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Purpose To estimate the effect of atropine eyedrops at different concentrations for myopia control in children.Methods We conducted a Bayesian random-effects network meta-analysis based on randomized controlled trials (RCT). Primary outcomes include changes in spherical equivalent error (SER) and changes in axial length (AL), mean difference (MD) together with 95% credible interval (CrI) were used to evaluate the efficacy.Results 28 RCTs (6608 children) were included in this review. Comparing ten atropine eyedrops (0.0025%, 0.005%, 0.01%, 0.02%, 0.025%, 0.05%, 0.1%, 0.25%, 0.5% and 1% concentrations) with the placebo, the MDs and 95%CrIs of changes in SER are −0.006 (−0.269, 0.256) D, 0.216 (−0.078, 0.508) D, 0.146 (0.094, 0.199) D, 0.167 (0.039, 0.297) D, 0.201 (0.064, 0.341) D, 0.344 (0.251, 0.440) D, 0.255 (0.114, 0.396) D, 0.296 (0.140, 0.452) D, 0.331 (0.215, 0.447) D, and 0.286 (0.195, 0.337) D, respectively. The MDs and 95%CrIs of changes in AL are −0.048 (−0.182, 0.085) mm, −0.078 (−0.222, 0.066) mm, −0.095 (−0.130, −0.060) mm, −0.096 (−0.183, −0.009) mm, −0.083 (−0.164, −0.004) mm, −0.114 (−0.176, −0.056) mm, −0.134 (−0.198, −0.032) mm, −0.174 (−0.315, −0.061) mm, −0.184 (−0.291, −0.073) mm, and −0.171 (−0.203, −0.097) mm, respectively.Whether evaluated by SER or AL, 1% concentration ranks first in efficacy, but the risk of photophobia is 17 times higher than 0.01% concentration.Conclusions 0.01% or higher concentration atropine eyedrops are effective for myopia control, while 0.0025% and 0.005% concentrations may not. As the concentration increases, the effect tends to increase, 1% concentration may have the strongest effect.

Graphene is an ideal platform to study the coherence of quantum interference pathways by tuning doping or laser excitation energy. The latter produces a Raman excitation profile that provides direct insight into the lifetimes of intermediate electronic excitations and, therefore, on quantum interference, which has so far remained elusive. Here, we control the Raman scattering pathways by tuning the laser excitation energy in graphene doped up to 1.05 eV. The Raman excitation profile of the G mode indicates its position and full width at half-maximum are linearly dependent on doping. Doping-enhanced electron–electron interactions dominate the lifetimes of Raman scattering pathways and reduce Raman interference. This will provide guidance for engineering quantum pathways for doped graphene, nanotubes, and topological insulators.

To combat increasingly sophisticated cyber attacks, the security community has proposed and deployed a large body of threat detection approaches to discover malicious behaviors on host systems and attack payloads in network traffic. Several studies have begun to focus on threat detection methods based on provenance data of host-level event tracing. On the other side, with the significant development of big data and artificial intelligence technologies, large-scale graph computing has been widely used. To this end, kinds of research try to bridge the gap between threat detection based on host log provenance data and graph algorithm, and propose the threat detection algorithm based on system provenance graph. These approaches usually generate the system provenance graph via tagging and tracking of system events, and then leverage the characteristics of the graph to conduct threat detection and attack investigation. For the purpose of deeply understanding the correctness, effectiveness, and efficiency of different graph-based threat detection algorithms, we pay attention to mainstream threat detection methods based on provenance graphs. We select and implement 5 state-of-the-art threat detection approaches among a large number of studies as evaluation objects for further analysis. To this end, we collect about 40GB of host-level raw log data in a real-world IT environment, and simulate 6 types of cyber attack scenarios in an isolated environment for malicious provenance data to build our evaluation datasets. The crosswise comparison and longitudinal assessment interpret in detail these detection approaches can detect which attack scenarios well and why. Our empirical evaluation provides a solid foundation for the improvement direction of the threat detection approach.

