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31.
Procedures for two-sample comparisons with multiple endpoints controlling the experimentwise error rate 总被引:3,自引:0,他引:3
Clinical trials are often concerned with the comparison of two treatment groups with multiple endpoints. As alternatives to the commonly used methods, the T2 test and the Bonferroni method, O'Brien (1984, Biometrics 40, 1079-1087) proposes tests based on statistics that are simple or weighted sums of the single endpoints. This approach turns out to be powerful if all treatment differences are in the same direction [compare Pocock, Geller, and Tsiatis (1987, Biometrics 43, 487-498)]. The disadvantage of these multivariate methods is that they are suitable only for demonstrating a global difference, whereas the clinician is further interested in which specific endpoints or sets of endpoints actually caused this difference. It is shown here that all tests are suitable for the construction of a closed multiple test procedure where, after the rejection of the global hypothesis, all lower-dimensional marginal hypotheses and finally the single hypotheses are tested step by step. This procedure controls the experimentwise error rate. It is just as powerful as the multivariate test and, in addition, it is possible to detect significant differences between the endpoints or sets of endpoints. 相似文献
32.
Frank?Qian Ye?Feng Yonglan?Zheng Temidayo?O.?Ogundiran Oladosu?Ojengbede Wei?Zheng William?Blot Christine?B.?Ambrosone Esther?M.?John Leslie?Bernstein Jennifer?J.?Hu Regina?G.?Ziegler Sarah?Nyante Elisa?V.?Bandera Sue?A.?Ingles Michael?F.?Press Katherine?L.?Nathanson Anselm?Hennis Barbara?Nemesure Stefan?Ambs Laurence?N.?Kolonel Olufunmilayo?I.?Olopade Christopher?A.?Haiman Dezheng?HuoEmail author 《Human genetics》2016,135(10):1145-1159
MicroRNAs (miRNA) regulate breast biology by binding to specific RNA sequences, leading to RNA degradation and inhibition of translation of their target genes. While germline genetic variations may disrupt some of these interactions between miRNAs and their targets, studies assessing the relationship between genetic variations in the miRNA network and breast cancer risk are still limited, particularly among women of African ancestry. We systematically put together a list of 822 and 10,468 genetic variants among primary miRNA sequences and 38 genes in the miRNA biogenesis pathway, respectively; and examined their association with breast cancer risk in the ROOT consortium which includes women of African ancestry. Findings were replicated in an independent consortium. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55–0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82–0.95, P = 3.99 × 10?4), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11–1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63–0.89, P = 0.001) were found to have significant associations in both discovery and validation phases. In a subgroup analysis, two SNPs were associated with risk of estrogen receptor (ER)-negative breast cancer, and three SNPs were associated with risk of ER-positive breast cancer. Several variants in miRNA and miRNA biogenesis pathway genes were associated with breast cancer risk. Risk associations varied by ER status, suggesting potential new mechanisms in etiology. 相似文献
33.
1. The evaluation of restoration measures is an important task of conservation biology. Inland sand dunes and dry, oligotrophic grasslands have become rare habitat types in large parts of Central Europe and their restoration and management is of major importance for the preservation of many endangered plant and insect species. Within such habitats, it is important to restore key ecosystem services, such as pollination networks. As wild bees are the most important pollinators in many ecosystems, they represent a suitable key group to evaluate restoration measures. Furthermore, the recent decline of many bee species and the potential ecological and economic consequences are currently topics of strong scientific interest.
2. We studied the succession of bee communities in response to restoration measures of sand dunes and sand grasslands and compared these communities with those of old sand dune complexes.
3. Our results show that wild bees respond rapidly to restoration measures indicated by a high species richness and abundance. The community structure of bees at restoration sites converged only slightly to those of the target sites. A higher similarity was found between bee communities at the restoration sites (sand dunes and grasslands), indicating that their close proximity was an important determinant of species overlap. Environmental factors such as the number of entomophilous plant species and moisture had a strong influence on wild bee species composition.
