全文获取类型
收费全文 | 379篇 |
免费 | 23篇 |
学科分类
医药卫生 | 402篇 |
出版年
2023年 | 3篇 |
2022年 | 2篇 |
2021年 | 3篇 |
2020年 | 3篇 |
2019年 | 5篇 |
2018年 | 6篇 |
2017年 | 8篇 |
2016年 | 9篇 |
2015年 | 14篇 |
2014年 | 13篇 |
2013年 | 23篇 |
2012年 | 23篇 |
2011年 | 31篇 |
2010年 | 17篇 |
2009年 | 14篇 |
2008年 | 15篇 |
2007年 | 21篇 |
2006年 | 15篇 |
2005年 | 9篇 |
2004年 | 18篇 |
2003年 | 11篇 |
2002年 | 7篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 7篇 |
1998年 | 8篇 |
1996年 | 7篇 |
1994年 | 2篇 |
1993年 | 7篇 |
1991年 | 6篇 |
1990年 | 10篇 |
1989年 | 12篇 |
1988年 | 5篇 |
1987年 | 6篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 6篇 |
1982年 | 2篇 |
1981年 | 5篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1976年 | 1篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1965年 | 1篇 |
1958年 | 1篇 |
1923年 | 1篇 |
排序方式: 共有402条查询结果,搜索用时 15 毫秒
1.
K Decaestecker E Decaestecker C Castellani M Jaspers H Cuppens K De Boeck 《The European respiratory journal》2004,23(5):679-684
In this European study, the phenotype in 68 patients, homozygous or compound heterozygous for the G85E mutation, was investigated. Each index case was compared with two cystic fibrosis (CF) patients from the same clinic, matched for age and sex: one with pancreatic sufficiency (PS) and one with pancreatic insufficiency (PI). When comparing 31 G85E/F508del and F508del/F508del patients, there were no differences in median age at diagnosis, mean sweat chloride value, most recent weight for height, most recent forced expiratory volume in one second % predicted, prevalence of chronic Pseudomonas aeruginosa colonisation and typical CF complications. However, PI was less frequent in the G85E/F508del group. Comparison of 55 G85E patients (with second mutation known and not classified as mild) with PS controls (n=44) showed that the G85E patients had a significantly higher sweat chloride, more often failure to thrive at diagnosis, higher prevalence of PI, worse current weight for height, higher prevalence of chronic P. aeruginosa colonisation and liver cirrhosis. Pulse-chase experiments revealed that G85E cystic fibrosis transmembrane conductance regulator failed to mature on a M470 as well as on a V470 background. Therefore, G85E is a class II mutation. Although there is variability in its clinical presentation, G85E mutation results in a severe phenotype. 相似文献
2.
Cellular and molecular characteristics of an immortalized ataxia-telangiectasia (group AB) cell line 总被引:1,自引:0,他引:1
Y Ziv N G Jaspers S Etkin T Danieli L Trakhtenbrot A Amiel Y Ravia Y Shiloh 《Cancer research》1989,49(9):2495-2501
Ataxia-telangiectasia (A-T) is a multisystem hereditary disease featuring neurodegeneration, immunodeficiency, extreme cancer proneness, chromosomal instability, and radiosensitivity. A-T is found in many ethnic groups, and is genetically heterogeneous: four complementation groups have been identified in A-T so far. Attempts to isolate the A-T gene are based in part on gene transfer experiments, using permanent A-T fibroblast lines, obtained by transformation with SV40. "Immortalization" of A-T primary diploid fibroblasts using SV40 is difficult, possibly because of the chromosomal instability of these cells. The number of currently available permanent A-T fibroblast lines is small, and not all of them have been assigned to specific complementation groups. Using the assay of X-ray induced inhibition of DNA synthesis, we have assigned the A-T strain AT22IJE to complementation group AB. Origin-defective SV40 was used to transfect these cells, and one transformant (AT22IJE-T), which survived crisis, was found to have the typical characteristics of permanent cell lines obtained in this way. "In-gel renaturation" analysis did not show any DNA amplification of high degree in AT22IJE-T. Cytogenetic analysis showed considerable chromosomal instability in the new cell line, and medium conditioned by these cells contained the clastogenic activity which is characteristic of the parental strain as well. Other parameters of the "cellular A-T phenotype" have also been retained in the immortalized cells: hypersensitivity to the lethal effects of X-rays and neocarzinostatin, as well as "radioresistant" DNA synthesis. However, the sensitivity of AT22IJE-T to both DNA-damaging agents is less pronounced than that of the parental cells. The capacity of the cells for uptake of foreign DNA was tested by introducing into them the plasmid pRSVneo, using three different transfection methods. Satisfactory frequency of G418-resistant transfectants (0.66%) was achieved using a protocol recently published by Chen and Okayama (Mol. Cell Biol., 7: 2745-2752, 1987), which was found to be superior to the traditional calcium phosphate transfection method and to the polybrene-based method. 相似文献
3.
