Therapeutic Usages of Oxygen Radical Scavengers in Human Diseases: Myths and Realities

Some distinct advances in pharmacologic manipulation of oxygen radical scavengers have been made which could ultimately greatly enhance the use of these reagents as drugs, as well as some innovative techniques for drug delivery. Unfortunately, most of the therapeutic reports in the literature, almost all of which are based on usage of standard (native) SOD and/or catalase, are still anecdotal and/or uncontrolled. A review of the human disedse/treatment literature suggests that further tightening of the scientific design of such trials is stjll badly needed; hopefully better experimental design will be applied when products such as PEG conjugates or genetically engineered polymers are ready for testing.     

The reconstruction and analysis of tissue specific human metabolic networks

Human tissues have distinct biological functions. Many proteins/enzymes are known to be expressed only in specific tissues and therefore the metabolic networks in various tissues are different. Though high quality global human metabolic networks and metabolic networks for certain tissues such as liver have already been studied, a systematic study of tissue specific metabolic networks for all main tissues is still missing. In this work, we reconstruct the tissue specific metabolic networks for 15 main tissues in human based on the previously reconstructed Edinburgh Human Metabolic Network (EHMN). The tissue information is firstly obtained for enzymes from Human Protein Reference Database (HPRD) and UniprotKB databases and transfers to reactions through the enzyme-reaction relationships in EHMN. As our knowledge of tissue distribution of proteins is still very limited, we replenish the tissue information of the metabolic network based on network connectivity analysis and thorough examination of the literature. Finally, about 80% of proteins and reactions in EHMN are determined to be in at least one of the 15 tissues. To validate the quality of the tissue specific network, the brain specific metabolic network is taken as an example for functional module analysis and the results reveal that the function of the brain metabolic network is closely related with its function as the centre of the human nervous system. The tissue specific human metabolic networks are available at .     

Consumer nueroscience: a new area of study for biomedical engineers

In scientific literature, the most accepted definition of consumer neuroscience or neuromarketing is that it is a field of study concerning the application of neuroscience methods to analyze and understand human behavior related to markets and marketing exchanges. First, it might seem strange that marketers would be interested in using neuroscience to understand consumer's preferences. Yet in practice, the basic goal of marketers is to guide the design and presentation of products in such a way that they are highly compatible with consumer preferences. To understand consumers preferences, several standard research tools are commonly used by marketers, such as personal interviews with the consumers, scoring questionnaries gathered from consumers, and focus groups. The reason marketing researchers are interested in using brain imaging tools instead of simply asking people for their preferences in front of marketing stimuli, arises from the assumption that people cannot (or do not want to) fully explain their preference when explicitly asked. Researchers in the field hypothesize that neuroimaging tools can access information within the consumer's brain during the generation of a preference or the observation of a commercial advertisement. The question of will this information be useful in further promoting the product is still up for debate in marketing literature. From the marketing researchers point of view, there is a hope that this body of brain imaging techniques will provide an efficient tradeoff between costs and benefits of the research. Currently, neuroscience methodology includes powerful brain imaging tools based on the gathering of hemodynamic or electromagnetic signals related to the human brain activity during the performance of a relevant task for marketing objectives. These tools are briefly reviewed in this article.     

Cellulose as a (bio)affinity carrier: properties,design and applications

This contribution presents a framework for the rational design of affinity sorbents based on cellulose materials as a support. A three-level evaluation procedure, utilizing the knowledge of physical, chemical and engineering theories, is discussed, which integrates the design of support, affinity sorbent and chromatographic contactor. The principal support properties, such as morphological, diffusional, hydrodynamic, mechanical or ligand-binding properties, are presented and literature data on them are surveyed.     

Cell transformation assays: are we barking up the wrong tree?

There has been a current resurgence of interest in the use of cell transformation for predicting carcinogenicity, which is based mainly on rodent carcinogenicity data. In view of this renewed interest, this paper critically reviews the published literature concerning the ability of the available assays to detect IARC Group 1 agents (known human carcinogens) and Group 2A agents (probable human carcinogens). The predictivity of the available assays for human and rodent non-genotoxic carcinogens (NGCs), in comparison with standard and supplementary in vitro and in vivo genotoxicity tests, is also discussed. The principal finding is that a surprising number of human carcinogens have not been tested for cell transformation across the three main assays (SHE, Balb/c 3T3 and C3H10T1/2), confounding comparative assessment of these methods for detecting human carcinogens. This issue is not being addressed in the ongoing validation studies for the first two of these assays, despite the lack of any serious logistical issues associated with the use of most of these chemicals. In addition, there seem to be no plans for using exogenous bio-transformation systems for the metabolic activation of pro-carcinogens, as recommended in an ECVAM workshop held in 1999. To address these important issues, it is strongly recommended that consideration be given to the inclusion of more human carcinogens and an exogenous source of xenobiotic metabolism, such as an S9 fraction, in ongoing and future validation studies. While cell transformation systems detect a high level of NGCs, it is considered premature to rely only on this endpoint for screening for such chemicals, as recently suggested. This is particularly important, in view of the fact that there is still doubt as to the relevance of morphological transformation to tumorigenesis in vivo, and the wide diversity of potential mechanisms by which NGCs are known to act. Recent progress with regard to increasing the objectivity of scoring the transformed phenotype, and prospects for developing human cell-based transformation assays, are reviewed.     

