Spatial conformation of human serotransferrin glycans]

The construction of molecular models for the human serotransferrin glycans shows that they present one compact section linked to the protein and constituted by the pentasaccharide alpha-Man-(1 leads to 3)-[alpha-Man-(1 leads to 6)]-beta-Man-(1 leads to 4)-beta-GlcNAc-(1 leads to 4)-beta-GlcNAc-(1 leads to)-Asn to which are attached two "antennae" consisting of the trisaccharide alpha-NANA-(2 leads to 6)-beta-Gal-(1 leads to 4)-beta-GlcNAc. The trisaccharide sequence beta-Man-(1 leads to 4)-beta-GlcNAc-(1 leads to 4)-beta-GlcNAc adopts a flat and rigid conformation, stabilised by hydrogen bonds. In contrast, the sequence alpha-NANA-(1 leads to 6)-beta-Gal-(1 leads to 4)-beta-GlcNAc-(1 leads to 2)-alpha-Man takes up a helical configuration. The two "antennae" can be disposed on the pentasaccharide core to give two possible configurations, one Y-shaped and the other T-shaped. In both cases, the general conformation of the glycans is perfectly compatible with their postulated role as a recognition signal.     

Permissible idealizations for the purpose of prediction

Every model leaves out or distorts some factors that are causally connected to its target phenomenon—the phenomenon that it seeks to predict or explain. If we want to make predictions, and we want to base decisions on those predictions, what is it safe to omit or to simplify, and what ought a causal model to describe fully and correctly? A schematic answer: the factors that matter are those that make a difference to the target phenomenon. There are several ways to understand differencemaking. This paper advances a view as to which is the most relevant to the forecaster and the decision-maker. It turns out that the right notion of differencemaking for thinking about idealization in prediction is also the right notion for thinking about idealization in explanation; this suggests a carefully circumscribed version of Hempel’s famous thesis that there is a symmetry between explanation and prediction.     

Unnatural acts: The transition from Natural Principles to Laws of Nature in Early Modern science

This paper's aim is to explain the transition that occurred during the Early Modern period, from Principles of Nature to Laws of Nature. Natural Principles are taken to be innate to substances and arise from their natures, while Laws of Nature are external and imposed from without. The paper takes the view that to explain this transition, one needs to examine the history of philosophical theories of substantial action. It argues that during the late Middle Ages and in the Early Modern era, philosophers began to disentangle substantial actions from the nature of substances. This process of disentangling action eventually led to the concept of Laws of Nature, according to which laws compel a body to act in a certain way even though its nature does not.     

2006～2010年革兰阴性菌对碳青霉烯类抗生素耐药性分析

目的调查分析我院20ff6～2010年临床分离的革兰阴性菌对碳青霉烯类抗生素的耐药性。方法采用纸片扩散法进行抗菌药物敏感实验,采用WHONET5．4软件及SPSS13．0软件进行数据分析。结果大肠埃希菌和肺炎克雷伯菌对亚胺培南和美罗培南的耐药率呈上升趋势,但最高不超过4．5％。铜绿假单胞菌对亚胺培南的耐药率2006年和2007年监测显示为21．3％和41％。2008年达到44．8％,在2009年下降为12．4％,但2010年爽迅速增加到30．1％。鲍曼不动杆菌对亚胺培南耐药率的逐年上升更为显著,从2006年9．1％上升到2010年的68％,差异具有统计学意义（P〈0．01）。嗜麦芽窄食单胞菌对碳青霉烯类抗生素天然耐药,2006年对亚胺培南耐药率为30％,但自2007年起就增加到80．8％,最高达100％。结论肠杆菌科细菌对碳青霉烯类敏感性高,近年耐药率有上升趋势。铜绿假单胞菌和鲍曼不动杆菌对碳青霉烯类耐药率高,尤其是鲍曼不动杆菌的分离率逐年增加,耐药形势严峻。临床应合理使用抗生素,减少多重耐药株的产生。     

