全文获取类型
收费全文 | 367篇 |
免费 | 20篇 |
出版年
2023年 | 3篇 |
2022年 | 7篇 |
2021年 | 10篇 |
2020年 | 8篇 |
2019年 | 12篇 |
2018年 | 8篇 |
2017年 | 9篇 |
2016年 | 5篇 |
2015年 | 12篇 |
2014年 | 20篇 |
2013年 | 24篇 |
2012年 | 33篇 |
2011年 | 19篇 |
2010年 | 22篇 |
2009年 | 12篇 |
2008年 | 17篇 |
2007年 | 22篇 |
2006年 | 18篇 |
2005年 | 13篇 |
2004年 | 15篇 |
2003年 | 13篇 |
2002年 | 8篇 |
2001年 | 5篇 |
2000年 | 6篇 |
1999年 | 5篇 |
1998年 | 3篇 |
1997年 | 2篇 |
1996年 | 4篇 |
1995年 | 1篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 8篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 6篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1974年 | 1篇 |
排序方式: 共有387条查询结果,搜索用时 31 毫秒
101.
102.
103.
Summary Tannase was produced by modified solid-state fermentation (MSSF) of tannin rich substrates by a co-culture of the two filamentous
fungi, Rhizopus oryzae and Aspergillus foetidus. The enzyme thus produced was then partially purified by solvent precipitation and DEAE-Sephadex column chromatography. A
study on the effects of temperature and pH was made on the activity of tannase so purified. The optimum values of incubation
time, reaction temperature and pH for tannase activity were 5 min, 40 °C and 5.0 respectively. The half-life period thermal
stability and kinetic constants (K
m 0.21 mM, V
max 4.9×10−2 M min-1 at 40 °C) of this tannase were determined and the effects of different metal ions, surfactants, chelators, denaturants and
inhibitors on the enzyme activity were also studied. 相似文献
104.
Christian Rosker Gargi Meur Emily J. A. Taylor Colin W. Taylor 《The Journal of biological chemistry》2009,284(8):5186-5194
Ryanodine receptors (RyR) are Ca2+ channels that mediate
Ca2+ release from intracellular stores in response to diverse
intracellular signals. In RINm5F insulinoma cells, caffeine, and
4-chloro-m-cresol (4CmC), agonists of RyR, stimulated Ca2+
entry that was independent of store-operated Ca2+ entry, and
blocked by prior incubation with a concentration of ryanodine that inactivates
RyR. Patch-clamp recording identified small numbers of large-conductance
(γK = 169 pS) cation channels that were activated by
caffeine, 4CmC or low concentrations of ryanodine. Similar channels were
detected in rat pancreatic β-cells. In RINm5F cells, the channels were
blocked by cytosolic, but not extracellular, ruthenium red. Subcellular
fractionation showed that type 3 IP3 receptors (IP3R3)
were expressed predominantly in endoplasmic reticulum, whereas RyR2 were
present also in plasma membrane fractions. Using RNAi selectively to reduce
expression of RyR1, RyR2, or IP3R3, we showed that RyR2 mediates
both the Ca2+ entry and the plasma membrane currents evoked by
agonists of RyR. We conclude that small numbers of RyR2 are selectively
expressed in the plasma membrane of RINm5F pancreatic β-cells, where they
mediate Ca2+ entry.Ryanodine receptors
(RyR)3 and inositol
1,4,5-trisphosphate receptors (IP3R)
(1,
2) are the archetypal
intracellular Ca2+ channels. Both are widely expressed, although
RyR are more restricted in their expression than IP3R
(3,
4). In common with many cells,
pancreatic β-cells and insulin-secreting cell lines express both
IP3R (predominantly IP3R3)
(5,
6) and RyR (predominantly RyR2)
(7). Both RyR and
IP3R are expressed mostly within membranes of the endoplasmic (ER),
where they mediate release of Ca2+. Functional RyR are also
expressed in the secretory vesicles
(8,
9) or, and perhaps more likely,
in the endosomes of β-cells
(10). Despite earlier
suggestions (11),
IP3R are probably not present in the secretory vesicles of
β-cells (8,
12,
13).All three subtypes of IP3R are stimulated by IP3 with
Ca2+ (1), and the
three subtypes of RyR are each directly regulated by Ca2+. However,
RyR differ in whether their most important physiological stimulus is
depolarization of the plasma membrane (RyR1), Ca2+ (RyR2) or
additional intracellular messengers like cyclic ADP-ribose. The latter
stimulates both Ca2+ release and insulin secretion in β-cells
(8,
14). The activities of both
families of intracellular Ca2+ channels are also modulated by many
additional signals that act directly or via phosphorylation
(15,
16). Although they commonly
mediate release of Ca2+ from the ER, both IP3R and RyR
select rather poorly between Ca2+ and other cations (permeability
ratio, PCa/PK ∼7)
(1,
17). This may allow
electrogenic Ca2+ release from the ER to be rapidly compensated by
uptake of K+ (18),
and where RyR or IP3R are expressed in other membranes it may allow
them to affect membrane potential.Both Ca2+ entry and release of Ca2+ from
intracellular stores contribute to the oscillatory increases in cytosolic
Ca2+ concentration ([Ca2+]i) that
stimulate exocytosis of insulin-containing vesicles in pancreatic β-cells
(7). Glucose rapidly
equilibrates across the plasma membrane (PM) of β-cells and its oxidative
metabolism by mitochondria increases the cytosolic ATP/ADP ratio, causing
KATP channels to close
(19). This allows an
unidentified leak current to depolarize the PM
(20) and activate
voltage-gated Ca2+ channels, predominantly L-type Ca2+
channels (21). The resulting
Ca2+ entry is amplified by Ca2+-induced Ca2+
release from intracellular stores
(7), triggering exocytotic
release of insulin-containing dense-core vesicles
(22). The importance of this
sequence is clear from the widespread use of sulfonylurea drugs, which close
KATP channels, in the treatment of type 2 diabetes. Ca2+
uptake by mitochondria beneath the PM further stimulates ATP production,
amplifying the initial response to glucose and perhaps thereby contributing to
the sustained phase of insulin release
(23). However, neither the
increase in [Ca2+]i nor the insulin release
evoked by glucose or other nutrients is entirely dependent on Ca2+
entry (7,
24) or closure of
KATP channels (25).