The detection rate and concentration of fluoroquinolone antibiotics in wastewater have experienced an upward trend in recent years, primarily attributed to their extensive utilization. The effects of fluorine substituents on the degradation of fluoroquinolone and the associated mechanism remain uncertain. This study aimed to assess the efficacy of freeze-activated periodate (Freezing/PI) in the degradation of three different fluoroquinolones with varying quantities of fluorine. Additionally, the study analyzed the underlying mechanism using density functional theory (DFT) calculations. The results showed that under the optimal experimental conditions (IO4-=0.05 mM, pH=3.0, freezing temperature=-25 ℃), the degradation rate of fluoroquinolone antibiotics reached 90.1% after 45 minutes of Freezing/PI process. Fluoroquinolone is primarily oxidized by non-free radical pathway, while co-existing substances such as HCO3-and humic acid inhibited the degradation of fluoroquinolone. The primary reaction pathway for the degradation of fluoroquinolone involves the cleavage and detachment of the piperazine ring. The reaction rates of the fluorine substituents at the C-7 and C-9 positions of lomefloxacin and flerofloxacin on the piperazine ring were found to be higher than that of ciprofloxacin. This can be attributed to the presence of synergistic electron conjugation. The objective of this experiment was to analyze additional influencing factors of the Freezing/PI process. The impact of the quantity of fluorine substituents on the reaction and the degradation of fluoroquinolone by free radical pathway were elucidated using DFT. This analysis offers insights into the potential application of the process in low-temperature environments and the management of fluorinated organic compounds.

As a sea route corridor, the 21st Century Maritime Silk Road (TCMSR) has a potential impact on container routing between Asia and Europe. In this paper, all considered ports along this corridor are assumed to be hub ports. When transporting containers along the TCMSR, this paper considers the subsidy policy, represented by a subsidy factor. In order to explore the attraction and subsidy analysis of the TCMSR, a bilevel programming model is proposed. The upper level model aims to determine the optimal subsidy factor along the TCMSR, and the lower level model is formulated as a hub line location problem. By enumerating all different values of the subsidy factor, the bilevel programming model is reduced to the lower level model. Computational experiments show that, the attraction of the TCMSR mainly depends on the subsidy policies to be implemented along the TCMSR.

The metal futures price fluctuation prediction model was constructed based on symbolic high-frequency time series using high-frequency data on the Shanghai Copper Futures Exchange from July 2014 to September 2018, and the sample was divided into 194 histogram time series employing symbolic time series. The next cycle was then predicted using the K-NN algorithm and exponential smoothing, respectively. The results show that the trend of the histogram of the copper futures earnings prediction is gentler than that of the actual histogram, the overall situation of the prediction results is better, and the overall fluctuation of the one-week earnings of the copper futures predicted and the actual volatility are largely the same. This shows that the results predicted by the K-NN algorithm are more accurate than those predicted by the exponential smoothing method. Based on the predicted one-week price fluctuations of copper futures, regulators and investors in China’s copper futures market can timely adjust their regulatory policies and investment strategies to control risks.

A high-throughput genotyping platform is presented that uses a one-primer assay to genotype offer 10,000 single nucleotide polymorphisms (SNPs) per individual on a single oligonucleotide array. This approach uses restriction digestion to fractionate the genome, followed by amplification of a specific fractionated subset of the genome.

Probable maximum precipitation (PMP), defined as the largest rainfall depth that could physically occur under a series of adverse atmospheric conditions, has been an important design criterion for critical infrastructures such as dams and nuclear power plants. To understand how PMP may respond to projected future climate forcings, we used a physics-based numerical weather simulation model to estimate PMP across various durations and areas over the Alabama-Coosa-Tallapoosa (ACT) River Basin in the southeastern United States. Six sets of Weather Research and Forecasting (WRF) model experiments driven by both reanalysis and global climate model projections, with a total of 120 storms, were conducted. The depth-area-duration relationship was derived for each set of WRF simulations and compared with the conventional PMP estimates. Our results showed that PMP driven by projected future climate forcings is higher than 1981–2010 baseline values by around 20% in the 2021–2050 near-future and 44% in the 2071–2100 far-future periods. The additional sensitivity simulations of background air temperature warming also showed an enhancement of PMP, suggesting that atmospheric warming could be one important factor controlling the increase in PMP. In light of the projected increase in precipitation extremes under a warming environment, the reasonableness and role of PMP deserve more in-depth examination. Numerical model is able to provide PMP estimates that are comparable to those from a conventional HMR approachThe increase of precipitable water versus the increase of PMP depth exhibits a large spread and does not fall near the 1:1 lineAn increase in the deterministic PMP storm upper bound in a warming environment is projected through two different modeling approaches