4. Synthesis and applications . The restoration of inland sand dune complexes provides opportunities for colonization by a diverse wild bee community. Although it is difficult to establish a given target community, restoration measures gave rise to a high pollinator diversity and abundance, suggesting that community function can be re-established. 相似文献
2. We studied the succession of bee communities in response to restoration measures of sand dunes and sand grasslands and compared these communities with those of old sand dune complexes.
3. Our results show that wild bees respond rapidly to restoration measures indicated by a high species richness and abundance. The community structure of bees at restoration sites converged only slightly to those of the target sites. A higher similarity was found between bee communities at the restoration sites (sand dunes and grasslands), indicating that their close proximity was an important determinant of species overlap. Environmental factors such as the number of entomophilous plant species and moisture had a strong influence on wild bee species composition.
4. Synthesis and applications . The restoration of inland sand dune complexes provides opportunities for colonization by a diverse wild bee community. Although it is difficult to establish a given target community, restoration measures gave rise to a high pollinator diversity and abundance, suggesting that community function can be re-established. 相似文献
34.
Eun-Yeong Bergsdorf Anselm A. Zdebik Thomas J. Jentsch 《The Journal of biological chemistry》2009,284(17):11184-11193
Members of the CLC gene family either function as chloride channels or as
anion/proton exchangers. The plant AtClC-a uses the pH gradient across the
vacuolar membrane to accumulate the nutrient
in this organelle. When AtClC-a was
expressed in Xenopus oocytes, it mediated
exchange
and less efficiently mediated Cl–/H+ exchange.
Mutating the “gating glutamate” Glu-203 to alanine resulted in an
uncoupled anion conductance that was larger for Cl– than
. Replacing the “proton
glutamate” Glu-270 by alanine abolished currents. These could be
restored by the uncoupling E203A mutation. Whereas mammalian endosomal ClC-4
and ClC-5 mediate stoichiometrically coupled
2Cl–/H+ exchange, their
transport is largely uncoupled from
protons. By contrast, the AtClC-a-mediated
accumulation in plant vacuoles
requires tight
coupling. Comparison of AtClC-a and ClC-5 sequences identified a proline in
AtClC-a that is replaced by serine in all mammalian CLC isoforms. When this
proline was mutated to serine (P160S), Cl–/H+
exchange of AtClC-a proceeded as efficiently as
exchange, suggesting a role of this residue in
exchange. Indeed, when the corresponding serine of ClC-5 was replaced by
proline, this Cl–/H+ exchanger gained efficient
coupling. When inserted into the model Torpedo chloride channel
ClC-0, the equivalent mutation increased nitrate relative to chloride
conductance. Hence, proline in the CLC pore signature sequence is important
for
exchange and conductance both in
plants and mammals. Gating and proton glutamates play similar roles in
bacterial, plant, and mammalian CLC anion/proton exchangers.CLC proteins are found in all phyla from bacteria to humans and either
mediate electrogenic anion/proton exchange or function as chloride channels
(1). In mammals, the roles of
plasma membrane CLC Cl– channels include transepithelial
transport
(2–5)
and control of muscle excitability
(6), whereas vesicular CLC
exchangers may facilitate endocytosis
(7) and lysosomal function
(8–10)
by electrically shunting vesicular proton pump currents
(11). In the plant
Arabidopsis thaliana, there are seven CLC isoforms
(AtClC-a–AtClC-g)2
(12–15),
which may mostly reside in intracellular membranes. AtClC-a uses the pH
gradient across the vacuolar membrane to transport the nutrient nitrate into
that organelle (16). This
secondary active transport requires a tightly coupled
exchange. Astonishingly, however, mammalian ClC-4 and -5 and bacterial EcClC-1
(one of the two CLC isoforms in Escherichia coli) display tightly
coupled Cl–/H+ exchange, but anion flux is largely
uncoupled from H+ when
is transported
(17–21).
