Polymorphism of human telomeric quadruplex structures

Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG). Compounds that can stabilize the intramolecular DNA G-quadruplexes formed in the human telomeric sequence have been shown to inhibit the activity of telomerase and telomere maintenance, thus the telomeric DNA G-quadruplex has been considered as an attractive target for cancer therapeutic intervention. Knowledge of intramolecular human telomeric G-quadruplex structure(s) formed under physiological conditions is important for structure-based rational drug design and thus has been the subject of intense investigation. This review will give an overview of recent progress on the intramolecular human telomeric G-quadruplex structures formed in K(+) solution. It will also give insight into the structure polymorphism of human telomeric sequences and its implications for drug targeting.     

Life Cycle Assessment of ICT

The use of information and communication technology (ICT) is growing throughout society, and new products and solutions are developed at an increasing rate. To enable environmental assessment of specific ICT products and other products that rely on ICT in some way, a more complete, detailed, and up‐to‐date study based on real measurements is needed. To date, similar studies have not been readily available or fully comprehensive. This study assessed the overall operational electricity use and life‐cycle–based carbon footprint (CF) relating to ICT in Sweden, including activities not commonly addressed previously, such as shared data transport networks and data centers and manufacturing of network infrastructure. Specific, detailed inventory data are presented and used for assessment of the Internet Protocol core network, data transmission, operator activities, and access network. These specific data, in combination with secondary, more generic data for end‐user equipment, allow a comprehensive overall assessment. The majority of the ICT network CF is the result of end‐user equipment, mainly personal computers, followed by third‐party enterprise networks and data centers and then access networks. The parts closest to the user proved to be clearly responsible for the majority of the impact. The results are presented for Swedish ICT networks and for ICT networks in general based on a global average electricity mix.     

A simulation support system for solving large physiological models on microcomputers

Although physiological modeling and computer simulation have become useful research tools to test new scientific theories and to design and analyze laboratory experiments, developing a new model can be a tedious process because the investigator must often write very complex and specific routines for data input and output. To facilitate the design of new models (as well as the use of existing models), we have developed MODSIM, a FORTRAN-based simulation support system for the IBM PC computer than can accommodate very large dynamic models having up to several thousand equations. It provides the investigator with utilities for continuous on-line graphical and/or tubular output, as well as facilities for dynamic interaction with the model. The user must only supply a model as a list of mathematical equations written in FORTRAN, along with the initial values of the model variables and parameters. The model is precompiled, compiled, and then linked to the MODSIM utilities. Without further programming, the user can then solve the model, select variables for graphical output, and stop the model at any time to analyze the data or to change a parameter before resuming the simulation. This simulation system makes it very easy to develop new models that actively interact with the experimental research of the investigator.     

A perspective on the diversity of human adaptability

Certain perspectives of morphological and functional diversities molded to adapt to highly technological environments remain to be evaluated, which leads us to consider what a truly healthy and comfortable environment is by focusing on the diversity of human adaptability based on the keywords of physiological anthropology, or physiological polymorphism, functional potentiality and whole body coordination. Each of the three keywords is outlined here, as well as the mutual relationship between them. A re-evaluation of the significance of polymorphism in the current living environment is also discussed here.     

Recombinant human alpha-1 proteinase inhibitor: towards therapeutic use

Summary. Human alpha-1-proteinase inhibitor is a well-characterized protease inhibitor with a wide spectrum of anti-protease activity. Its major physiological role is inhibition of neutrophil elastase in the lungs, and its deficiency is associated with progressive ultimately fatal emphysema. Currently in the US, only plasma-derived human alpha-1-proteinase inhibitor is available for augmentation therapy, which appears to be insufficient to meet the anticipated clinical demand. Moreover, despite effective viral clearance steps in the manufacturing process, the potential risk of contamination with new and unknown pathogens still exists. In response, multiple efforts to develop recombinant versions of human alpha-1-proteinase inhibitor, as an alternative to the plasma-derived protein, have been reported. Over the last two decades, various systems have been used to express the human gene for alpha-1-proteinase inhibitor. This paper reviews the recombinant versions of human alpha-1-proteinase inhibitor produced in various hosts, considers current major safety and efficacy issues regarding recombinant glycoproteins as potential therapeutics, and the factors that are impeding progress in this area¹. ¹ The opinions expressed in this paper reflect the authors’ personal views, based on published data and the information available from the public domains, and have no relation to the official statements, if any, held by the US FDA, National Institutes of Health, or the US Department of Health and Human Services. FDA official recommendations for plasma protein therapeutics and recombinant proteins regarding safety, purity, and potency of new drugs and biologics produced by recombinant DNA technology are referred below as the US FDA Guidances.     

