首页 | 本学科首页   官方微博 | 高级检索  
相似文献
 共查询到20条相似文献,搜索用时 31 毫秒
1.
Death Receptor 5 (DR5) agonists demonstrate anti-tumor activity in preclinical models but have yet to demonstrate robust clinical responses. A key limitation may be the lack of patient selection strategies to identify those most likely to respond to treatment. To overcome this limitation, we screened a DR5 agonist Nanobody across >600 cell lines representing 21 tumor lineages and assessed molecular features associated with response. High expression of DR5 and Casp8 were significantly associated with sensitivity, but their expression thresholds were difficult to translate due to low dynamic ranges. To address the translational challenge of establishing thresholds of gene expression, we developed a classifier based on ratios of genes that predicted response across lineages. The ratio classifier outperformed the DR5+Casp8 classifier, as well as standard approaches for feature selection and classification using genes, instead of ratios. This classifier was independently validated using 11 primary patient-derived pancreatic xenograft models showing perfect predictions as well as a striking linearity between prediction probability and anti-tumor response. A network analysis of the genes in the ratio classifier captured important biological relationships mediating drug response, specifically identifying key positive and negative regulators of DR5 mediated apoptosis, including DR5, CASP8, BID, cFLIP, XIAP and PEA15. Importantly, the ratio classifier shows translatability across gene expression platforms (from Affymetrix microarrays to RNA-seq) and across model systems (in vitro to in vivo). Our approach of using gene expression ratios presents a robust and novel method for constructing translatable biomarkers of compound response, which can also probe the underlying biology of treatment response.  相似文献   

2.
Likelihood ratio tests are derived for bivariate normal structural relationships in the presence of group structure. These tests may also be applied to less restrictive models where only errors are assumed to be normally distributed. Tests for a common slope amongst those from several datasets are derived for three different cases – when the assumed ratio of error variances is the same across datasets and either known or unknown, and when the standardised major axis model is used. Estimation of the slope in the case where the ratio of error variances is unknown could be considered as a maximum likelihood grouping method. The derivations are accompanied by some small sample simulations, and the tests are applied to data arising from work on seed allometry.  相似文献   

3.
In a stratified analysis, the results from different strata if homogeneity assumption is met are pooled together to obtain a single summary estimate for the common effect parameter. However, the effect can appear homogeneous across strata using one measure but heterogeneous using another. Consequently, two researchers analyzing the same data can arrive at conflicting conclusions if they use different effect measures. In this paper, the author draws on the sufficient component cause model to develop a stratified-analysis method regarding a particular effect measure, the ‘peril ratio’. When there is no mechanistic interaction between the exposure under study and the stratifying variable (i.e., when they do not work together to complete any sufficient cause), the peril ratio is constant across strata. The author presents formulas for the estimation of such a common peril ratio. Three real data are re-analyzed for illustration. When the data is consistent with peril-ratio homogeneity in a stratified analysis, researchers can use the formulas in this paper to pool the strata.  相似文献   

4.
Question: Since increases in altitude and grazing intensity generally result in decreases in height growth of alpine grasslands, plant height may integrate effects of environmental stress and grazing disturbance and provide better assessments of the variation in root: shoot (R: S) biomass ratio than other variables. However, it is unclear if there is a general relationship between plant height and R:S ratio across grassland ecosystems. Such knowledge would be helpful for root biomass estimation in grasslands. Location: An altitudinal transect in the Gonghe Basin (2880–4040 m a.s.l.), northeast Tibetan plateau. Methods: We measured standing biomass both above‐ground and below‐ground, maximum plant height (MPH) and soil variables across 43 plots. Results: Climatic variables explained the variations in MPH and R: S ratio of undegraded grasslands better than soil variables (46–50% vs < 19%), while those of degraded grasslands generally showed insignificant correlations with climatic and soil variables. There was a general relationship between R: S ratio and MPH (negative, R2= 0.76, P< 0.001) across degraded and undegraded grasslands. The relationship was used to predict R: S ratio in 13 additional plots in steppe grasslands of Inner Mongolia, and good agreement of expected and observed values has been found (R2= 0.87, P < 0.001). Conclusions: MPH, that is relatively easy to measure, can be used to predict R:S ratio at plot to regional scales. It is promising to develop a new method for large‐scale estimation of root biomass in grasslands using MPH and shoot biomass avoiding tedious procedures of physical measuring of above and below‐ground biomass.  相似文献   