The lack of appropriate expression systems for plant CLC transporters
(12) has so far impeded
structure-function analysis that may shed light on the ability of AtClC-a to
perform efficient
exchange. This dearth of data contrasts with the extensive mutagenesis work
performed with CLC proteins from animals and bacteria.The crystal structure of bacterial CLC homologues
(22,
23) and the investigation of
mutants (17,
19–21,
24–29)
have yielded important insights into their structure and function. CLC
proteins form dimers with two largely independent permeation pathways
(22,
25,
30,
31). Each of the monomers
displays two anion binding sites
(22). A third binding site is
observed when a certain key glutamate residue, which is located halfway in the
permeation pathway of almost all CLC proteins, is mutated to alanine
(23). Mutating this gating
glutamate in CLC Cl– channels strongly affects or even
completely suppresses single pore gating
(23), whereas CLC exchangers
are transformed by such mutations into pure anion conductances that are not
coupled to proton transport
(17,
19,
20). Another key glutamate,
located at the cytoplasmic surface of the CLC monomer, seems to be a hallmark
of CLC anion/proton exchangers. Mutating this proton glutamate to
nontitratable amino acids uncouples anion transport from protons in the
bacterial EcClC-1 protein (27)
but seems to abolish transport altogether in mammalian ClC-4 and -5
(21). In those latter
proteins, anion transport could be restored by additionally introducing an
uncoupling mutation at the gating glutamate
(21).The functional complementation by AtClC-c and -d
(12,
32) of growth phenotypes of a
yeast strain deleted for the single yeast CLC Gef1
(33) suggested that these
plant CLC proteins function in anion transport but could not reveal details of
their biophysical properties. We report here the first functional expression
of a plant CLC in animal cells. Expression of wild-type (WT) and mutant
AtClC-a in Xenopus oocytes indicate a general role of gating and
proton glutamate residues in anion/proton coupling across different isoforms
and species. We identified a proline in the CLC signature sequence of AtClC-a
that plays a crucial role in
exchange. Mutating it to serine, the residue present in mammalian CLC proteins
at this position, rendered AtClC-a Cl–/H+ exchange
as efficient as
exchange. Conversely, changing the corresponding serine of ClC-5 to proline
converted it into an efficient
exchanger. When proline replaced the critical serine in Torpedo
ClC-0, the relative conductance of
this model Cl– channel was drastically increased, and
“fast” protopore gating was slowed. 相似文献
35.
Detection of Hemolysin Variants of Shiga Toxin-Producing Escherichia coli by PCR and Culture on VancomycinCefixime-Cefsulodin Blood Agar
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Anselm Lehmacher Heidi Meier Stojanka Aleksic Jochen Bockemühl 《Applied microbiology》1998,64(7):2449-2453
The presence of a hemolysin-encoding gene, elyA or hlyA, from Shiga toxin-producing Escherichia coli (STEC) was detected by PCR in each of 95 strains tested. PCR products of elyA from human STEC isolates of serovars frequently detected in Germany, such as O157:H−, O103:H2, O103:H−, O26:H11, and O26:H−, showed nucleotide sequences identical to previously reported ones for O157:H7 and O111:H− strains. Compared to them, four elyA amplicons derived from human isolates of rare STEC serovars showed identity of about 98% but lacked an AluI restriction site. However, the nucleotide sequence of an amplicon derived from a porcine O138:K81:H− STEC strain was identical to the corresponding region of hlyA, encoding alpha-hemolysin, from E. coli. This hlyA amplicon showed 68% identity with the nucleotide sequence of the corresponding elyA fragment. It differed from the elyA PCR product in restriction fragments generated by AluI, EcoRI, and MluI. Of the 95 representative STEC strains, 88 produced hemolysin on blood agar supplemented with vancomycin (30 mg/liter), cefixime (20 μg/liter), and cefsulodin (3 mg/liter) (BVCC). The lowest added numbers of two to six STEC CFU per g of stool or per ml of raw milk were detectable on BVCC plates after seeding of the preenrichment broth, modified tryptic soy broth (mTSB) supplemented with novobiocin (10 mg/liter), with 16 STEC strains. These strains represented the seven prevailing serovars diagnosed from German patients. However, with ground-beef samples, PCR was essential to identify the lowest added numbers of two to six STEC CFU among colonies of hemolyzing Enterobacteriaceae, such as Serratia spp. and alpha-hemolysin-producing E. coli. We conclude that preenrichment of stool and food samples in mTSB for 6 h followed by overnight culturing on BVCC is a simple method for the isolation and presumptive identification of STEC. 相似文献
36.
