Very low-noise ENG amplifier system using CMOS technology.

In this paper, we describe the design and testing of a system for recording electroneurographic signals (ENG) from a multielectrode nerve cuff (MEC). This device, which is an extension of the conventional nerve signal recording cuff, enables ENG to be classified by action potential velocity. In addition to electrical measurements, we provide preliminary in vitro data obtained from frogs that demonstrate the validity of the technique for the first time. Since typical ENG signals are extremely small, on the order of 1 1 microV, very low-noise, high-gain amplifiers are required. The ten-channel system we describe was realized in a 0.8 microm CMOS technology and detailed measured results are presented. The overall gain is 10 000 and the total input-referred root mean square (rms) noise in a bandwidth 1 Hz-5 kHZ is 291 nV. The active area is 12 mm(2) and the power consumption is 24 mW from +/-2.5 V power supplies.     

21世纪初ICRP建议书草案

在过去的几年中，国际放射防护委员会鼓励对其计划将于2005年发表的下一个建议书表述辐射防护理念的最佳方式开展讨论。现在的建议书是由1990年发表的第60号出版物提出的，而且得到过去12年里发表的其它出版物的补充。现在显然委员会有必要总结在大约10个报告中推荐的数值数量的完整性。本文将完成这项工作，并由此而表明前进方向，提出一个简明且比较一致的21世纪初防护理念的表述。当然并不意在进行根本的修改，而是建议对现行政策做出连贯一致的表述，对其应用进行简化。     

Quality of Service Networking for High Performance Grid Applications

This paper reports on different efforts to provide quality of service (QoS) Networking to Grid applications done in the context of the MB-NG, GRS and DataTAG EU projects. These are leading edge network research projects involving more that 50 researchers in the UK, Europe and North America, concerned with the development and testing of protocols and standards for the next generation of high speed networks. We have implemented and tested the Differentiated Services Architecture (DiffServ) in a multi-domain, 2.5 Gbits/s network (the first such deployment) defining appropriate Service Level Agreements (SLAs) to be used between administrative domains to guarantee end-to-end Quality of Service. We characterised several hardware implementations of DiffServ and concluded on their appropriateness for several network scenarios. Since current and future Grid applications will have to use modified mechanisms of congestion control we have evaluated old and new TCP implementations over a Differentiated Services Networks. These quality of service tests have also included innovative MPLS (Multi-Protocol Label Switching) experiments to establish guaranteed bandwidth connections to Grid applications in a fast and efficient way. We have also developed a software based bandwidth broker architecture for Grids based on IETF standards which allows applications to transparently request dynamic and advanced reservations and implemented it in a real experimental network. We finally report on experiences delivering Quality of Service networking to high performance applications like Particle Physics data transfer and High Performance Computation. This includes quantitative results on the performance improvements that QoS brought to real data transfers in the context of High Performance Computing.     

Retailers' tagging practices: a potential liability?

This study investigates the coverage of federally mandated information on over‐the‐counter (OTC) drug labels by electronic article surveillance (EAS) tags applied to the exterior of cartons. Using adult‐strength analgesics containing acetaminophen as a case study, researchers investigated the issue in Houston, Texas (24 stores) and Lansing, Michigan (33 stores). The information obscured by EAS tags was identified and classified for a total of 849 packages using a standardized data collection instrument. The results indicated that 293 packages examined, or 34.5%, had information mandated by the US Food and Drug Administration (US FDA) fully or partially obscured by the EAS tags. Retailers and manufacturers should be aware of such practices to reduce potential liability. Recommendations for improving EAS tag usage on OTC products are presented. Copyright © 2004 John Wiley & Sons, Ltd.     

