BMP type II receptor as a therapeutic target in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the artery lumen that eventually causes right heart failure and death. The most common cause of PAH is inactivating mutations in the gene encoding a bone morphogenetic protein type II receptor (BMPRII). Current therapeutic options for PAH are limited and focused mainly on reversal of pulmonary vasoconstriction and proliferation of vascular cells. Although these treatments can relieve disease symptoms, PAH remains a progressive lethal disease. Emerging data suggest that restoration of BMPRII signaling in PAH is a promising alternative that could prevent and reverse pulmonary vascular remodeling. Here we will focus on recent advances in rescuing BMPRII expression, function or signaling to prevent and reverse pulmonary vascular remodeling in PAH and its feasibility for clinical translation. Furthermore, we summarize the role of described miRNAs that directly target the BMPR2 gene in blood vessels. We discuss the therapeutic potential and the limitations of promising new approaches to restore BMPRII signaling in PAH patients. Different mutations in BMPR2 and environmental/genetic factors make PAH a heterogeneous disease and it is thus likely that the best approach will be patient-tailored therapies.     

Differential display analysis of gene expression in invertebrates

Screening for differentially expressed genes is a straightforward approach to study the molecular basis for changes in gene expression. Differential display analysis has been used by investigators in diverse fields of research since it was developed. Differential display has also been the approach of choice to investigate changes in gene expression in response to various biological challenges in invertebrates. We review the application of differential display analysis of gene expression in invertebrates, and provide a specific example using this technique for novel gene discovery in the nematode Caenorhabditis elegans.     

Testing cumulative prediction errors in event study methodology

This paper reconsiders event study methodology, a very popular technique in the applied finance literature, within the context of testing cumulative prediction errors. It extends the conventional test statistics in two directions. First, it accounts fully for the increased variance of prediction errors outside of the estimation period and for the cumulation of these errors across different event windows. Second, it also takes account of the fact that market model residuals are typically serially correlated, heteroscedastic and non-normal. The statistics are compared with the conventional approach by reassessing a previous application of the methodology to the impact of management buyouts.     

Today’s and tomorrow’s imaging and circulating biomarkers for pulmonary arterial hypertension

The pathobiology of pulmonary arterial hypertension (PAH) involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to an increase in pulmonary vascular resistance, right heart failure and death. Its etiology may be idiopathic, but PAH is also frequently associated with underlying conditions such as connective tissue diseases. During the past decade, more than welcome novel therapies have been developed and are in development, including those increasingly targeting the remodeling process. These therapeutic options modestly increase the patients' long-term survival, now approaching 60% at 5 years. However, non-invasive tools for confirming PAH diagnosis, and assessing disease severity and response to therapy, are tragically lacking and would help to select the best treatment. After exclusion of other causes of pulmonary hypertension, a final diagnosis still relies on right heart catheterization, an invasive technique which cannot be repeated as often as an optimal follow-up might require. Similarly, other techniques and biomarkers used for assessing disease severity and response to treatment generally lack specificity and have significant limitations. In this review, imaging as well as current and future circulating biomarkers for diagnosis, prognosis, and follow-up are discussed.     

Molecular diagnosis of parasites

Summary New developments in molecular biology have generated exciting possibilities for improved diagnosis of parasitic diseases. Through gene clonign and expression and peptide synthesis, defined parasite antigens can be produced in vitro for use in serodiagnosis, while nuclear hybridization techniques offer a vastly improved approach to identification of parasites in the tissue specimens of infected hosts as a means of diagnosis. Furthermore, the advent of the polymerase chain reaction technique has made it possible to increase the sensitivity of nuclear hybridization techniques, through amplification of target DNA sequences of the parasites in test material, by in situ synthesis of these sequences prior to hybridization with the diagnostic probe. Finally, through the use of monoclonal antibody technology, it is possible to design highly specific and sensitive serological assays, as well as assays for parasite antigen detection in tissue fluids and in the excreta of infected hosts, as a means of diagnosis.     

Molecular diagnosis of parasites

New developments in molecular biology have generated exciting possibilities for improved diagnosis of parasitic diseases. Through gene cloning and expression and peptide synthesis, defined parasite antigens can be produced in vitro for use in serodiagnosis, while nuclear hybridization techniques offer a vastly improved approach to identification of parasites in the tissue specimens of infected hosts as a means of diagnosis. Furthermore, the advent of the polymerase chain reaction technique has made it possible to increase the sensitivity of nuclear hybridization techniques, through amplification of target DNA sequences of the parasites in test material, by in situ synthesis of these sequences prior to hybridization with the diagnostic probe. Finally, through the use of monoclonal antibody technology, it is possible to design highly specific and sensitive serological assays, as well as assays for parasite antigen detection in tissue fluids and in the excreta of infected hosts, as a means of diagnosis.     

