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Most biological models of intermediate size, and probably all large models, need to cope with the fact that many of their parameter values are unknown. In addition, it may not be possible to identify these values unambiguously on the basis of experimental data. This poses the question how reliable predictions made using such models are. Sensitivity analysis is commonly used to measure the impact of each model parameter on its variables. However, the results of such analyses can be dependent on an exact set of parameter values due to nonlinearity. To mitigate this problem, global sensitivity analysis techniques are used to calculate parameter sensitivities in a wider parameter space. We applied global sensitivity analysis to a selection of five signalling and metabolic models, several of which incorporate experimentally well-determined parameters. Assuming these models represent physiological reality, we explored how the results could change under increasing amounts of parameter uncertainty. Our results show that parameter sensitivities calculated with the physiological parameter values are not necessarily the most frequently observed under random sampling, even in a small interval around the physiological values. Often multimodal distributions were observed. Unsurprisingly, the range of possible sensitivity coefficient values increased with the level of parameter uncertainty, though the amount of parameter uncertainty at which the pattern of control was able to change differed among the models analysed. We suggest that this level of uncertainty can be used as a global measure of model robustness. Finally a comparison of different global sensitivity analysis techniques shows that, if high-throughput computing resources are available, then random sampling may actually be the most suitable technique.  相似文献   

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Finding an appropriate functional form to describe population growth based on key properties of a described system allows making justified predictions about future population development. This information can be of vital importance in all areas of research, ranging from cell growth to global demography. Here, we use this connection between theory and observation to pose the following question: what can we infer about intrinsic properties of a population (i.e., degree of heterogeneity, or dependence on external resources) based on which growth function best fits its growth dynamics? We investigate several nonstandard classes of multi-phase growth curves that capture different stages of population growth; these models include hyperbolic–exponential, exponential–linear, exponential–linear–saturation growth patterns. The constructed models account explicitly for the process of natural selection within inhomogeneous populations. Based on the underlying hypotheses for each of the models, we identify whether the population that it best fits by a particular curve is more likely to be homogeneous or heterogeneous, grow in a density-dependent or frequency-dependent manner, and whether it depends on external resources during any or all stages of its development. We apply these predictions to cancer cell growth and demographic data obtained from the literature. Our theory, if confirmed, can provide an additional biomarker and a predictive tool to complement experimental research.  相似文献   

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Two Decades of River Restoration in California: What Can We Learn?   总被引:4,自引:0,他引:4  
As part of the National River Restoration Science Synthesis (NRRSS), we developed a summary database of 4,023 stream restoration projects built in California since 1980, from which we randomly selected 44 records for in‐depth interviews with project managers. Despite substantial difficulties in gathering the data, we were able to draw conclusions about current design, implementation, monitoring, and evaluation practices used in California projects and compare them with national trends. Although more than half of the projects for which we conducted interviews were located in watersheds for which a management or assessment plan had been prepared, these plans had a limited impact on site selection. We also found that the state lacks a consistent framework for design, monitoring, and reporting restoration projects, and that although monitoring is far more widespread than the information in the NRRSS summary database would suggest, there are still problems with the type, duration, and reporting of monitoring. The general lack of systematic, objective assessment of completed projects hinders the advance of restoration science.  相似文献   

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SYNOPSIS. The Ediacaran fossils of the latest Precambrian haveat one time or another been grouped with almost every extantkingdom, and also lumped into separate kingdom-level taxa. Thishas often been based on the facile use of a few characters,or on some sort of "overall similarity." This has not been avery fruitful approach; if anything, it has held back understandingof the Ediacaran organisms and of their significance for laterhistory. While many of the simpler forms remain problematic,careful study of the more complex forms gives good reasons toplace at least some of them with the Animalia. A complementaryapproach is to use sources of information such as the distributionof fossils across space, time, and paleoenvironments. The resultsmay feed back into systematic work, allowing us to constructand test more robust hypotheses of these organisms' evolutionaryrelationships.  相似文献   

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In this article, we describe an 8- to 10-day inquiry safari designed for middle/high school students to investigate hominid evolution using replica skulls of extant and extinct vertebrates. Students begin the unit using their own skulls and proceed to use the replica skulls of extant vertebrates to construct an understanding of how skulls can be used to interpret and infer diets, dentition, dental formulae, bipedal or quadrupedal locomotion, and the social structure of animals. They are then able to use this knowledge to construct similar inferences for extinct fossil hominids. Using radiometric dating data, the students develop possible phylogenetic pathways for hominid evolution. The lessons promote the use of inquiry skills including journaling, observing, drawing, puzzle-making, using taxonomic keys, and investigating into deep geological time.  相似文献   

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Background

Due to an ageing population and demographic changes worldwide, a higher prevalence of heart disease is forecasted, which causes an even higher demand for cardiac implants in future. The increasing high incidence of clinical adverse events attributed especially to high-risk medical devices has led an advocated change from many stakeholders. This holds especially true for devices like cardiac implants, with their high-risk nature and high complication rates associated with considerable mortality, due to their frequent use in older populations with frequent co-morbidities. To ensure patients’ safety, the objective of this study is to analyze different cardiac implants recall reasons and different recall systems, based on an overview of the recalls of cardiac implant medical devices in the last decade. On the basis of the results from this structured analysis, this study provides recommendations on how to avoid such recalls from a manufacturer perspective, as well as how to timely react to an adverse event from a post-surveillance system perspective.