组合摩擦材料研究

由于国内外摩擦材料的研究仍处于经验阶段，我们提出组合摩擦材料的概念并进行了组合摩擦材料研究，旨在解决摩擦材料配方研究中存在的三个问题：如何选择原材料，如何匹配原材料含量和摩擦材料性能优化。组合摩擦材料研究包括用组合方法筛选和评价原材料和用黄金分割法优化摩擦材料配方是解决经验地尝试法研究摩擦材料配方的一个有效途径。用组合方法筛选和评价原材料，通过组合路线考察原材料间的相互作用，寻找具有协同效应的原材料组合规律，可以合理选择原材料和合理设计摩擦材料配方。用黄金分割法可以优化摩擦材料性能。通过组合摩擦材料研究可以实现摩擦材料的研究从经验走向科学。两个实例证明了组合摩擦材料研究的可行性。     

T cell receptor bias for MHC: co-evolution or co-receptors?

In contrast to antibodies, which recognize antigens in native form, αβ T cell receptors (TCRs) only recognize antigens as peptide fragments bound to MHC molecules, a feature known as MHC restriction. The mechanism by which MHC restriction is imposed on the TCR repertoire is an unsolved problem that has generated considerable debate. Two principal models have been advanced to explain TCR bias for MHC. According to the germline model, MHC restriction is intrinsic to TCR structure because TCR and MHC molecules have co-evolved to conserve germline-encoded TCR sequences with the ability to bind MHC, while eliminating TCR sequences lacking MHC reactivity. According to the selection model, MHC restriction is not intrinsic to TCR structure, but is imposed by the CD4 and CD8 co-receptors that promote signaling by delivering the Src tyrosine kinase Lck to TCR–MHC complexes through co-receptor binding to MHC during positive selection. Here, we review the evidence for and against each model and conclude that both contribute to determining TCR specificity, although their relative contributions remain to be defined. Thus, TCR bias for MHC reflects not only germline-encoded TCR–MHC interactions but also the requirement to form a ternary complex with the CD4 or CD8 co-receptor that is geometrically competent to deliver a maturation signal to double-positive thymocytes during T cell selection.     

Improved methods of combining forecasts

It is well known that a linear combination of forecasts can outperform individual forecasts. The common practice, however, is to obtain a weighted average of forecasts, with the weights adding up to unity. This paper considers three alternative approaches to obtaining linear combinations. It is shown that the best method is to add a constant term and not to constrain the weights to add to unity. These methods are tested with data on forecasts of quarterly hog prices, both within and out of sample. It is demonstrated that the optimum method proposed here is superior to the common practice of letting the weights add up to one.     

A simple method for the preparation of antibodies to the mitochondrial biotin-dependent carboxylases

Heterologous antiserum to the 3 biotin-dependent carboxylases was prepared by selective removal of these enzymes from human liver on an avidin-sepharose column. A carboxylase-avidin-sepharose matrix was used as an antigen to produce anti-carboxylase antibodies. The resultant antisera can be used to purify the specific carboxylases, to prepare monoclonal antibodies to these enzymes or to study inherited carboxylase deficiencies and biotin-dependent intermediary metabolism.     

Olfactory ensheathing cells are attracted to, and can endocytose, bacteria

Olfactory ensheathing cells (OECs) have been shown previously to express Toll-like receptors and to respond to bacteria by translocating nuclear factor-kappaB from the cytoplasm to the nucleus. In this study, we show that OECs extended significantly more pseudopodia when they were exposed to Escherichia coli than in the absence of bacteria (p=0.019). Co-immunoprecipitation showed that E. coli binding to OECs was mediated by Toll-like receptor 4. Lyso-Tracker, a fluorescent probe that accumulates selectively in lysosomes, and staining for type 1 lysosome-associated membrane proteins demonstrated that endocytosed FITC-conjugated E. coli were translocated to lysosomes. They appeared to be subsequently broken down, as shown by transmission electron microscopy. No obvious adherence to the membrane and less phagocytosis was observed when OECs were incubated with inert fluorescent microspheres. The ability of OECs to endocytose bacteria supports the notion that OECs play an innate immune function by protecting olfactory tissues from bacterial infection.     