Molecular cloning, expression, and characterization of a functional single-chain Fv antibody to the mycotoxin zearalenone

The heavy-chain and kappa light-chain variable region genes of an antizearalenone hybridoma cell line (2G3-6E3-2E2) were isolated by PCR and joined by a DNA linker encoding peptide (Gly4Ser)3 as a single-chain Fv (scFv) DNA fragment. The scFv DNA fragment was cloned into a phagemid (pCANTAB5E) and expressed as a fusion protein with E tag and phage M13 p3 in Escherichia coli TG1. In the presence of helper phage M13K07, the scFv fusion protein was displayed on the surfaces of recombinant phages. High-affinity scFv phages were enriched through affinity selection in microtiter wells coated with zearalenone-ovalbumin conjugate. The selected recombinant phages were used to infect E. coli HB2151 for the production of soluble scFv antibodies. One selected clone (pQY1.5) in HB2151 secreted a soluble scFv antibody (QY1.5) with a high zearalenone-binding affinity (concentration required for 50% inhibition of binding, 14 ng/ml), similar to that of parent monoclonal antibody in a competitive indirect enzyme-linked immunosorbent assay. However, scFv QY1.5 exhibited higher cross-reactivity with zearalenone analogs and had greater sensitivity to methanol destabilization than the parent monoclonal antibody did. Nucleotide sequence analyses revealed that the light-chain portion of scFv QY1.5 had a nucleotide sequence identity of 97% to a mouse germ line gene VK23.32 in mouse kappa light-chain variable region subgroup V, whereas the heavy-chain nucleotide sequence was classified as mouse heavy-chain subgroup III (D) but without any closely related members having highly homologous complementarity-determining region sequences. The potential of soluble scFv QY1.5 for routine screening of zearalenone and its analogs was demonstrated with zearalenone-spiked corn extracts.     

Defective Thyroglobulin: Cell Biology of Disease

The primary functional units of the thyroid gland are follicles of various sizes comprised of a monolayer of epithelial cells (thyrocytes) surrounding an apical extracellular cavity known as the follicle lumen. In the normal thyroid gland, the follicle lumen is filled with secreted protein (referred to as colloid), comprised nearly exclusively of thyroglobulin with a half-life ranging from days to weeks. At the cellular boundary of the follicle lumen, secreted thyroglobulin becomes iodinated, resulting from the coordinated activities of enzymes localized to the thyrocyte apical plasma membrane. Thyroglobulin appearance in evolution is essentially synchronous with the appearance of the follicular architecture of the vertebrate thyroid gland. Thyroglobulin is the most highly expressed thyroid gene and represents the most abundantly expressed thyroid protein. Wildtype thyroglobulin protein is a large and complex glycoprotein that folds in the endoplasmic reticulum, leading to homodimerization and export via the classical secretory pathway to the follicle lumen. However, of the hundreds of human thyroglobulin genetic variants, most exhibit increased susceptibility to misfolding with defective export from the endoplasmic reticulum, triggering hypothyroidism as well as thyroidal endoplasmic reticulum stress. The human disease of hypothyroidism with defective thyroglobulin (either homozygous, or compound heterozygous) can be experimentally modeled in thyrocyte cell culture, or in whole animals, such as mice that are readily amenable to genetic manipulation. From a combination of approaches, it can be demonstrated that in the setting of thyroglobulin misfolding, thyrocytes under chronic continuous ER stress exhibit increased susceptibility to cell death, with interesting cell biological and pathophysiological consequences.     

Bioinformatic Analysis of Na+, K+-ATPase Regulation through Phosphorylation of the Alpha-Subunit N-Terminus

The Na⁺, K⁺-ATPase is an integral membrane protein which uses the energy of ATP hydrolysis to pump Na⁺ and K⁺ ions across the plasma membrane of all animal cells. It plays crucial roles in numerous physiological processes, such as cell volume regulation, nutrient reabsorption in the kidneys, nerve impulse transmission, and muscle contraction. Recent data suggest that it is regulated via an electrostatic switch mechanism involving the interaction of its lysine-rich N-terminus with the cytoplasmic surface of its surrounding lipid membrane, which can be modulated through the regulatory phosphorylation of the conserved serine and tyrosine residues on the protein’s N-terminal tail. Prior data indicate that the kinases responsible for phosphorylation belong to the protein kinase C (PKC) and Src kinase families. To provide indications of which particular enzyme of these families might be responsible, we analysed them for evidence of coevolution via the mirror tree method, utilising coevolution as a marker for a functional interaction. The results obtained showed that the most likely kinase isoforms to interact with the Na⁺, K⁺-ATPase were the θ and η isoforms of PKC and the Src kinase itself. These theoretical results will guide the direction of future experimental studies.     

Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in Abeta-induced cytotoxicity

Endoplasmic reticulum-associated amyloid beta-peptide (Abeta)-binding protein (ERAB)/L-3-hydroxyacyl-CoA dehydrogenase type II (HADH II) is expressed at high levels in Alzheimer's disease (AD)-affected brain, binds Abeta, and contributes to Abeta-induced cytotoxicity. Purified recombinant ERAB/HADH II catalyzed the NADH-dependent reduction of S-acetoacetyl-CoA with a Km of approximately 68 microM and a Vmax of approximately 430 micromol/min/mg. The contribution of ERAB/HADH II enzymatic activity to Abeta-mediated cellular dysfunction was studied by site-directed mutagenesis in the catalytic domain (Y168G/K172G). Although COS cells cotransfected to overexpress wild-type ERAB/HADH II and variant beta-amyloid precursor protein (betaAPP(V717G)) showed DNA fragmentation, cotransfection with Y168G/K172G-altered ERAB and betaAPP(V717G) was without effect. We thus asked whether the enzyme might recognize alcohol substrates of which the aldehyde products could be cytotoxic; ERAB/HADH II catalyzed oxidation of a variety of simple alcohols (C2-C10) to their respective aldehydes in the presence of NAD+ and NAD-dependent oxidation of 17beta-estradiol. Addition of micromolar levels of synthetic Abeta(1-40) to purified ERAB/HADH II inhibited, in parallel, reduction of S-acetoacetyl-CoA (Ki approximately 1.6 microM), as well as oxidation of 17beta-estradiol (Ki approximately 3.2 microM) and (-)-2-octanol (Ki approximately 2.6 microM). Because micromolar levels of Abeta were required to inhibit ERAB/HADH II activity, whereas Abeta binding to ERAB/HADH II occurred at much lower concentrations (Km approximately 40-70 nM), the latter more closely simulating Abeta levels within cells, Abeta perturbation of ERAB/HADH II was likely to result from mechanisms other than the direct modulation of enzymatic activity. Cells cotransfected to overexpress ERAB/HADH II and betaAPP(V717G) generated malondialdehyde-protein and 4-hydroxynonenal-protein epitopes, which were detectable only at the lowest levels in cells overexpressing either ERAB/HADH II or betaAPP(V717G) alone. Generation of such toxic aldehydes was not observed in cells contransfected to overexpress Y168G/K172G-altered ERAB and betaAPP(V717G). We conclude that the generalized alcohol dehydrogenase activity of ERAB/HADH II is central to the cytotoxicity observed in an Abeta-rich environment.     

国际放射防护委员会新建议书准备工作的进展

国际放射防护委员会（ＩＣＲＰ）使用的低水平电离辐射照射的致癌危险已经受到了挑战,有人说它太高,同时也有人说它太低。本文说明,流行病学的证据总是在低剂量受到限制,因此,为了评价生物学危险,理解致癌的细胞机制就愈加重要。从而,通过分析,找出为什么会对ＩＣＲＰ提出挑战,特别是对线性无阈响应模型提出挑战的原因。通过对这些问题的认真考虑,ＩＣＲＰ主委员会现正研究一种经修改的简化方法,它是建筑在着眼于个体的哲     

Mathematical models of the transitions between endocrine therapy responsive and resistant states in breast cancer

Endocrine therapy, targeting the oestrogen receptor pathway, is the most common treatment for oestrogen receptor-positive breast cancers. Unfortunately, these tumours frequently develop resistance to endocrine therapies. Among the strategies to treat resistant tumours are sequential treatment (in which second-line drugs are used to gain additional responses) and intermittent treatment (in which a ‘drug holiday’ is imposed between treatments). To gain a more rigorous understanding of the mechanisms underlying these strategies, we present a mathematical model that captures the transitions among three different, experimentally observed, oestrogen-sensitivity phenotypes in breast cancer (sensitive, hypersensitive and independent). To provide a global view of the transitions between these phenotypes, we compute the potential landscape associated with the model. We show how this oestrogen response landscape can be reshaped by population selection, which is a crucial force in promoting acquired resistance. Techniques from statistical physics are used to create a population-level state-transition model from the cellular-level model. We then illustrate how this population-level model can be used to analyse and optimize sequential and intermittent oestrogen-deprivation protocols for breast cancer. The approach used in this study is general and can also be applied to investigate treatment strategies for other types of cancer.