Passive diastolic modelling of human ventricles: Effects of base movement and geometrical heterogeneity

Left-ventricular (LV) remodelling, associated with diastolic heart failure, is driven by an increase in myocardial stress. Therefore, normalisation of LV wall stress is the cornerstone of many therapeutic treatments. However, information regarding such regional stress–strain for human LV is still limited. Thus, the objectives of our study were to determine local diastolic stress–strain field in healthy LVs, and consequently, to identify the regional variations amongst them due to geometric heterogeneity. Effects of LV base movement on diastolic model predictions, which were ignored in the literature, were further explored. Personalised finite-element modelling of five normal human bi-ventricles was carried out using subject-specific myocardium properties. Model prediction was validated individually through comparison with end-diastolic volume and a new shape-volume based measurement of LV cavity, extracted from magnetic resonance imaging. Results indicated that incorporation of LV base movement improved the model predictions (shape-volume relevancy of LV cavity), and therefore, it should be considered in future studies. The LV endocardium always experienced higher fibre stress compared to the epicardium for all five subjects. The LV wall near base experienced higher stress compared to equatorial and apical locations. The lateral LV wall underwent greater stress distribution (fibre and sheet stress) compared to other three regions. In addition, normal ranges of different stress–strain components in different regions of LV wall were reported for five healthy ventricles. This information could be used as targets for future computational studies to optimise diastolic heart failure treatments or design new therapeutic interventions/devices.     

An EFE model on skin-sleeve interactions during arm rotation

Skin and garment constitute a dynamic contact system for human body comfort and protection. Although dermatological injuries due to fabric actions during human body movement are common, there is still no general guidance or standard for measuring or evaluating skin/garment contact interactions, especially, during intense sports. A three-dimensional explicit finite element (EFE) model combined with Augmented Lagrange algorithm (ALA) is developed to simulate interactions between skin and fabric during rotation of the arm. Normalized effective shear stresses at the interface between skin and the sleeve during the arm rotation are provided to reflect the severity of the interactions. The effects due to changes in fabric properties, fabric-skin gap, and arm rotation rate are also illustrated. It has been demonstrated from our predictions that factors such as elastic modulus, friction coefficients, density of fabric, and the initial gap between skin and fabric influence significantly the shear stress and thus the discomfort and even injury potential to skin during intensive body movement such as sports and military. Thus this study for the first time confirms quantitatively that poorly chosen fabric with inappropriate garment design renders adverse actions on human skin.     

Applied genome research in the field of human vaccines

Prophylactic vaccination has made an essential contribution to the improvement of human health over the 20th century. However, we still lack efficient vaccines against major human diseases such as malaria or tuberculosis. Today, the design of therapeutic vaccines referred to as 'pharmaccines' is actively investigated in order to treat diseases such as cancer. In that context, novel ways to rationalize and accelerate vaccine discovery are needed. A series of advances in the fields of molecular biology and computer science, have greatly accelerated the rate at which candidate vaccine antigens can be discovered. In this review, we will present and discuss how applied genome research may facilitate antigen discovery and the design of new prophylactic and therapeutic vaccines.     

Annotating Diseases Using Human Phenotype Ontology Improves Prediction of Disease-Associated Long Non-coding RNAs

Recently, many long non-coding RNAs (lncRNAs) have been identified and their biological function has been characterized; however, our understanding of their underlying molecular mechanisms related to disease is still limited. To overcome the limitation in experimentally identifying disease–lncRNA associations, computational methods have been proposed as a powerful tool to predict such associations. These methods are usually based on the similarities between diseases or lncRNAs since it was reported that similar diseases are associated with functionally similar lncRNAs. Therefore, prediction performance is highly dependent on how well the similarities can be captured. Previous studies have calculated the similarity between two diseases by mapping exactly each disease to a single Disease Ontology (DO) term, and then use a semantic similarity measure to calculate the similarity between them. However, the problem of this approach is that a disease can be described by more than one DO terms. Until now, there is no annotation database of DO terms for diseases except for genes. In contrast, Human Phenotype Ontology (HPO) is designed to fully annotate human disease phenotypes. Therefore, in this study, we constructed disease similarity networks/matrices using HPO instead of DO. Then, we used these networks/matrices as inputs of two representative machine learning-based and network-based ranking algorithms, that is, regularized least square and heterogeneous graph-based inference, respectively. The results showed that the prediction performance of the two algorithms on HPO-based is better than that on DO-based networks/matrices. In addition, our method can predict 11 novel cancer-associated lncRNAs, which are supported by literature evidence.     