The methodological defense of realism scrutinized

I revisit an older defense of scientific realism, the methodological defense, a defense developed by both Popper and Feyerabend. The methodological defense of realism concerns the attitude of scientists, not philosophers of science. The methodological defense is as follows: a commitment to realism leads scientists to pursue the truth, which in turn is apt to put them in a better position to get at the truth. In contrast, anti-realists lack the tenacity required to develop a theory to its fullest. As a consequence, they are less likely to get at the truth.My aim is to show that the methodological defense is flawed. I argue that a commitment to realism does not always benefit science, and that there is reason to believe that a research community with both realists and anti-realists in it may be better suited to advancing science. A case study of the Copernican Revolution in astronomy supports this claim.     

The double transfer of thermodynamics: From physics to chemistry and from Europe to America

The aim of this study is twofold: to explore, first, the influence of the intellectual and social conditions on the transfer of thermodynamics to chemistry and thereby the making of chemical thermodynamics, and second, the way that this knowledge was transferred from Europe to America. Consequently, it is of interest to examine the methodological approaches used by physicists and chemists to transfer thermodynamics to chemistry, to evaluate the potential of this science to offer solutions to existing chemical problems, and to discuss the attitude of the scientific community towards these new ideas. The development of chemical thermodynamics in America followed a different route compared to the European experience. Although it was transferred from Europe, it had distinctive characteristics imposed by a different traditional, intellectual and social milieu. This study focuses on the content of the transferred knowledge to America and the direction that this knowledge assumed by the American scientists. As a paradigm, the chemical thermodynamics of Gilbert Newton Lewis will be considered.     

Alzheimer’s disease and CADASIL are heritable,adult-onset dementias that both involve damaged small blood vessels

This essay explores an alternative pathway to Alzheimer’s dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.     

Our impasse in developing a malaria vaccine

Malaria presents a challenge to world health that to date has been beyond the abilities of researchers to conquer. This critique presents some of the strategies employed by the parasite to overcome immunity and the immunological challenges that we face to develop vaccines. A conclusion is that a vaccine must identify novel antigens or epitopes that are not normally immunogenic and which are therefore not under immune pressure and most likely to be conserved between different strains. Such antigens are most likely to be targets of cellular immunity. The case for a whole parasite blood stage vaccine is presented based on these premises.     

Genetic and environmental influences on reactive and spontaneous locomotor activities in rats

Paired groups of rats (derived from divergent, selective breeding or living in divergent environmental conditions) were compared with regard to locomotor activities. Intrapair differences were found to vary non-systematically, depending upon whether the rats were initially exposed to a test-environment with or without a slight environmental modification (reactive activities), or were allowed to habituate extensively to the environment (spontaneous activity). Since the behavioral patterns were found to represent distinct entities, this pointed to the necessity of differentiating clearly between spontaneous and reactive activities and indicated, once again, that both genetic and environmental influences are important in these behaviors and must be taken into account. Accepting and controlling for these variables makes it possible to use the factor of individual differences in laboratory animal behavior to advantage.     

Night shift paralysis

Summary 12% of night nurses surveyed claimed to have suffered from a totally incapacitating paralysis that may be related to sleep paralysis, and contribute to impaired levels of safety on the night shift. The incidence of this paralysis is shown to be age-related, largely confined to the early hours of the morning, and to increase over consecutive night shifts.Acknowledgments. We wish to dedicate this paper to Professor Dr Günther Hildebrandt, Director of the Institut für Arbeitsphysiologie und Rehabilitationsforschung, University of Marburg/Lahn in honor of his 60th birthday. We also wish to thank the Nursing Officers and nurses concerned for their help in this study.     

