of pure lipid. 相似文献