5.
Group-sequential tests may be applied to trials in which the number of patients is fixed, a response variable is measured for each patient at successive follow-up visits, and the accumulated responses are compared across treatment groups. The standard theory is inapplicable because the increments in the accumulated responses are no longer independent. An adjustment can be made to allow for the ratio of between-patient to within-patient variance and for possible first-order autocorrelation. The method is illustrated by reference to a dental trial.  相似文献   

6.
DNA sequence copy number has been shown to be associated with cancer development and progression. Array-based comparative genomic hybridization (aCGH) is a recent development that seeks to identify the copy number ratio at large numbers of markers across the genome. Due to experimental and biological variations across chromosomes and hybridizations, current methods are limited to analyses of single chromosomes. We propose a more powerful approach that borrows strength across chromosomes and hybridizations. We assume a Gaussian mixture model, with a hidden Markov dependence structure and with random effects to allow for intertumoral variation, as well as intratumoral clonal variation. For ease of computation, we base estimation on a pseudolikelihood function. The method produces quantitative assessments of the likelihood of genetic alterations at each clone, along with a graphical display for simple visual interpretation. We assess the characteristics of the method through simulation studies and analysis of a brain tumor aCGH data set. We show that the pseudolikelihood approach is superior to existing methods both in detecting small regions of copy number alteration and in accurately classifying regions of change when intratumoral clonal variation is present. Software for this approach is available at http://www.biostat.harvard.edu/ approximately betensky/papers.html.  相似文献   

7.
A light-scattering technique used to measure the water permeability across closed biomembranes is described, which is based on the different indices of refraction of D2O and H2O. This transient technique is compared with a similar method using D2O-sensitive fluorophores in the intravesicular space. The results of both techniques are equivalent although the signal-to-noise ratio favors the light-scattering or turbidity experiment. The light-scattering method is only applicable to larger particles (no point-scatterers) and is easily extended to biological objects. Data on the H2O/D2O exchange across membranes of ghosts from human erythrocytes suggest two mechanisms: the D2O and H2O permeation through the membrane and a slower D2O-induced conformational change of membraneous proteins.  相似文献   

8.
Craig Loehle 《Ecography》2012,35(6):487-498
A new approach to habitat distribution modeling is presented and tested with data on North American plants. The relative frequency function (RFF) algorithm compares the relative frequencies of a species’ sample points to that of random points or absence points on the landscape to compute a frequency ratio. The relative frequency ratio r is smoothed across the range of values using moving, overlapping windows. The ratio of frequencies at a sample point for each variable is used to compute the geometric mean score for all data with non‐missing values. Variables are added using a forward stepwise method. Confidence intervals are computed with bootstrap resampling. The method was tested with artificial and species habitat and geographic range data. The RFF method in all cases gave results comparable to other methods tested. For the species with good geographic range maps, the results were consistent with known biogeography. The RFF method is particularly well‐suited to irregularly shaped distributions and can classify sample points even when the data contain missing values. The method is extremely simple to use and comes with a free software tool, does not require a large sample size, does not require absence data, and is more interpretable and portable than certain other methods.  相似文献   