This paper seeks to model and forecast the Chinese nonferrous metals futures market volatility and allows new insights into the time-varying volatility of realized volatility and leverage effects using high-frequency data. The LHAR-CJ model is extended and the empirical research on copper and aluminum futures in Shanghai Futures Exchange suggests the dynamic dependencies and time-varying volatility of realized volatility, which are captured by long memory HAR-GARCH model. Besides, the findings also show the significant weekly leverage effects in Chinese nonferrous metals futures market volatility. Finally, in-sample and out-of-sample forecasts are investigated, and the results show that the LHAR-CJ-G model, considering time-varying volatility of realized volatility and leverage effects, effectively improves the explanatory power as well as out-of sample predictive performance.

The multiferroic BiFeO3 powders with perovskite structure were synthesized by sol-gel auto-combustion and conventional sol-gel methods, respectively. As-prepared powders were characterized by XRD, SEM and VSM techniques to investigate phase structure, microstructure and magnetic properties. The results show that the pure phase BiFeO3 powders are obtained successfully by sol-gel auto-combustion after calcining at 650°C for 2h and leaching by HNO3. Compared with conventional sol-gel method which got pure phase BiFeO3 powders at 800°C for 3h, the sol-gel auto-combustion technique can get more pure powders at low temperature, short time and low cost. The particle sizes of the BiFeO3 powders are smaller and well distributed by the sol-gel auto-combustion method than that of the conventional sol-gel method. Furthermore, the magnetic properties at room temperature prepared by the sol-gel auto-combustion methods are significant higher than that of conventional sol-gel method.

A numerical simulation on the deformation behavior of AZ31 magnesium alloy during backward extrusion with counter pressure was investigated by FE software DEFORM. The results show that the steady load increases nonlinearly with the increment of counter pressure. The equivalent strain gradient decreases significantly results from the counter pressure and the unevenness in the top of wall disappeared approximately when the counter pressure is 10~15MPa. Furthermore, there are obviously shear band along the inner fillet to outer fillet of workpiece. Higher hydrostatic pressure generated with counter pressure compared that of no counter pressure leads to improve the plastic deformation limit. The damage factor is reduced significantly in the backward extrusion with counter pressure, which is beneficial to the improvement of crack.

The flow stress behavior of the 7085 aluminum alloy was studied through single-pass compression experiment by using MMS-300 simulator within temperature range of 300-450°C and strain rate range of 0.01-10s-1. Dynamic recrystallization occurs in hot compression of 7085 alloy and the stress-strain curves are presented as wave with higher deformation temperature and strain rate. Increasing of deformation velocity and reducing temperature results in higher peak stress. Then a mathematical model has been developed to predict the stress-strain curves based on phenomenological representation of the curves and the traditional theories for constitutive equations which incorporate the power law. The constitutive equation expressed in terms of peak stress, peak strain and additional parameters to predict flow stress. The stress-strain curves of 7085 alloy predicted by this model are in good agreement with experimental results.

From the perspective of long-term and short-term, the methods of TY causality test, generalized impulse response function, variance decomposition were used to investigate the impacts of international oil prices and macroeconomic variables on Chinese gold, silver and platinum prices, but also the feedback effects of Chinese precious metal prices under this impact. The results show that international oil prices play an important role in precious metal price variation both in long-term and short-term, and exchange rate only has an effect in short-term, while interest rate is ineffective in predicting precious metal prices. In addition, precious metal prices have some feedback effects on international oil prices and interest rate in short-term.