Forecasting the price of crude oil via convenience yield predictions

The paper develops an oil price forecasting technique which is based on the present value model of rational commodity pricing. The approach suggests shifting the forecasting problem to the marginal convenience yield, which can be derived from the cost‐of‐carry relationship. In a recursive out‐of‐sample analysis, forecast accuracy at horizons within one year is checked by the root mean squared error as well as the mean error and the frequency of a correct direction‐of‐change prediction. For all criteria employed, the proposed forecasting tool outperforms the approach of using futures prices as direct predictors of future spot prices. Vis‐à‐vis the random‐walk model, it does not significantly improve forecast accuracy but provides valuable statements on the direction of change. Copyright © 2007 John Wiley & Sons, Ltd.     

Forecasting the duration of short‐term deflation episodes

The paper proposes a simulation‐based approach to multistep probabilistic forecasting, applied for predicting the probability and duration of negative inflation. The essence of this approach is in counting runs simulated from a multivariate distribution representing the probabilistic forecasts, which enters the negative inflation regime. The marginal distributions of forecasts are estimated using the series of past forecast errors, and the joint distribution is obtained by a multivariate copula approach. This technique is applied for estimating the probability of negative inflation in China and its expected duration, with the marginal distributions computed by fitting weighted skew‐normal and two‐piece normal distributions to autoregressive moving average ex post forecast errors and using the multivariate Student t copula.     

Heuristic analogy in Ars Conjectandi: From Archimedes' De Circuli Dimensione to Bernoulli's theorem

This article investigates the way in which Jacob Bernoulli proved the main mathematical theorem that undergirds his art of conjecturing—the theorem that founded, historically, the field of mathematical probability. It aims to contribute a perspective into the question of problem-solving methods in mathematics while also contributing to the comprehension of the historical development of mathematical probability. It argues that Bernoulli proved his theorem by a process of mathematical experimentation in which the central heuristic strategy was analogy. In this context, the analogy functioned as an experimental hypothesis. The article expounds, first, Bernoulli's reasoning for proving his theorem, describing it as a process of experimentation in which hypothesis-making is crucial. Next, it investigates the analogy between his reasoning and Archimedes' approximation of the value of π, by clarifying both Archimedes' own experimental approach to the said approximation and its heuristic influence on Bernoulli's problem-solving strategy. The discussion includes some general considerations about analogy as a heuristic technique to make experimental hypotheses in mathematics.     

Chromosome stabilizing structures in mitotic Indian muntjac (Muntiacus muntjak) cells1

Summary A new technique which removes all membranes, cytoskeletal elements, organelles, but preserves intact metaphase, anaphase and telophase configurations is combined with scanning electron microscopy (SEM) as an approach for direct visualization of chromosomal behavior in late mitosis. With this approach we are able to confirm the presence of a centromeric ring which stabilizes the centromeres during the cell cycle and present evidence for a lattice-like sheet of interchromatidic fibers in late mitosis.Supported by the National Institute of Health Grant CA32572 to L. D. Hodge.     

Occurrence of inhibitory histamine H2-receptors in isolated pulmonary blood vessels of dogs and rats

Summary Isolated, helically cut strips of pulmonary arteries and veins of dogs, and pulmonary arteries of rats, precontracted with norepinephrine or 5-HT exhibited potent concentration-dependent relaxations to impromidine and dimaprit (histamine H₂-agonists). The occurrence of inhibitory histamine H₂-receptors in the pulmonary vasculature could play a modulatory role in hypoxic pulmonary vasoconstriction.Supported by research grants NHLBI-18002, NHLBI-18015 and DA-02339 from the USPHS. We are grateful to Dr D.D.A. Owen of Smith, Kline & French Ltd, England for the generous supply of dimaprit and impromidine. Requests for reprints should be addressed to B.M. Altura.     

Forecasting the business cycle without using minimum autocorrelation factors

We introduce a forecasting technique based on multivariate ideas previously applied in remote sensing. The approach has the trivial but nonetheless fundamental purpose of dividing the information inherent in the time series into important and unimportant. Important information is used for forecasting purposes while the unimportant is discarded. Although related to vector autoregression, giving asymptotically the same estimates, there are reasons to believe that the approach gives better precision of parameter estimates for finite samples as well as more precise predictions.     