9.
Evolutionary biologists have long been interested in the macroevolutionary consequences of various selection pressures, yet physiological responses to selection across deep time are not well understood. In this paper, we investigate how a physiologically relevant morphological trait, surface area to volume ratio (SA:V) of lungless salamanders, has evolved across broad regional and climatic variation. SA:V directly impacts an organisms’ ability to retain water, leading to the expectation that smaller SA:Vs would be advantageous in arid, water-limited environments. To explore the macroevolutionary patterns of SA:V, we first develop an accurate method for estimating SA:V from linear measurements. Next, we investigate the macroevolutionary patterns of SA:V across 257 salamander species, revealing that higher SA:Vs phylogenetically correlate with warmer, wetter climates. We also observe higher SA:V disparity and rate of evolution in tropical species, mirrored by higher climatic disparity in available and occupied tropical habitats. Taken together, these results suggest that the tropics have provided a wider range of warmer, wetter climates for salamanders to exploit, thereby relaxing desiccation pressures on SA:V. Overall, this paper provides an accurate, efficient method for quantifying salamander SA:V, allowing us to demonstrate the power of physiological selection pressures in influencing the macroevolution of morphology.  相似文献   

10.
Summary The red cell pH of lamprey (Lampetra fluviatilis) was measured using the DMO method (based on the passive distribution of the wead acid, DMO, across the red cell membrane). The measured red cell pH was higher than the pH of the incubation medium throughout the pH range (7.2–8.2) studied, and higher than the red cell pH calculated from the chloride distribution ratio. Treatment of cells with the metabolic inhibitors 2,4-dinitrophenol or KCN caused a drop in the red cell pH to values lower than the pH of incubation medium, and abolished the difference between the measured red cell pH and the pH calculated from the chloride distribution ratio. These data strongly suggest that the proton gradient across lamprey red cell membrane is actively maintained. Acid extrusion from lamprey red cells may require sodium, as indicated by the observation that when choline was substituted for sodium in the incubation medium, the intracellular pH decreased significantly.  相似文献   

11.
Sex ratio of progeny should be balanced if costs and benefits of rearing sons and daughters are equal. However, shifts in sex ratio have been demonstrated across bird species and it was suggested that females are able to adjust the primary sex ratio. One possible mechanism is the glucocorticoid corticosterone which rises under stressful conditions and can be deposited into egg yolk by mothers. We analysed primary sex ratio of common terns Sterna hirundo from 2006 to 2008 and related it to maternal baseline corticosterone level, laying date and year. Therefore, we took 101 blood samples of 71 breeding females via blood sucking bugs, a method with negligible stress for the birds. Sex ratio did not differ from parity in any of the analysed years, which were characterized by poor food availability and breeding success. Only within 1 year there was a tendency for more females in the last hatched chick. Neither corticosterone level nor laying date or year showed an influence on hatching sex ratio. The negative result concerning primary sex ratio and maternal baseline corticosterone level might suggest conditions to be good enough for mothers to prevent them from depositing high levels of corticosterone into eggs.  相似文献   

12.
Demembranated cilia of Tetrahymena pyriformis were extracted with KCl or Tris-EDTA and the crude dyneins from each resolved by sucrose density gradient sedimentation into 14S-K, 30S-K, 14S-E and 30S-E dyneins, respectively. The calmodulin activation ratio (ATPase activity in presence of added calmodulin/ATPase activity in absence of added calmodulin) did not vary across the 30S dynein fractions regardless of the method of extraction nor did it vary across the 14S-E region. However, in going from the “heavy” fractions to the “light” fractions of the 14S-K region, it increased markedly. The concentration of calmodulin required for half-maximal activation did not differ appreciably in the “light” versus the “heavy” fractions of the 14S-K region, suggesting that the affinity for calmodulin does not vary in these fractions. SDS-polyacrylamide gel electrophoresis studies showed the presence of several polypeptides that varied in a systematic fashion across the 14S-K region and hence may be involved in regulating the sensitivity of 14S-K dynein ATPase activity to added calmodulin.  相似文献   