Magnetic shielding of grain-oriented silicon steel was investigated. Ball scribing with spacing of 2 to 16 mm was performed at peak flux densities of 8.0 mT to 1.3 T. Magnetic shielding efficiency was calculated, including absorption, reflection and inner multi-reflection shielding efficiencies. Magnetic shielding efficiency (MSE) increase ratios after different scribing spacing were compared, and thickness requirement to achieve absorption shielding of 50 dB was also calculated. The results show that magnetic shielding efficiencies of C711 and H668 silicon steels increase by 4.79 and 3.15 dB respectively after scribing of 16 mm. Before scribing, shielding efficiency of H668 steel was higher than that of C711 steel, while after scribing, both absorption and shielding efficiency gaps were largely abridged between C711 and H668 steels. Plate thickness of C711 steel could be reduced from 3.18 mm without scribing to 2.20 mm after scribing of 16 mm. There is no apparent thickness reduction at lower flux densities; while the peak flux density is above 0.3 T, the shielding effect becomes apparent, and the thickness could be reduced from 2.28 mm without scribing to 1.70 mm with scribing spacing of 16 mm. Magnetizing process and its effect on variation of magnetic shielding were also analyzed.

The flow stress behavior of the 7075-T6 aluminum alloy was studied through single-pass compression experiment by using MMS-300 simulator within temperature range of 300-450°C and strain rate range of 0.01-40s-1. Then a simulation of compression was carried out and the influence of deformation velocity on load and deformation heating was investigated according to the relationship between stress and strain. The results show that dynamic recrystallization occurs in hot compression of 7075-T6 alloy and the stress-strain curves are presented as wave. Furthermore, the flow stress curves have the same wave period and the fluctuation range increases with an increase of strain rate and a decrease of strain. Increasing of deformation velocity results in higher critical strain but the value decreases when the deformation velocity is much higher. The temperature rise increases with the increase of deformation velocity and decrease of deformation temperature. The maximum of temperature rise is more than about 30°C, so that the deformation heating is significant.

Constitutive equations and dynamic recrystallization (DRX) model of GH4169 alloy were investigated using compression tests with temperature 940(℃)-1060(℃) and strain rate 0.001(s-1)-0.1(s-1). A coupled numerical simulation between thermal-mechanical and microstructure evolution was realized through embedding the developed user subroutines into the FEM software DEFORM-3D system. The simulated results show that higher speed of upper die is useful to the DRX but much higher and lower speed of upper die go against improving the finer and uniform of grain size in the blade. Furthermore, the grains are finer and uniform in the blade body compared with those of blade rabbet and damper platform. The experimental results of microstructure under the same forging condition were studied and the average grain degrees in the blade are over 9. The calculated results of microstructure have a good agreement with the measured value from experimental data and the prediction error is less than 7.0%. Therefore, the DRX model and developed program is reliable to optimize and improve the parameters in the blade finish forging.

Finite element method (FEM) has been one of the most important numerical simulation tools with the development of computer technology. However, it is only used to simulate and analyze different process offline in many fields because of the longer computational time. The influencing factors of prediction of temperature in the strip rolling by FEM including equations, mesh and storage of matrix was investigated in the paper. The lumped heat capacity matrix was introduced to resolve the oscillation problem and improve precision. Furthermore, the refined elements layer upon layer was discussed to improve solution efficiency and precision. In addition, in order to improve the solution efficiency one dimensional compressed storage method was employed to carry out in the solution of equations. The FEM program code for the solution of temperature was embed in the online rolling control system program successfully. The predictive results are in good agreement with the measured value. The computational time and precision are satisfied in the strip rolling process.

Rigid plastic finite element method (RPFEM) is one of the most efficient numerical methods during the rolling process. Realizing FEM online application has been main target for many researchers. The influence of compile method, elements number, compressible parameter, friction factor and convergent criteria were investigated and RPFEM model of fast solution to strip rolling was proposed in this work. Compile method and compressible parameter have less influence on calculated rolling force. However, the iteration steps are reduced and computational efficiency is improved greatly with compile method of release and compressible parameter 0.01. The change of calculated rolling force becomes less but iteration steps become more and more with the increment of elements number. Both accuracy and efficiency is satisfying with the change of elements number from 50 to 200. In addition, the typical rolling schedule from a certain plant has been solved with the developed program FFEM-2D by FORTRAN. The predicted rolling force has a good agreement with the measured value. The iteration steps change from 12 to 36 and computational time is less than 200(ms) with the model in one pass rolling. Therefore, the accuracy is satisfying and computational time fully meets the basic requirements of FEM online application. Keywords: Rolling; RPFEM; Fast solution; Computational time