Perspectives on environmental adaptability and physiological polymorphism in thermoregulation

The environmental adaptability of human beings has progressed according to various environments experienced in the course of evolution. Therefore, various phenotypes for environmental adaptability exist and are considered to be physiological polymorphism. Physiological polymorphism in thermoregulation is influenced by genotype, individual characteristics, environmental factors, cultural factors, etc. Moreover, it is thought that physiological polymorphism is evidenced more clearly in physiological responses to extreme situations and/or changing conditions than in environments where homeostasis is easily maintained. In the field of physiological anthropology, I think that it is important not only to discover the physiological responses that demonstrate polymorphism, but also to hypothesize about the mechanisms and the processes by which such polymorphisms were formed, and their meaning for human beings. Such discussions may be supposed to lead to an evaluation of the environmental adaptability of humans from the viewpoint of physiological anthropology.     

Human hemoglobin: polymorphism, neutrality of variants, evolutionary aspect

Integrated analysis of the polymorphism of human hemoglobin has been made using populational genetics, hematological, physiological, protein chemistry and molecular biology data. The known variants of human hemoglobin are conventionally classified as "widely common", "less common" and "rare", depending on their contribution to polymorphism. The importance of homeostasis and compensatory reactions for maintaining the resistance of the human body against mutant hemoglobins is emphasized. Hb D Punjab and Hb O Arab being relatively neutral, the genetic structure of populations may restrict their distribution. A hypothesis is put forward concerning the possible role of an increased local conformational mobility of protein in creating neutral protein variants. It is proposed to discriminate between truly neutral and pseudoneutral protein variants. In case of possible changes in the genetic and environmental factors, the former are not subject to selection, while the latter may be. Contribution to neutral evolution can be made only by truly neutral variants. In a compensated heterozygotic state the truly neutral and pseudoneutral variants may give rise to new functions and adaptively valuable properties in protein. The evolution of proteins is believed to proceed from a stage which is consistent with M. Kimura's concept of neutrality of protein polymorphism toward a stage which is consistent with the concept of selectionism. It is concluded, that the currently observed degree of polymorphism of human hemoglobin corresponds to the present stage of molecular evolution of the protein.     

Structural polymorphism of human telomere G-quadruplex induced by a pyridyl carboxamide molecule

In this work, we described a kinetically slow (hour-scale) but thermodynamically favored G-quadruplex conversion induced by a pyridyl carboxamide molecule. This slow transition was observed through CD spectra and gels, and its final stable parallel conformation was identified by 2-aminopurine experiments. Kinetic experiments indicated that this slow process was a first-order reaction, implying it was a unimolecular conversion. Quite distinctly from other reported ligand-driven G-quadruplex conformation alteration, this slow conversion reveals a novel insight into G-quadruplex polymorphism, in accordance with the behavior of human telomere G-quadruplex in a molecular crowding environment in K(+) solution, further enriching the known structural polymorphism of human telomere DNA and providing new consideration for drug design based on G-quadruplexes.     

Training mechanical engineering students to utilize biological inspiration during product development

The use of bio-inspiration for the development of new products and devices requires new educational tools for students consisting of appropriate design and manufacturing technologies, as well as curriculum. At the University of Maryland, new educational tools have been developed that introduce bio-inspired product realization to undergraduate mechanical engineering students. These tools include the development of a bio-inspired design repository, a concurrent fabrication and assembly manufacturing technology, a series of undergraduate curriculum modules and a new senior elective in the bio-inspired robotics area. This paper first presents an overview of the two new design and manufacturing technologies that enable students to realize bio-inspired products, and describes how these technologies are integrated into the undergraduate educational experience. Then, the undergraduate curriculum modules are presented, which provide students with the fundamental design and manufacturing principles needed to support bio-inspired product and device development. Finally, an elective bio-inspired robotics project course is present, which provides undergraduates with the opportunity to demonstrate the application of the knowledge acquired through the curriculum modules in their senior year using the new design and manufacturing technologies.     

WebSat ‐ A web software for microsatellite marker development

Simple sequence repeats (SSR), also known as microsatellites, have been extensively used as molecular markers due to their abundance and high degree of polymorphism. We have developed a simple to use web software, called WebSat, for microsatellite molecular marker prediction and development. WebSat is accessible through the Internet, requiring no program installation. Although a web solution, it makes use of Ajax techniques, providing a rich, responsive user interface. WebSat allows the submission of sequences, visualization of microsatellites and the design of primers suitable for their amplification. The program allows full control of parameters and the easy export of the resulting data, thus facilitating the development of microsatellite markers.     

Manufacturing intelligence for class prediction and rule generation to support human capital decisions for high-tech industries

Human capital is one of the critical resources for high-tech industries such as semiconductor manufacturing to maintain their competitive advantages, yet it is seldom addressed in literature. Owing to the changing nature of knowledge workers in high-tech industries, jobs cannot be easily delineated. Thus, conventional personnel selection approaches based on static job characteristics no longer suffice. Focusing on the needs in real settings, this study aims to develop a manufacturing intelligence framework that integrates the rough set theory, support vector machine, and decision tree to extract useful patterns and intelligence from huge human resource data and production data to enhance the decision quality of human resource management that include identifying high-potential talents who fit the company culture and allocating the job with functional nature that matches the characteristics of the talent. To assess the validity of this approach, empirical studies were conducted on the basis of real data collected from semiconductor companies for comparison. The results have shown the practical viability of this approach.     