Impact of climate change on wetland ecosystems: A critical review of experimental wetlands

Climate change is identified as a major threat to wetlands. Altered hydrology and rising temperature can change the biogeochemistry and function of a wetland to the degree that some important services might be turned into disservices. This means that they will, for example, no longer provide a water purification service and adversely they may start to decompose and release nutrients to the surface water. Moreover, a higher rate of decomposition than primary production (photosynthesis) may lead to a shift of their function from being a sink of carbon to a source. This review paper assesses the potential response of natural wetlands (peatlands) and constructed wetlands to climate change in terms of gas emission and nutrients release. In addition, the impact of key climatic factors such as temperature and water availability on wetlands has been reviewed. The authors identified the methodological gaps and weaknesses in the literature and then introduced a new framework for conducting a comprehensive mesocosm experiment to address the existing gaps in literature to support future climate change research on wetland ecosystems. In the future, higher temperatures resulting in drought might shift the role of both constructed wetland and peatland from a sink to a source of carbon. However, higher temperatures accompanied by more precipitation can promote photosynthesis to a degree that might exceed the respiration and maintain the carbon sink role of the wetland. There might be a critical water level at which the wetland can preserve most of its services. In order to find that level, a study of the key factors of climate change and their interactions using an appropriate experimental method is necessary. Some contradictory results of past experiments can be associated with different methodologies, designs, time periods, climates, and natural variability. Hence a long-term simulation of climate change for wetlands according to the proposed framework is recommended. This framework provides relatively more accurate and realistic simulations, valid comparative results, comprehensive understanding and supports coordination between researchers. This can help to find a sustainable management strategy for wetlands to be resilient to climate change.     

Impact of climate change on wetland ecosystems: A critical review of experimental wetlands

Climate change is identified as a major threat to wetlands. Altered hydrology and rising temperature can change the biogeochemistry and function of a wetland to the degree that some important services might be turned into disservices. This means that they will, for example, no longer provide a water purification service and adversely they may start to decompose and release nutrients to the surface water. Moreover, a higher rate of decomposition than primary production (photosynthesis) may lead to a shift of their function from being a sink of carbon to a source. This review paper assesses the potential response of natural wetlands (peatlands) and constructed wetlands to climate change in terms of gas emission and nutrients release. In addition, the impact of key climatic factors such as temperature and water availability on wetlands has been reviewed. The authors identified the methodological gaps and weaknesses in the literature and then introduced a new framework for conducting a comprehensive mesocosm experiment to address the existing gaps in literature to support future climate change research on wetland ecosystems. In the future, higher temperatures resulting in drought might shift the role of both constructed wetland and peatland from a sink to a source of carbon. However, higher temperatures accompanied by more precipitation can promote photosynthesis to a degree that might exceed the respiration and maintain the carbon sink role of the wetland. There might be a critical water level at which the wetland can preserve most of its services. In order to find that level, a study of the key factors of climate change and their interactions using an appropriate experimental method is necessary. Some contradictory results of past experiments can be associated with different methodologies, designs, time periods, climates, and natural variability. Hence a long-term simulation of climate change for wetlands according to the proposed framework is recommended. This framework provides relatively more accurate and realistic simulations, valid comparative results, comprehensive understanding and supports coordination between researchers. This can help to find a sustainable management strategy for wetlands to be resilient to climate change.     

Subjective intervention in formal models

Success in forecasting using mathematical/statistical models requires that the models be open to intervention by the user. In practice, a model is only one component of a forecasting system, which also includes the users/forecasters as integral components. Interaction between the user and the model is necessary to adequately cater for events and changes that go beyond the existing form of the model. In this paper we consider Bayesian forecasting models open to interventions, of essentially any form, to incorporate subjective information made available to the user. We discuss principles of intervention and derive theoretical results that provide the means to formally incorporate feedforward interventions into Bayesian models. Two example time series are considered to illustrate why and when such interventions may be necessary to sustain predictive performance.