37.
38.
A genetic screen for dominant modifiers of a small-wing phenotype in Drosophila melanogaster identifies proteins involved in splicing and translation
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Coelho CM Kolevski B Walker CD Lavagi I Shaw T Ebert A Leevers SJ Marygold SJ 《Genetics》2005,171(2):597-614
Studies in the fly, Drosophila melanogaster, have revealed that several signaling pathways are important for the regulation of growth. Among these, the insulin receptor/phosphoinositide 3-kinase (PI3K) pathway is remarkable in that it affects growth and final size without disturbing pattern formation. We have used a small-wing phenotype, generated by misexpression of kinase-dead PI3K, to screen for novel mutations that specifically disrupt organ growth in vivo. We identified several complementation groups that dominantly enhance this small-wing phenotype. Meiotic recombination in conjunction with visible markers and single-nucleotide polymorphisms (SNPs) was used to map five enhancers to single genes. Two of these, nucampholin and prp8, encode pre-mRNA splicing factors. The three other enhancers encode factors required for mRNA translation: pixie encodes the Drosophila ortholog of yeast RLI1, and RpL5 and RpL38 encode proteins of the large ribosomal subunit. Interestingly, mutations in several other ribosomal protein-encoding genes also enhance the small-wing phenotype used in the original screen. Our work has therefore identified mutations in five previously uncharacterized Drosophila genes and provides in vivo evidence that normal organ growth requires optimal regulation of both pre-mRNA splicing and mRNA translation. 相似文献
39.
Pedro Ordunez Elisa Prieto-Lara Vilma Pinheiro Gawryszewski Anselm J. M. Hennis Richard S. Cooper 《PloS one》2015,10(10)
Background
Cardiovascular diseases (CVD) are the underlying cause 1.6 million deaths per year in the Americas, accounting for 30% of total mortality and 38% of by non-communicable deaths diseases (NCDs). A 25% reduction in premature mortality due four main NCDs was targeted by the 2011 High-level Meeting of the General Assembly on the Prevention and Control of NCDs. While overall CVD mortality fell in the Americas during the past decade, trends in premature CVD mortality during the same period have not been described, particularly in the countries of Latin America and the Caribbean.Methods
This is a population-based trend-series study based on a total of 6,133,666 deaths to describe the trends and characteristics of premature mortality due to CVD and to estimates of the average annual percentage of change during the period 2000–2010 in the Americas.Findings
Premature mortality due to CVD in the Americas fell by 21% in the period 2000–2010 with a -2.5% average annual rate of change in the last 5 year—a statistically significant reduction of mortality—. Mortality from ischemic diseases, declined by 25% - 24% among men and 26% among women. Cerebrovascular diseases declined by 27% -26% among men and 28% among women. Guyana, Trinidad and Tobago, the Dominican Republic, Bahamas, and Brazil had CVD premature mortality rates over 200 per 100,000 population, while the average for the Region was 132.7. US and Canada will meet the 25% reduction target before 2025. Mexico, Costa Rica, Venezuela, Dominican Republic, Panama, Guyana, and El Salvador did not significantly reduce premature mortality among men and Guyana, the Dominican Republic, and Panama did not achieve the required annual reduction in women.Conclusions
Trends in premature mortality due to CVD observed in last decade in the Americas would indicate that if these trends continue, the Region as a whole and a majority of its countries will be able to reach the goal of a 25% relative reduction in premature mortality even before 2025. 相似文献40.
Anne E. den Heijer Yvonne Groen Anselm B. M. Fuermaier Marieke J. G. van Heuvelen Eddy A. van der Zee Lara Tucha Oliver Tucha 《PloS one》2015,10(11)