Evaluation of Tools for Modeling Manufacturing Systems Design with Multiple Levels of Detail

This paper presents an investigation of simulation packages regarding their ability to model business processes related to manufacturing systems. Three simulation packages are investigated: VS7, SIMAN/CINEMA IV, and SIMFACTORY II.5. These packages are evaluated with regard to their capabily of modeling problems related to the manufacturing systems design (MSD) framework, which involves different levels of detail: the conceptual modeling level and the detailed design level. The investigation is based on a case study related to manufacturing systems. The main objective of this investigation is to examine the manufacturing simulation packages and their ability to offer variable detail modeling. Research findings suggest that no simulation environment offers sufficiently flexible facilities for the variable detailed modeling of manufacturing systems design. The paper proposes a method for systems entity classification to increase the levels of detail in an effective manner without duplication of data collection and model building efforts.     

An Infrastructure for Integrated Automation System Implementation

Evolution of advanced manufacturing technologies and the new manufacturing paradigm has enriched the computer integrated manufacturing (CIM) methodology. The new advances have put more demands for CIM integration technology and associated supporting tools. One of these demands is to provide CIM systems with better software architecture, more flexible integration mechanisms, and powerful support platforms. In this paper, we present an integrating infrastructure for CIM implementation in manufacturing enterprises to form an integrated automation system. A research prototype of an integrating infrastructure has been developed for the development, integration, and operation of integrated CIM system. It is based on the client/server structure and employs object-oriented and agent technology. System openness, scalability, and maintenance are ensured by conforming to international standards and by using effective system design software and management tools.     

A genome-scale, constraint-based approach to systems biology of human metabolism

The recent sequencing and annotation of the human genome enables a new era in biomedicine that will be based on an interdisciplinary, systemic approach to the elucidation and treatment of human disease. Reconstruction of genome-scale metabolic networks is an important part of this approach since networks represent the integration of diverse biological data such as genome annotations, high-throughput data, and legacy biochemical knowledge. This article will describe Homo sapiens Recon 1, a functionally tested, genome-scale reconstruction of human cellular metabolism, and its capabilities for facilitating the understanding of physiological and disease metabolic states.     

Tolerance and suppressor mechanisms in experimental autoimmune encephalomyelitis: implications for immunotherapy of human autoimmune diseases

Recent advances in understanding antigen recognition at the level of the trimolecular complex have provided new approaches for selective immunotherapy. Many of these approaches have been applied successfully to the animal model experimental autoimmune encephalomyelitis, and some are being tested in the human disease multiple sclerosis. In addition, new approaches utilizing nonspecific modulation of immune function are being explored in animals and humans. Immunospecific therapy in autoimmune diseases will ultimately be based on understanding how the normal immune system maintains unresponsiveness to self and how this state of self-tolerance is broken. Strategies for specific immune intervention in human diseases based on components of the trimolecular complex will have to take into account the polymorphism of the major histocompatibility complex in humans and the degree of heterogeneity among autoimmune T cells that react with an autoantigen.     

Recent Advances in Design for Environment at Motorola

Motorola is a large electronics company that uses design for environment (DfE) t o address our customers' environmental needs. In working to integrate environmental considerations into product design, Motorola has encountered new challenges in product design, and as a result has had to develop new frameworks and employ new analytical tools. This article describes those challenges and Motorola's efforts to date. The examination of how products are designed in Motorola led to the realization that there are distinct phases in design: concept development, detail design, and prototype manufacture. In the earlier phases where the greatest flexibility for product reconfiguration exists, there is the least amount of detailed information available for use in making environmental assessments. In an effort to match the data availability to the environmental assessment needs, Motorola developed a tiered approach to DE using a matrix-based abridged life-cycle assessment (LCA) in the concept development stage, a scoring system based in part on multiattribute value theory in the detail design stage, and potentially full-scale life-cycle assessment in the prototype manufacturing stage.     

Technology outlook for real-time quality attribute and process parameter monitoring in biopharmaceutical development—A review

Real-time monitoring of bioprocesses by the integration of analytics at critical unit operations is one of the paramount necessities for quality by design manufacturing and real-time release (RTR) of biopharmaceuticals. A well-defined process analytical technology (PAT) roadmap enables the monitoring of critical process parameters and quality attributes at appropriate unit operations to develop an analytical paradigm that is capable of providing real-time data. We believe a comprehensive PAT roadmap should entail not only integration of analytical tools into the bioprocess but also should address automated-data piping, analysis, aggregation, visualization, and smart utility of data for advanced-data analytics such as machine and deep learning for holistic process understanding. In this review, we discuss a broad spectrum of PAT technologies spanning from vibrational spectroscopy, multivariate data analysis, multiattribute chromatography, mass spectrometry, sensors, and automated-sampling technologies. We also provide insights, based on our experience in clinical and commercial manufacturing, into data automation, data visualization, and smart utility of data for advanced-analytics in PAT. This review is catered for a broad audience, including those new to the field to those well versed in applying these technologies. The article is also intended to give some insight into the strategies we have undertaken to implement PAT tools in biologics process development with the vision of realizing RTR testing in biomanufacturing and to meet regulatory expectations.