In order to predict the microstructure evolution and grain size of GH4169 alloy blade in finish forging process and optimize the parameters, a coupled simulation between thermal mechanical and microstructure evolution was realized through embedding the developed user subroutines into the DEFORM-3D software. The temperature, equivalent strain, dynamic recrystallization fraction, average grain size and grain size distribution were predicted and discussed. The experimental results of microstructure under the same forging condition were investigated. The average grain degree in the blade rabbet and body are 8 and 10 respectively. The calculated results of microstructure have a good agreement with the measured value from experimental data and the prediction error of average grain size is less than 6.7%. The developed program is reliable and the accuracy is satisfying. The distribution of grain size along the blade body is decreased from the middle to the leading and back edge. The shape and microstructure after finish forging under the condition of technology parameters meet the user’s requirement. Keywords: Blade, GH4169 alloy, Numerical simulation, Microstructure, Forging

It is necessary to know the heat transfer intensity for predicting temperature distribution in the hot strip rolling process. The HTC (heat transfer coefficient) was usually obtained by the experiments and mathematical model. In this paper the HTC prediction was discussed based on the measured or target temperature by the proposed finite element method (FEM). The temperature evolution and HTC in the hot strip rolling process according to a certain plant were analyzed by the iteration calculation. The result shows that the HTC between strip and work roll was much more than the value in the air cooling and water cooling process. Furthermore, the HTC value is lower in the air cooling process compared with that of water cooling. The maximum and minimum value of HTC were about 1.5×105 (W/m2.K) and 80(W/m2.K) respectively. The temperature in the rough rolling according to the predicted HTC has been solved and the calculated results have a good agreement to the meausred value. Therefore, the research could be used to control the temperature distribution accurately and optimize the parameters.

In order to obtain the thermal comfort work environment, the distribution of temperature and airflow velocity in typical computer room of school building is discussed with different supply air angles and velocities of incidence by CFD model. The calculated temperature after cooling in the room has a good agreement with the measured value. Furthermore, the distribution of temperature and airflow is uniform and the environment is comfort for working with supply air angles and velocity of incidence 45° and 60° and supply air velocity of incidence 1m/s comparing with that of other parameters. Additionally, the change of temperature becomes slow down with the increment of time and the air-conditioning has less influence on the change of temperature after about 900s with supply air angle and velocity of incidence 45°and 1m/s, respectively. The research is of great significance both in theory and practice to design air conditioning systems and evaluate the thermal comfort conditions.

In order to predict the evolution of microstructure and grain size in TC6 alloy blade finish forging process and optimize the parameters, a series of constitutive equations for dynamic recrystallization and grain growth were developed and implemented into a 3D FE simulator. The grain size has been illustrated for the upsetting of TC6 alloy and the calculated grain size is in a good agreement with the experimental results, which shows that the microstructure prediction tool was validated and reliable. Then the distribution of stress, strain, temperature and microstructure, grain size and deformation has been predicted in TC6 alloy blade forging successfully using the 3D FEM at 930℃ deformation temperature, 250℃ die temperature and 50mm/s deformation velocity. The results show that the temperature of blade edge is higher than that of center because heat transfer, friction work and deformation work. The equivalent stress and strain have the same distribution as temperature after forging and the refined grain is obtained because of dynamic rescrystallization occurred with larger deformation. The uniform distribution of grain size are obtained in the blade and the shape after finish forging under the condition of technology parameters meet the user’s requirement comparing the calculated deformation with experimental results.

Multi-pass ECAP process of pure Al for square samples (Φ＝90º, Ψ＝37º, pressing speed of 1mm/s), was simulated by using 3D finite element method (FEM).The distribution of equivalent strain for two and four passes was compared. The results showed that route A leads to non-uniform distribution of equivalent strain during multi-pass ECAP. The distribution of equivalent strain is uniform in BC route, but the value of equivalent strain is larger in C route. The simulation results were compared with the experimental ones with previous work in the literature. The simulation also shows that equivalent strain and load increase with pass increasing.