Predominance of null mutations in ataxia-telangiectasia 总被引:15,自引:4,他引:15
Gilad S; Khosravi R; Shkedy D; Uziel T; Ziv Y; Savitsky K; Rotman G; Smith S; Chessa L; Jorgensen TJ; Harnik R; Frydman M; Sanal O; Portnoi S; Goldwicz Z; Jaspers NG; Gatti RA; Lenoir G; Lavin MF; Tatsumi K; Wegner RD; Shiloh Y; Bar-Shira A 《Human molecular genetics》1996,5(4):433-439
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving
cerebellar degeneration, immunodeficiency, chromosomal instability,
radiosensitivity and cancer predisposition. The responsible gene, ATM, was
recently identified by positional cloning and found to encode a putative
350 kDa protein with a Pl 3-kinase-like domain, presumably involved in
mediating cell cycle arrest in response to radiation-induced DNA damage.
The nature and location of A-T mutations should provide insight into the
function of the ATM protein and the molecular basis of this pleiotropic
disease. Of 44 A-T mutations identified by us to date, 39 (89%) are
expected to inactivate the ATM protein by truncating it, by abolishing
correct initiation or termination of translation, or by deleting large
segments. Additional mutations are four smaller in-frame deletions and
insertions, and one substitution of a highly conserved amino acid at the Pl
3-kinase domain. The emerging profile of mutations causing A-T is thus
dominated by those expected to completely inactivate the ATM protein. ATM
mutations with milder effects may result in phenotypes related, but not
identical, to A-T.
相似文献
4.
Vankeerberghen A; Wei L; Jaspers M; Cassiman JJ; Nilius B; Cuppens H 《Human molecular genetics》1998,7(11):1761-1769
In order to gain a better insight into the structure and function of the
regulatory domain (RD) of the cystic fibrosis transmembrane conductance
regulator (CFTR) protein, 19 RD missense mutations that had been identified
in patients were functionally characterized. Nine of these (I601F, L610S,
A613T, D614G, I618T, L619S, H620P, G628R and L633P) resulted in aberrant
processing. No or a very small number of functional CFTR proteins will
therefore appear at the cell membrane in cells expressing these mutants.
These mutations were clustered in the N- terminal part of the RD,
suggesting that this subdomain has a folding pattern that is very sensitive
to amino acid changes. Mutations that caused no aberrant processing were
further characterized at the electrophysiological level. First, they were
studied at the whole cell level in Xenopus laevis oocytes. Mutants that
induced a whole cell current that was significantly different from
wild-type CFTR were subsequently analysed at the single channel level in
COS1 cells transiently expressing the different mutant and wild-type
proteins. Three mutant chloride channels, G622D, R792G and E822K CFTR, were
characterized by significantly lower intrinsic chloride channel activities
compared with wild-type CFTR. Two mutations, H620Q and A800G, resulted in
increased intrinsic chloride transport activities. Finally, T665S and E826K
CFTR had single channel properties not significantly different from
wild-type CFTR.
相似文献
5.
Dr. Med. C. Jaspers R. Haase H. Pfingsten G. Benker D. Reinwein 《Journal of molecular medicine (Berlin, Germany)》1993,71(7):547-551
Summary We studied the efficacy and tolerability of a repeatable long-acting parenteral depot-bromocriptine preparation (Parlodel LAR) in 14 acromegalic patients, 10 of whom had received oral bromocriptine therapy previously, 2 of them showing intolerance to oral bromocriptine. Patients received i.m. injections of 50–100 mg depot-bromocriptine at 4-week intervals for 3–24 months (median 6). Growth hormone profiles were assessed by four daily samples at 4-week intervals. Main daily growth hormone levels decreased from 52.1 ±12.3 g/l (mean ± SEM) to 19.4 ± 4.7 g/l on the day of injection. In 6 patients, growth hormone values were lowered by more than 50%, whereas IGF-I levels decreased only slightly and growth hormone values during the oral glucose tolerance test remained non-suppressible. Tumour sizes were not affected. Two women became pregnant and were delivered of healthy babies. Side-effects typical of bromocriptine occurred frequently on the days of injection and diminished in most patients after 2 months of therapy despite increasing dosage. Compared with previous oral bromocriptine therapy, 9 of 10 patients preferred the depot preparation, whereas the reduction of growth hormone levels was similar during both treatments. In conclusion, depot-bromocriptine should be considered for acromegalic patients intolerant to oral bromocriptine.Abbreviations br
Bromocriptine
- oral br.
oral bromocriptine
- depot-br.
depot-bromocriptine
- GH
growth hormone
- oGTT
oral glucose tolerance test
- GnRH
gonadotropin-releasing hormone
- TRH
thyrotropin-releasing hormone 相似文献
6.