Methods and Findings

A systematic search of cardiac implant recalls information has been performed in the PubMed, ScienceDirect and Scopus databases, as well as data sources in regulatory authorities from 193 UN Member States. Data has been extracted for the years 2004-2014 with the following criteria applied: cardiac implant medical device recalls and reasons for recall, associated harm or risk to patients. From the data sources described above, eleven regulatory authorities and 103 recall reports have been included in this study. The largest cardiac implant categories include ICDs 40.8%, pacemakers 14.5% and stents 14.5%. Regarding the recall reasons, the majority of reports were related to device battery problems (33.0%) and incorrect therapy delivery (31.1%). From a total of 103 recall reports, five reported death and serious injuries. Our review highlights weaknesses in the current cardiac implant recall system, including data reporting and management issues and provides recommendations for the improvement of safety information and management.

Conclusion

Due to the mortality associated with the nature of cardiac implants, the traceability and transparency of safety hazards information is crucial. By a structured analysis of recall reasons and their efficient management, important knowledge is gained to inform an effective safety-reporting system for monitoring the safety of cardiac implanted patients, ideally by building up cardiac implant registries worldwide in the future.  相似文献   

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Efforts to increase affinity in the design of new therapeutic molecules have tended to lead to greater lipophilicity, a factor that is generally agreed to be contributing to the low success rate of new drug candidates. Our aim is to provide a structural perspective to the study of lipophilic efficiency and to compare molecular interactions created over evolutionary time with those designed by humans. We show that natural complexes typically engage in more polar contacts than synthetic molecules bound to proteins. The synthetic molecules also have a higher proportion of unmatched heteroatoms at the interface than the natural sets. These observations suggest that there are lessons to be learnt from Nature, which could help us to improve the characteristics of man-made molecules. In particular, it is possible to increase the density of polar contacts without increasing lipophilicity and this is best achieved early in discovery while molecules remain relatively small.  相似文献   

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What Can Medicine Learn from the Human DNA Sequence?   总被引:1,自引:0,他引:1  
The cooperation of biochemistry with clinical medicine consists of two overlapping temporal phases. Phase 1 of the cooperation, which still is not finished, is characterized by joint work on the pathogenesis and diagnostics of systemic metabolic diseases, whereas in phase 2 the cooperation on tissue and cell specific as well as on molecular diseases is prevailing. In view of the conceptual revolution and shift in paradigm, which biochemistry and medicine are presently experiencing, the content of cooperation between the two disciplines will profoundly change. It will become deeply influenced by the results of the research into the human genome and human proteome. Biochemistry will strongly be occupied to relate the thousands of protein coding genes to the structure and function of the encoded proteins, and medicine will be concerned in finding new protein markers for diagnostics, to identify novel drug targets, and to investigate, for example, the proteomes of the variety of tumors to aid tumor classification, to mention only a few areas of interest which medicine will have in the progress of human genome research. The review summarizes the recent achievements in sequencing the human DNA as published in February 2001 by the International Human Genome Sequencing Consortium and Celera Genomics and discusses their significance in respect to the further development of molecular, in particular genetic, medicine as an interdisciplinary field of the modern clinical sciences. Only biochemistry can provide the conceptual and experimental basis for the causal understanding of biological mechanisms as encoded in the genome of an organism.  相似文献   

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Identifying sources of the apparent variability in non-stationary scenarios is a fundamental problem in many biological data analysis settings. For instance, neurophysiological responses to the same task often vary from each repetition of the same experiment (trial) to the next. The origin and functional role of this observed variability is one of the fundamental questions in neuroscience. The nature of such trial-to-trial dynamics however remains largely elusive to current data analysis approaches. A range of strategies have been proposed in modalities such as electro-encephalography but gaining a fundamental insight into latent sources of trial-to-trial variability in neural recordings is still a major challenge. In this paper, we present a proof-of-concept study to the analysis of trial-to-trial variability dynamics founded on non-autonomous dynamical systems. At this initial stage, we evaluate the capacity of a simple statistic based on the behaviour of trajectories in classification settings, the trajectory coherence, in order to identify trial-to-trial dynamics. First, we derive the conditions leading to observable changes in datasets generated by a compact dynamical system (the Duffing equation). This canonical system plays the role of a ubiquitous model of non-stationary supervised classification problems. Second, we estimate the coherence of class-trajectories in empirically reconstructed space of system states. We show how this analysis can discern variations attributable to non-autonomous deterministic processes from stochastic fluctuations. The analyses are benchmarked using simulated and two different real datasets which have been shown to exhibit attractor dynamics. As an illustrative example, we focused on the analysis of the rat''s frontal cortex ensemble dynamics during a decision-making task. Results suggest that, in line with recent hypotheses, rather than internal noise, it is the deterministic trend which most likely underlies the observed trial-to-trial variability. Thus, the empirical tool developed within this study potentially allows us to infer the source of variability in in-vivo neural recordings.  相似文献   