The concept of the first and the second singularity point was introduced in the paper. The singularity points would lead to the iteration divergence in the solution of rolling by rigid plasticity finite element method. Double velocity model and parabolic model of relative slip velocity were proposed for solution of the first and the second singularity point respectively. The influence of the models to improve the effects of singularity point on calculating time and iteration step was discussed according to the practical strip rolling condition. The results showed that for the element numbers from 200 to 2000, the iteration step and total calculating time was reduced about 8~67% by the double velocity model in the same condition compared to normal model for the solution of first singularity point. The iteration step and calculating time was reduced about 15~61% with the parabolic model of relative slip velocity. The double velocity model and parabolic model of relative slip velocity could be used to improve the convergence and increase efficiency of the solution in strip rolling by rigid plasticity finite element method.

The program was developed by finite element method to calculate the temperature distribution in hot strip rolling process. The heat transfer coefficients of air cooling. water cooling and thermal resistance between work roll and strip were analyzed. A new heat generation rate model was proposed according to the influence of source current density. work frequency. air gap and distance to edge on induction heating by finite element method (FEM). The heat generation rate was considered in the thermal analysis to predict the temperature distribution in the induction heating. The influence of induction heating on the strip temperature was investigated for different slab thicknesses. The temperature difference became more and more obvious with the increase of thickness. The strip could be heated quickly by the induction heating both in surface and center because of the thermal conductivity and skin effect. The heat loss of radiation has important influence on the surface temperature. The surface temperature could be heated quickly by high frequency when the strip is thicker.

High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIFpathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude.

Understanding the distribution of human genetic variation is an important foundation for research into the genetics of common diseases. Some of the alleles that modify common disease risk are themselves likely to be common and, thus, amenable to identification using gene-association methods. A problem with this approach is that the large sample sizes required for sufficient statistical power to detect alleles with moderate effect make gene-association studies susceptible to false-positive findings as the result of population stratification [1, 2]. Such type I errors can be eliminated by using either family-based association tests or methods that sufficiently adjust for population stratification [3–5]. These methods require the availability of genetic markers that can detect and, thus, control for sources of genetic stratification among populations. In an effort to investigate population stratification and identify appropriate marker panels, we have analysed 11,555 single nucleotide polymorphisms in 203 individuals from 12 diverse human populations. Individuals in each population cluster to the exclusion of individuals from other populations using two clustering methods. Higher-order branching and clustering of the populations are consistent with the geographic origins of populations and with previously published genetic analyses. These data provide a valuable resource for the definition of marker panels to detect and control for population stratification in population-based gene identification studies. Using three US resident populations (European-American, African-American and Puerto Rican), we demonstrate how such studies can proceed, quantifying proportional ancestry levels and detecting significant admixture structure in each of these populations.

ABSTRACTThe basis of bactericidal versus bacteriostatic action of antibiotics and the mechanism of bacterial cell death are largely unknown. Related to this important issue is the essential invulnerability to killing of persisters: cells forming a small subpopulation largely responsible for the recalcitrance of biofilms to chemotherapy. To learn whether death is accompanied by changes in expression of particular genes, we compared transcription profiles of log-phase Escherichia colitreated with bactericidal concentrations of two unrelated antibiotics: ampicillin and ofloxacin. Massive changes in transcription profile were observed in response to either agent, and there was a significant overlap in genes whose transcription was affected. A small group of mostly uncharacterized genes was induced and a much larger set was transcriptionally repressed by both antibiotics. Among the repressed genes were those required for flagellar synthesis, energy metabolism, transport of small molecules, and protein synthesis.

We consider the problem of estimating values associated with gene expression from oligonucleotide arrays. Such estimates should linearly track concentration, yield non-negative results, have statistical guarantees of robustness against outliers, and allow estimates of significance and variance.