This suggests that glucose metabolism may also more directly activate RyR
(7,
26) and/or IP3R
(27) to cause release of
Ca2+ from intracellular stores. A change in the ATP/ADP ratio is
one means whereby nutrient metabolism may be linked to opening of
intracellular Ca2+ channels because both RyR
(28) and IP3R
(1) are stimulated by ATP.The other major physiological regulators of insulin release are the
incretins: glucagon-like peptide-1 and glucose-dependent insulinotropic
hormone (29). These hormones,
released by cells in the small intestine, stimulate synthesis of cAMP in
β-cells and thereby potentiate glucose-evoked insulin release
(30). These pathways are also
targets of drugs used successfully to treat type 2 diabetes
(29). The responses of
β-cells to cAMP involve both cAMP-dependent protein kinase and epacs
(exchange factors activated by cAMP)
(31,
32). The effects of the latter
are, at least partly, due to release of Ca2+ from intracellular
stores via RyR
(33–35)
and perhaps also via IP3R
(36). The interplays between
Ca2+ and cAMP signaling generate oscillatory changes in the
concentrations of both messengers
(37). RyR and IP3R
are thus implicated in mediating responses to each of the major physiological
regulators of insulin secretion: glucose and incretins.Here we report that in addition to expression in intracellular stores,
which probably include both the ER and secretory vesicles and/or endosomes,
functional RyR2 are also expressed in small numbers in the PM of RINm5F
insulinoma cells and rat pancreatic β-cells. 相似文献
105.
A QTL study on late leaf spot and rust revealed one major QTL for molecular breeding for rust resistance in groundnut (Arachis hypogaea L.) 总被引:1,自引:0,他引:1
Y. P. Khedikar M. V. C. Gowda C. Sarvamangala K. V. Patgar H. D. Upadhyaya R. K. Varshney 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2010,120(5):971-984
Late leaf spot (LLS) and rust are two major foliar diseases of groundnut (Arachis hypogaea L.) that often occur together leading to 50–70% yield loss in the crop. A total of 268 recombinant inbred lines of a mapping
population TAG 24 × GPBD 4 segregating for LLS and rust were used to undertake quantitative trait locus (QTL) analysis. Phenotyping
of the population was carried out under artificial disease epiphytotics. Positive correlations between different stages, high
to very high heritability and independent nature of inheritance between both the diseases were observed. Parental genotypes
were screened with 1,089 simple sequence repeat (SSR) markers, of which 67 (6.15%) were found polymorphic. Segregation data
obtained for these markers facilitated development of partial linkage map (14 linkage groups) with 56 SSR loci. Composite
interval mapping (CIM) undertaken on genotyping and phenotyping data yielded 11 QTLs for LLS (explaining 1.70–6.50% phenotypic
variation) in three environments and 12 QTLs for rust (explaining 1.70–55.20% phenotypic variation). Interestingly a major
QTL associated with rust (QTLrust01), contributing 6.90–55.20% variation, was identified by both CIM and single marker analysis (SMA). A candidate SSR marker
(IPAHM 103) linked with this QTL was validated using a wide range of resistant/susceptible breeding lines as well as progeny
lines of another mapping population (TG 26 × GPBD 4). Therefore, this marker should be useful for introgressing the major
QTL for rust in desired lines/varieties of groundnut through marker-assisted backcrossing. 相似文献
106.