13.
A common reference for cDNA microarray hybridizations   总被引:4,自引:3,他引:1  
Comparisons of expression levels across different cDNA microarray experiments are easier when a common reference is co-hybridized to every microarray. Often this reference consists of one experimental control sample, a pool of cell lines or a mix of all samples to be analyzed. We have developed an alternative common reference consisting of a mix of the products that are spotted on the array. Pooling part of the cDNA PCR products before they are printed and their subsequent amplification towards either sense or antisense cRNA provides an excellent common reference. Our results show that this reference yields a reproducible hybridization signal in 99.5% of the cDNA probes spotted on the array. Accordingly, a ratio can be calculated for every spot, and expression levels across different hybridizations can be compared. In dye-swap experiments this reference shows no significant ratio differences, with 95% of the spots within an interval of ±0.2-fold change. The described method can be used in hybridizations with both amplified and non-amplified targets, is time saving and provides a constant batch of common reference that lasts for thousands of hybridizations.  相似文献   

14.
Comparing a protein's concentrations across two or more treatments is the focus of many proteomics studies. A frequent source of measurements for these comparisons is a mass spectrometry (MS) analysis of a protein's peptide ions separated by liquid chromatography (LC) following its enzymatic digestion. Alas, LC-MS identification and quantification of equimolar peptides can vary significantly due to their unequal digestion, separation, and ionization. This unequal measurability of peptides, the largest source of LC-MS nuisance variation, stymies confident comparison of a protein's concentration across treatments. Our objective is to introduce a mixed-effects statistical model for comparative LC-MS proteomics studies. We describe LC-MS peptide abundance with a linear model featuring pivotal terms that account for unequal peptide LC-MS measurability. We advance fitting this model to an often incomplete LC-MS data set with REstricted Maximum Likelihood (REML) estimation, producing estimates of model goodness-of-fit, treatment effects, standard errors, confidence intervals, and protein relative concentrations. We illustrate the model with an experiment featuring a known dilution series of a filamentous ascomycete fungus Trichoderma reesei protein mixture. For 781 of the 1546 T. reesei proteins with sufficient data coverage, the fitted mixed-effects models capably described the LC-MS measurements. The LC-MS measurability terms effectively accounted for this major source of uncertainty. Ninety percent of the relative concentration estimates were within 0.5-fold of the true relative concentrations. Akin to the common ratio method, this model also produced biased estimates, albeit less biased. Bias decreased significantly, both absolutely and relative to the ratio method, as the number of observed peptides per protein increased. Mixed-effects statistical modeling offers a flexible, well-established methodology for comparative proteomics studies integrating common experimental designs with LC-MS sample processing plans. It favorably accounts for the unequal LC-MS measurability of peptides and produces informative quantitative comparisons of a protein's concentration across treatments with objective measures of uncertainties.  相似文献   

15.
We are interested in developing fluorescence methods for quantifying lateral variations in the dipole potential across cell surfaces. Previous work in this laboratory showed that the ratio of fluorescence intensities of the voltage-sensitive dye di-8-ANEPPS using excitation wavelengths at 420 and 520 nm correlates well with measurements of the dipole potential. In the present work we evaluate the use of di-8-ANEPPS and an emission ratiometric method for measuring dipole potentials, as Bullen and Saggau (Biophys. J. 65 (1999) 2272-2287) have done to follow changes in the membrane potential in the presence of an externally applied field. Emission ratiometric methods have distinct advantages over excitation methods when applied to fluorescence microscopy because only a single wavelength is needed for excitation. We found that unlike the excitation ratio, the emission ratio does not correlate with the dipole potential of vesicles made from different lipids. A difference in the behaviour of the emission ratio in saturated compared to unsaturated lipid vesicles was noted. Furthermore, the emission ratio did not respond in the same way as the excitation ratio when cholesterol, 6-ketocholestanol, 7-ketocholesterol, and phloretin were added to dimyristoylphosphatidylcholine (DMPC) vesicles. We attribute the lack of correlation between the emission ratio and the dipole potential to simultaneous changes in membrane fluidity caused by changes in membrane composition, which do not occur when the electric field is externally applied as in the work of Bullen and Saggau. Di-8-ANEPPS can, thus, only be used via an excitation ratiometric method to quantify the dipole potential.  相似文献   