Megakaryocytic maturation was analyzed in long-term bone marrow cultures in the absence of added growth factors. Megakaryocytes could be observed for periods of up to 13 weeks in both the supernatant and stromal layer of these cultures. Using acetylcholinesterase staining for enumeration and sizing of megakaryocytes, and a novel rat antimu-rine platelet monoclonal antibody (MoAb) that detects only megakaryocytes in bone marrow, the number, volume, and ploidy of these cells were assessed microscopically and by flow cytometry. Correlation of these measurements with ambient interleukin-6 (IL-6) levels showed no relationship between IL-6 bioactivity and megakaryocyte number. Conversely, the relatively high IL-6 bioactivity present during the first 2 weeks of culture was correlated with increased megakaryocytic size and ploidy, while the relatively lower IL-6 bioactivity present after week 3 corresponded to decreased megakaryocytic size and ploidy. Addition of neutralizing anti-IL-6 MoAb decreased megakaryocytic size and ploidy at times when ambient IL-6 levels were relatively high, while the addition of exogenous IL-6 increased size and ploidy at times when endogenous IL-6 concentrations were low. The data show that long-term bone marrow cultures can be used as a means to evaluate megakaryocytic maturation in vitro, and suggest that, to some extent, IL-6 plays a role in the maturation process in this system. © 1991 by The American Society of Hematology.

A variety of drugs have been used to treat B-lymphocyte neoplasms, including both cell cycle-specific (CCS) and non-cell-cycle-specific drugs. Although the therapy for such cancers is complex and can include both types of drugs, the efficacy of these drugs in inducing cell death remains unclear. In this paper we have concentrated on specific CCS drugs and have examined their ability to induce programmed cell death (apoptosis) in Burkitt's lymphoma cell lines derived from patients. The CCS drugs chosen were hydroxyurea and aphidicolin (active in late G1, early S phase), the topoisomerase poisons camptothecin and etoposide (S, early G2phase) and vincristine and Taxol (late G2, M phase). These choices allow comparison of two drugs with differing modes of action for each of the various phases of the cell cycle. Our results indicate that the variation in apoptosis between drugs that act at the same phase of the cell cycle is negligible. Both S/G2and G2/M blockers are very potent at inducing apoptosis whereas G1/S blockers are ineffective in the induction of apoptosis. In addition, marked kinetic variations in the rate of apoptosis induction were observed, etoposide and camptothecin being more rapid in their action than the other agents. The order of effectiveness in inducing apoptosis on a kinetic basis was S/G2agents ⪢ G2/M agents ⪢ G1/S agents. In this study we have also found that growth inhibition was induced by all the CCS agents chosen and by anti-IgM in various Burkitt's lymphoma lines. Furthermore c-mycwas down-regulated under similar conditions. Since apoptosis was only selectively induced by some of the CCS agents, it implies c-mycexpression is associated with growth regulation and c-myc down-regulation is an insufficient condition for the induction of apoptosis. In addition, cotreatments using the CCS and other agents revealed the following: Cotreatment using two CCS drugs which act at the same stage in the cell cycle showed either no change or only additivity to the effects seen with either agent alone. However, cotreatment with CCS drugs showed that an inhibitory effect is found between G1/S and G2/M drugs or S/G2and G2/M drugs. No effect was found between G1/S and S/G2drugs. Anti-IgM, which by itself was capable of inducing apoptosis, was observed to augment apoptosis induced by very low concentrations of G2/M-acting drugs but it has little effect on G1/S or the S/G2drugs. The inhibitory effect of anti-CD40 or TNF-α on anti-IgM-induced apoptosis did not carry over to an effect on apoptosis induction by the CCS agents. Thus specific combinations of agents may lead to either enhancement, inhibition, or no interactive effect on apoptosis.