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Gopalan SS  Durairaj V 《PloS one》2012,7(1):e29936

Background and Objectives

This paper focuses on the inadequate attention on women''s non-maternal healthcare in low- and middle-income countries. The study assessed the purchase of and financial access to non-maternal healthcare. It also scoped for mainstreaming household financial resources in this regard to suggest for alternatives.

Methods

A household survey through multi-stage stratified sampling in the state of Orissa interviewed rural women above 15 years who were neither pregnant nor had any pregnancy-related outcome six weeks preceding the survey. The questions explored on the processes, determinants and outcomes of health seeking for non-maternal ailments. The outcome measures were healthcare access, cost of care and financial access. The independent variables for bivariate and multivariate analyses were contextual factors, health seeking and financing pattern.

Results

The survey obtained a response rate of 98.64% and among 800 women, 43.8% had no schooling and 51% were above 60 years. Each woman reported at least one episode of non-maternal ailment; financial constraints prevented 68% from receiving timely and complete care. Distress coping measures (e.g. borrowings) dominated the financing source (67.9%) followed by community–based measures (32.1%). Only 6% had financial risk-protection; financial risk of not obtaining care doubled for women aged over 60 years (OR 2.00, 95% CI 0.84–4.80), seeking outpatient consultation (OR 2.01, 95% CI 0.89–4.81), facing unfavourable household response (OR 2.04, 95% CI 1.09–3.83), and lacking other financial alternatives (OR 2.13, 95% CI 1.11–4.07). When it comes to timely mobilization of funds and healthcare seeking, 90% (714) of the households preferred maternal care to non-maternal healthcare.

Conclusion

The existing financing options enable sub-optimal purchase of women''s non-maternal healthcare. Though dominant, household economy extends inadequate attention in this regard owing to its unfavourable approach towards non-maternal healthcare and limited financial capacity and support from other financial resources.  相似文献   

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The sequestration of Plasmodium falciparum-infected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. In contrast to P. falciparum, much less is known about sequestration in other Plasmodium parasites, including those species that are used as models to study severe malaria. Here, we review the cytoadherence properties of irbcs of the rodent parasite Plasmodium berghei ANKA, where schizonts demonstrate a clear sequestration phenotype. Real-time in vivo imaging of transgenic P. berghei parasites in rodents has revealed a CD36-dependent sequestration in lungs and adipose tissue. In the absence of direct orthologs of the P. falciparum proteins that mediate binding to human CD36, the P. berghei proteins and/or mechanisms of rodent CD36 binding are as yet unknown. In addition to CD36-dependent schizont sequestration, irbcs accumulate during severe disease in different tissues, including the brain. The role of sequestration is discussed in the context of disease as are the general (dis)similarities of P. berghei and P. falciparum sequestration.  相似文献   

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Due to their self-renewal and tumorigenic properties, tumor-initiating cells (TICs) have been hypothesized to be important targets for colorectal cancer (CRC). However the study of TICs is hampered by the fact that the identification and culturing of TICs is still a subject of extensive debate. Floating three-dimensional spheroid cultures (SC) that grow in serum-free medium supplemented with growth factors are supposed to be enriched in TICs. We generated SC from fresh clinical tumor specimens and compared them to SC isolated from CRC cell-lines as well as to adherent differentiated counterparts. Patient-derived SC display self-renewal capacity and can induce serial transplantable tumors in immuno-deficient mice, which phenotypically resemble the tumor of origin. In addition, the original tumor tissue and established SC retain several similar CRC-relevant mutations. Primary SC express key stemness proteins such as SOX2, OCT4, NANOG and LGR5 and importantly show increased chemoresistance ability compared to their adherent differentiated counterparts and to cell line-derived SC. Strikingly, cells derived from spheroid or adherent differentiating culture conditions displayed similar self-renewal capacity and equally formed tumors in immune-deficient mice, suggesting that self-renewal and tumor-initiation capacity of TICs is not restricted to phenotypically immature spheroid cells, which we describe to be highly plastic and able to reacquire stem-cell traits even after long differentiation processes. Finally, we identified two genes among a sphere gene expression signature that predict disease relapse in CRC patients. Here we propose that SC derived from fresh patient tumor tissue present interesting phenotypic features that may have clinical relevance for chemoresistance and disease relapse and therefore represent a valuable tool to test for new CRC-therapies that overcome drug resistance.  相似文献   

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