7.
The VLA-4 integrin (CD49d/CD29), initially discovered on lymphoid cells, is actually known to be highly expressed on T cells, B cells, monocytes, and derived cell lines. Unlike other VLA integrins, mainly involved in cell-matrix adhesive interactions, VLA-4 has also been implicated in several cellular interactions. Based on the published alpha 4 cDNA sequence, a 1,142-bp alpha 4 cDNA fragment was amplified using the polymerase chain reaction. This fragment was used to isolate three overlapping genomic clones from a phage library. By Southern analysis with the cDNA probe, and using the polymerase chain reaction on DNA isolated from a panel of human/mouse somatic cell hybrids, the alpha 4 gene was mapped to chromosome 2. Fluorescence in situ hybridization confirmed this assignment and allowed a more precise mapping to chromosome 2q31-32. 相似文献
8.
Amino acid metabolism was investigated in atrophied soleus muscle from rats subjected to six days of tail-cast, hindlimb suspension. The fresh-frozen unloaded muscle showed higher concentrations of tyrosine and glutamate but lower amounts of aspartate, glutamine, ammonia, and a lower ratio of glutamine to glutamate than normal muscle. The atrophied muscle also showed faster in vitro production of alanine and tyrosine, and slower utilization of glutamate and aspartate. Despite a greater activity of glutamine synthetase, synthesis of glutamine was slower in the soleus muscle of suspended rats than in control muscle. Provision of ammonium chloride and/or glutamate showed that this slower synthesis of glutamine in the atrophied soleus probably was due to limiting amounts of free ammonia and not of glutamate. Flux through AMP deaminase was probably slower as demonstrated by the maintenance of a greater pool of total adenine nucleotides and by the slower release of nucleosides by the incubated soleus muscle of suspended v control rats. The extensor digitorum longus muscles of suspended animals showed greater glutamine production, glutamine synthetase activity, and aspartate utilization than control muscles. Data from muscles of intact, adrenalectomized and adrenalectomized, cortisol-treated rats suggested that the greater glutamine synthetase activity was mediated possibly by higher circulating glucocorticoid hormones and a greater response of the soleus muscle to these hormones. Glutamine synthesis in skeletal muscle may be regulated primarily by the availability of ammonia, which is associated with the degradation of adenine nucleotides, and secondarily by the amount of glutamine synthetase and glutamate in the tissue. 相似文献
9.
Richard T. Jaspers Nathalie Bravenboer 《Clinical reviews in bone and mineral metabolism》2014,12(1):27-43
In elderly with a sedentary lifestyle, often suffering from sarcopenia to osteopenia, a training intervention could be an effective countermeasure for bone as well as muscle. Both bone and muscle adapt their mass and strength in response to mechanical loading in part via similar signaling pathways. Bone as well as muscle produces a wide variety of growth factors and cytokines in response to mechanical loading, which are important for their adaptations. It has been hypothesized that in addition to mechanical stimuli, muscle and bone communicate by these factors. Whether such biochemical interaction between both tissues is physiological is a still subject of debate. Here, we provide an overview of a range of biological factors possibly involved in the biochemical cross talk between bone and muscle. In addition, we discuss the plausibility that such interactions are involved in non-pathological adaptation of both tissues, either in paracrine or in endocrine fashion. As yet, convincing experimental evidence for biochemical cross talk between muscle and bone is very limited. Several studies have shown that muscle-derived factors are involved in bone fracture healing as well as in bone adaptation in case of muscle pathology. For involvement of cross talk between muscle and bone in physiological adaptation, there is no definite proof yet. Detailed knowledge of the biochemical interactions between muscle and bone is of clinical importance. It can help to discover pharmacological treatment to be used alone or in parallel with exercise training, thereby reducing the need for high-impact exercise. 相似文献
10.
Several reports suggest a significant correlation between hand preference quotients and Magical Ideation Scale (MIS) scores, such that individuals with mixed prefer ences have higher MIS scores. In a sample of 156 male and 257 female undergraduate university students no significant correlation was found between MIS scores and hand preference; hand preference being defined in numerous ways, and using short and long hand preference questionnaires to assess handedness. An index of left–right confusion was significantly related to MIS score, but only in females. We suggest that the role of subjects' response style and general approach to filling out questionnaires should be fully explored before “neurological” causes of links between hand preference and other questionnaire‐assessed behavioural variables are invoked. 相似文献