Inorganic cofactors (Mn, Ca2+ and Cl-) are essential for oxidation of H2O to O2 by Photosystem II. The Mn reductants NH2OH and its N-methyl derivatives have been employed as probes to further examine the interactions between these species and Mn at the active site of H2O oxidation. Results of these studies show that the size of a hydroxylamine derivative regulates its ability to inactivate O2 evolution activity, and that this size-dependent inhibition behavior arises from the protein structure of Photosystem II. A set of anions (Cl-, F- and SO42-) is able to slow NH2OH and CH3NHOH inactivation of intact Photosystem II membranes by exerting a stabilizing influence on the extrinsic 23 and 17 kDa polypeptides. In contrast to this non-specific anion effect, only Cl- is capable of attenuating CH3NHOH and (CH3)2NOH inhibition in salt-washed preparations lacking the 23 and 17 kDa polypeptides. However, Cl- fails to protect against NH2OH inhibition in salt-washed membranes. These results indicate that the attack by NH2OH and its N-methyl derivatives on Mn occurs at different sites in the O2-evolving complex. The small reductant NH2OH acts at a Cl--insensitive site whereas the inhibitions by CH3NHOH and (CH3)2NOH involve a site that is Cl- sensitive. These findings are consistent with earlier studies showing that the size of primary amines controls the Cl- sensitivity of their binding to Mn in the O2-evolving complex.

Motivation: A high density of single nucleotide polymorphism (SNP) coverage on the genome is desirable and often an essential requirement for population genetics studies. Region-specific or chromosome-specific linkage studies also benefit from the availability of as many high quality SNPs as possible. The availability of millions of SNPs from both Perlegen and the public domain and the development of an efficient microarray-based assay for genotyping SNPs has brought up some interesting analytical challenges. Effective methods for the selection of optimal subsets of SNPs spanning the genome and methods for accurately calling genotypes from probe hybridization patterns have enabled the development of a new microarray-based system for robustly genotyping over 100 000 SNPs per sample. Results: We introduce a new dynamic model-based algorithm (DM) for screening over 3 million SNPs and genotyping over 100 000 SNPs. The model is based on four possible underlying states: Null, A, AB and B for each probe quartet. We calculate a probe-level log likelihood for each model and then select between the four competing models with an SNP-level statistical aggregation across multiple probe quartets to provide a high-quality genotype call along with a quality measure of the call. We assess performance with HapMap reference genotypes, informative Mendelian inheritance relationship in families, and consistency between DM and another genotype classification method. At a call rate of 95.91% the concordance with reference genotypes from the HapMap Project is 99.81% based on over 1.5 million genotypes, the Mendelian error rate is 0.018% based on 10 trios, and the consistency between DM and MPAM is 99.90% at a comparable rate of 97.18%. We also develop methods for SNP selection and optimal probe selection. Availability: The DM algorithm is available in Affymetrix's Genotyping Tools software package and in Affymetrix's GDAS software package. See http://www.affymetrix.com for further information. 10K and 100K mapping array data are available on the Affymetrix website. Contact: xiaojun_di@affymetrix.com

Motivation: Analysis of many thousands of single nucleotide polymorphisms (SNPs) across whole genome is crucial to efficiently map disease genes and understanding susceptibility to diseases, drug efficacy and side effects for different populations and individuals. High density oligonucleotide microarrays provide the possibility for such analysis with reasonable cost. Such analysis requires accurate, reliable methods for feature extraction, classification, statistical modeling and filtering. Results: We propose the modified partitioning around medoids as a classification method for relative allele signals. We use the average silhouette width, separation and other quantities as quality measures for genotyping classification. We form robust statistical models based on the classification results and use these models to make genotype calls and calculate quality measures of calls. We apply our algorithms to several different genotyping microarrays. We use reference types, informative Mendelian relationship in families, and leave-one-out cross validation to verify our results. The concordance rates with the single base extension reference types are 99.36% for the SNPs on autosomes and 99.64% for the SNPs on sex chromosomes. The concordance of the leave-one-out test is over 99.5% and is 99.9% higher for AA, AB and BB cells. We also provide a method to determine the gender of a sample based on the heterozygous call rate of SNPs on the X chromosome. See http://www.affymetrix.com for further information. The microarray data will also be available from the Affymetrix web site. Availability: The algorithms will be available commercially in the Affymetrix software package.

X-ray absorption spectroscopy has been used to characterize the Mn site in the photosynthetic oxygen evolving complex (OEC) reaction center core complex. Treatment in the dark with hydroxylamine or with dihydroquinone results in a shift of the XANES spectra to lower energy, consistent with reduction at the Mn site. Structural changes are seen in the EXAFS as well. In both cases, the structural changes are completely reversible on illumination.