16.
The analysis of differential gene expression in microarray experiments requires the development of adequate statistical tools. This article describes a simple statistical method for detecting differential expression between two conditions with a low number of replicates. When comparing two group means using a traditional t-test, gene-specific variance estimates are unstable and can lead to wrong conclusions. We construct a likelihood ratio test while modelling these variances hierarchically across all genes, and express it as a t-test statistic. By borrowing information across genes we can take advantage of their large numbers, and still yield a gene-specific test statistic. We show that this hierarchical t-test is more powerful than its traditional version and generates less false positives in a simulation study, especially with small sample sizes. This approach can be extended to cases where there are more than two groups.  相似文献   

17.
研究了鼠肝线粒体内膜体呼吸链复合体Ⅱ+Ⅲ的H~+/2e比与Δψ的相关性及其调节因素。证明:(1)用光谱法测得复合体Ⅱ+Ⅲ的电子传递与质子转移初速度的H~+/2e比值接近4,与铁氰化钾脉冲法测得的结果相同。H~+/2e随着ΔμH~+升高而逐渐下降。荧光透析法测定不同Fe~(3+)还原速率建立的不同Δψ时,证明H~+回漏对Δψ和H~+泵出速度的依赖性。讨论了呼吸链复合体Ⅱ+Ⅲ电子传递与质子转移之间的偶联以及“Redoxslip”和“protonleak”的现象。(2)抑制剂实验说明线粒体内膜中Ca~(2+)、Pi与H~+的协同运输系统对线粒体内膜H~+泵出及H~+回漏作用有一定的调控作用。  相似文献   

18.
Unidirectional 22Na-traced sodium influx or 42K-traced potassium efflux across the membranes of voltage-clamped squid giant axons was measured at various membrane potentials under bi-ionic conditions. Tetrodotoxin almost entirely eliminated the extra K+ efflux induced by short repetitive depolarizations in the presence of tetraethylammonium or 3,4-diaminopyridine. A method of determining the voltage dependence of the unidirectional flux through voltage-gated channels is described. This technique was used to obtain the unidirectional flux-voltage relation for the sodium channel in bi-ionic and single-ion conditions. It allows the determination of the unidirectional flux at the zero-current potential which, for influx, was found to be approximately 20% of the value measured 80 mV negative to the zero-current potential. The unidirectional flux ratio under bi-ionic conditions was also measured and the flux ratio exponent found to average 1.15 with an external sodium and an internal potassium solution. A three-barrier, two-site, multi-occupancy model previously obtained for other conditions was found to predict a similar non-unity average for the flux ratio exponent. It is also shown that some single-occupancy models can predict non-unity values for the flux ratio exponent in bi-ionic conditions.  相似文献   

19.
The thermodynamic forces on electrons (delta Eh) and protons (delta p) across mitochondrial complexes I, III and IV were measured in isolated mitochondria respiring on succinate. The force ratio (delta Eh/delta p) across complex I close to equilibrium was found to be about 2. The equilibrium force ratio across complex I was measured during sulphite oxidation and was again close to 2. These results indicate that the proton/electron stoichiometry of complex I is 2, in conditions of high protonmotive force.  相似文献   

20.
Some convincing support for sex ratio theory comes from the cross-species relationship between sex ratio and brood size in gregarious bethylid wasps (Hymenoptera: Bethylidae), in which the proportion males declines as brood size increases as predicted under local mate competition. It is unknown how widely such relationships hold within parasitoid wasps as a whole. We assemble a dataset on sex ratio and brood size for gregarious Braconidae and Ichneumonidae. Their sex ratios deviate substantially from those of bethylids; sex ratios differ widely across species; and they are not significantly related to brood size across species. Several factors explain the heterogeneity in sex ratios including across-species differences in mating system, sex determining mechanism, and sexual asymmetries in larval competition and polyembryony leading to single-sexed broods.  相似文献   

设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号