森林生态系统健康诊断研究进展及亚高山针叶林健康诊断的思考

本文主要从目标途径、生态系统途径和综合途径三个方面介绍了森林生态系统健康概念及其内涵，并分析了森林生态系统健康的评价指标体系及其标准。一般认为，不同的森林生态系统健康评估要根据具体的社会经济因素、生物物理环境、森林生态系统的自然属性选择合适的指标体系和标准。考虑到亚高山地区面临的主要任务是生物多样性保护和以水土保持为重点的生态功能恢复，因此采用生态系统学派(强调生态功能)为主进行健康诊断更具有实际意义，据此提出了亚高山针叶林健康状况诊断指标及其方案。     

Understanding paternal genome demethylation through live-cell imaging and siRNA

Identification of a DNA demethylase responsible for zygotic paternal DNA demethylation has been one of the most challenging goals in the field of epigenetics. Several candidate molecules have been proposed, but their involvement in the demethylation remains controversial, partly due to the difficulty of preparing a sufficient quantity of materials for biochemical analysis. In this review, we utilize a recently developed method for live-cell imaging of mouse zygotes combined with RNA interference (RNAi) to search for factors that affect zygotic paternal DNA demethylation. The combined use of various fluorescent probes and RNAi is a useful approach for the study of not only DNA demethylation but also the spatiotemporal dynamics of histone depositions in zygotes, although it is not appropriate for large-scale screening or knockdown of genes that are abundantly expressed before fertilization. This new technique enables us to understand the epigenetic hierarchy during cellular response and differentiation in preimplantation embryos.     

Against the empirical viability of the Deutsch–Wallace–Everett approach to quantum mechanics

The subjective Everettian approach to quantum mechanics presented by Deutsch and Wallace fails to constitute an empirically viable theory of quantum phenomena. The decision theoretic implementation of the Born rule realized in this approach provides no basis for rejecting Everettian quantum mechanics in the face of empirical data that contradicts the Born rule. The approach of Greaves and Myrvold, which provides a subjective implementation of the Born rule as well but derives it from empirical data rather than decision theoretic arguments, avoids the problem faced by Deutsch and Wallace and is empirically viable. However, there is good reason to cast doubts on its scientific value.     

A comparison of models for forecasting the discovery of hydrocarbon deposits

There are many geologic resource assessment techniques available that can be used to estimate the hydrocarbon potential of frontier basins. The techniques do not, however, produce discovery rate forecasts, which are critical to government and industry planners. Various methods of predicting the discovery rate in frontier basins are reviewed and appraised within the context of the drilling history of Canada's Scotian Shelf. The reviewed models include a mean historical discovery rate technique, the exponential decline model, a logistic curve technique and a class of models based on a sampling without replacement approach to prediction. Models are found to perform best over the longer forecast horizons, with those models based on the sampling without replacement technique tending to perform best.     

Dynamics of proteins in Golgi membranes: comparisons between mammalian and plant cells highlighted by photobleaching techniques

In less than a decade the green fluorescent protein (GFP) has become one of the most popular tools for cell biologists for the study of dynamic processes in vivo. GFP has revolutionised the scientific approach for the study of vital organelles, such as the Golgi apparatus. As Golgi proteins can be tagged with GFP, in most cases without altering their targeting and function, it is a great substitute to conventional dyes used in the past to highlight this compartment. In this review, we cover the application of GFP and its spectral derivatives in the study of Golgi dynamics in mammalian and plant cells. In particular, we focus on the technique of selective photobleaching known as fluorescence recovery after photobleaching, which has successfully shed light on essential differences in the biology of the Golgi apparatus in mammalian and plant cells.     

基于随机时间自动机和统计模型检验技术的无线传感网络协议建模与分析

近年来,传感器技术得到了长足而有效的提升,无线传感网络（WSN）以其开放、动态的特征获得了极大的关注,并成为了互联网计算的一个重要组成．WSN系统行为复杂,经常面临信息丢失、节点动态变化等不确定因素,且网络中的节点一旦部署将很难更改、维护．因此,为了保证相关应用的正常工作,在系统设计阶段对WSN中的底层协议进行质量保障就成为了一项非常重要的研究问题．系统设计人员不仅需要保证协议功能上的正确性,还应该评估协议在目标工作环境下的性能,以保证其可以胜任相应的工作需求．针对以上问题,本文提出了一种基于随机时间自动机和统计模型检验技术的WSN协议建模、分析和评估途径．在建模阶段,首先将采用时间自动机对协议在理想环境下的基本业务流程进行建模．考虑到WSN系统实际工作中会遇到的各种不确定性因素,将用带权分枝来对模型进行扩展,生成协议的随机时间自动机．在验证阶段,首先采用经典模型检验技术,在理想时间自动机上检验相关功能性质,保证协议工作逻辑的正确性．为评估协议在不同条件下的具体性能,则在随机时间自动机上用统计模型检验技术对其进行数值分析,以进行参数配置、性能预测、协议比较等工作．为展示该途径的可用性及其技术细节,本文对两种著名的WSN时间同步协议,TPSN和FTSP分别进行了完整的建模与评估．