Swarnima Agnihotri Dharm Dutt C. H. Tyagi Alok Kumar J. S. Upadhyaya 《World journal of microbiology & biotechnology》2010,26(8):1349-1359
Fungi producing xylanases are plentiful but alkali-thermo-tolerant fungi producing cellulase-poor xylanase are rare. Out of
12 fungal strains isolated from various sources, Coprinellus disseminatus SW-1 NTCC 1165 yielded the highest xylanase activity (362.1 IU/ml) with minimal cellulase contamination (0.64 IU/ml). The
solid state fermentation was more effective yielding 88.59% higher xylanase activity than that of submerged fermentation.
An incubation period of 7 days at 37°C and pH 6.4 accelerated the xylanase production up to the maximum level. Among various
inexpensive agro-residues used as carbon source, wheat bran induced the maximum xylanase titres (469.45 IU/ml) while soya
bean meal was the best nitrogen source (478.5 IU/ml). A solid substrate to moisture content ratio of 1:3 was suitable for
xylanase production while xylanase titre was repressed with the addition of glucose and lactose. The xylanase and laccase
activities under optimized conditions were 499.60 and 25.5 IU/ml, respectively along with negligible cellulase contamination
(0.86 IU/ml). Biochemical characterization revealed that optimal xylanase activity was observed at pH 6.4 and temperature
55°C and xylanase is active up to pH 9 (40.33 IU/ml) and temperature 85°C (48.81 IU/ml). SDS–PAGE and zymogram analysis indicated
that molecular weight of alkali-thermo-tolerant xylanase produced by C. disseminatus SW-1 NTCC 1165 was 43 kDa. 相似文献
107.
108.
All CG dinucleotides along exons 5-8 of the p53 tumor suppressor gene contain endogenous 5-methylcytosine (MeC). These same sites (e.g., codons 157, 158, 245, 248, and 273) are mutational hot spots in smoking-induced lung cancer. Several groups used the UvrABC endonuclease incision assay to demonstrate that methylated CG dinucleotides of the p53 gene are the preferred binding sites for the diol epoxides of bay region polycyclic aromatic hydrocarbons (PAH). In contrast, effects of endogenous cytosine methylation on the distribution of DNA lesions induced by tobacco-specific nitrosamines, e.g., 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), have not been elucidated. In the work presented here, a stable isotope labeling HPLC-ESI-MS/MS approach was employed to analyze the reactivity of the N7 and O6 positions of guanines within hemimethylated and fully methylated CG dinucleotides toward NNK-derived methylating and pyridyloxobutylating species. 15N3-labeled guanine bases were placed within synthetic DNA sequences representing endogenously methylated p53 codons 154, 157, and 248, followed by treatment with acetylated precursors to NNK diazohydroxides. HPLC-ESI-MS/MS analysis was used to determine the relative yields of N7- and O6-guanine adducts at the 15N3-labeled position. In all cases, the presence of MeC inhibited the formation of N7-methylguanine, O6-methylguanine, and O6-pyridyloxobutylguanine at a neighboring G, with the greatest decrease observed in fully methylated dinucleotides and at guanines preceded by MeC. Furthermore, the O6-Me-dG/N7-Me-G molar ratios were decreased in the presence of the 5'-neighboring MeC, suggesting that the observed decline in O6-alkylguanine adduct yields is, at least partially, a result of an altered reactivity pattern in methylated CG dinucleotides. These results indicate that, unlike N2-guanine adducts of PAH diol epoxides, NNK-induced N7- and O6-alkylguanine adducts are not preferentially formed at the endogenously methylated CG sites within the p53 tumor suppressor gene. 相似文献
109.
Upadhyaya M Majounie E Thompson P Han S Consoli C Krawczak M Cordeiro I Cooper DN 《Human genetics》2003,112(1):12-17
Three members of a Portuguese family, who exhibited clinical evidence of neurofibromatosis type 1 (NF1), were found to possess different heritable and pathological mutations in their NF1 genes: a 1.5-Mb deletion spanning the entire NF1 gene, a truncating CGA-->TGA transition in exon 22 (R1241X), and a frameshift mutation in exon 29 (5406insT). All three lesions occurred de novo and are likely to have been generated by different mutational mechanisms. At least two of the mutations occurred on different chromosomal backgrounds. The probability of finding three non-identical NF1 gene lesions arising de novo in a family with NF1 is very remote, too low to be readily accepted as mere coincidence. A number of possible explanations for this unique finding were therefore explored, but none were found to be wholly convincing. This report nevertheless serves as a reminder that it is unwise, even in the case of an autosomal dominant condition, to extrapolate from the detection of a single mutation in a specific individual to assuming an identical molecular genetic aetiology in other clinically affected members of the same family. 相似文献
110.
NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes 总被引:8,自引:0,他引:8
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Douglas J Hanks S Temple IK Davies S Murray A Upadhyaya M Tomkins S Hughes HE Cole TR Rahman N 《American journal of human genetics》2003,72(1):132-143
Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes. 相似文献