CRISPR/Cas9-mediated gene editing. A promising strategy in hematological disorders

The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has revolutionized the gene editing field, making it possible to interrupt, insert or replace a sequence of interest with high precision in the human genome. Its easy design and wide applicability open up a variety of therapeutic alternatives for the treatment of genetic diseases. Indeed, very promising approaches for the correction of hematological disorders have been developed in the recent years, based on the self-renewal and multipotent differentiation properties of hematopoietic stem and progenitor cells, which make this cell subset the ideal target for gene therapy purposes. This technology has been applied in different congenital blood disorders, such as primary immunodeficiencies, X-linked severe combined immunodeficiency, X-linked chronic granulomatous disease or Wiskott–Aldrich syndrome, and inherited bone marrow failure syndromes, such as Fanconi anemia, congenital amegakaryocytic thrombocytopenia or severe congenital neutropenia. Furthermore, CRISPR/Cas9-based gene editing has been implemented successfully as a novel therapy for cancer immunotherapy, by the development of promising strategies such as the use of oncolytic viruses or adoptive cellular therapy to the chimeric antigen receptor–T-cell therapy. Therefore, considering the variety of genes and mutations affected, we can take advantage of the different DNA repair mechanisms by CRISPR/Cas9 in different manners, from homology-directed repair to non-homologous-end-joining to the latest emerging technologies such as base and prime editing. Although the delivery systems into hematopoietic stem and progenitor cells are still the bottleneck of this technology, some of the advances in genome editing shown in this review have already reached a clinical stage and show very promising preliminary results.     

Molecular drug targets and structure based drug design: A holistic approach

Access to the complete human genome sequence as well as to the complete sequences of pathogenic organisms provides information that can result in an avalanche of therapeutic targets. Structure-based design is one of the first techniques to be used in drug design. Structure based design refers specifically to finding and complementing the 3D structure (binding and/or active site) of a target molecule such as a receptor protein. The aim of this review is to give an outline of studies in the field of structure based drug design that has helped in the discovery process of new drugs. The emphasis will be on comparative/homology modeling.     

The influence of host and non‐host companion plants on the behaviour of pest insects in field crops

Companion plants grown as ‘trap crops’ or ‘intercrops’ can be used to reduce insect infestations in field crops. The ways in which such reductions are achieved are being described currently using either a chemical approach, based on the ‘push‐pull strategy’, or a biological approach, based on the ‘appropriate/inappropriate landing theory’. The chemical approach suggests that insect numbers are reduced by chemicals from the intercrop ‘repelling’ insects from the main crop, and by chemicals from the trap‐crop ‘attracting’ insects away from the main crop. This approach is based on the assumptions that (1) plants release detectable amounts of volatile chemicals, and (2) insects ‘respond’ while still some distance away from the emitting plant. We discuss whether the above assumptions can be justified using the ‘appropriate/inappropriate landing theory’. Our tenet is that specialist insects respond only to the volatile chemicals released by their host plants and that these are released in such small quantities that, even with a heightened response to such chemicals, specialist insects can only detect them when a few metres from the emitting plant. We can find no robust evidence in the literature that plant chemicals ‘attract’ insects from more than 5 m and believe that ‘trap crops’ function simply as ‘interception barriers’. We can also find no evidence that insects are ‘repelled’ from landing on non‐host plants. Instead, we believe that ‘intercrops’ disrupt host‐plant finding by providing insects with a choice of host (appropriate) and non‐host (inappropriate) plant leaves on which to land, as our research has shown that, for intercropping to be effective, insects must land on the non‐host plants. Work is needed to determine whether non‐host plants are repellent (chemical approach) or ‘non‐stimulating’ (biological approach) to insects.     

侵袭性真菌病的诊断：现状与展望

近二十年来,医学科学很多领域都取得重大进步。但全球范围内,侵袭性真菌病的发病率及死亡率却仍明显上升,严重威胁人类健康。侵袭性真菌病发病隐匿、临床表现不典型、治疗手段有限、病死率与致残率高,早期、特异的诊断对于改善预后意义重大。目前,以培养、病理为代表的形态学诊断方法虽有局限,但仍是侵袭性真菌病诊断的金标准;以G试验、GM试验、高分辨率CT为代表的新兴血清学及影像学诊断方法值得在临床大力推广;而以PCR技术为基础的核酸诊断技术方法前景光明,但其临床应用之路却仍任重而道远。联合使用并不断改良现有培养、病理等形态学诊断方法、血清学方法及先进影像学技术是提高侵袭性真菌病诊断水平的现实最佳途径。     

Extensive feature detection of N-terminal protein sorting signals

MOTIVATION: The prediction of localization sites of various proteins is an important and challenging problem in the field of molecular biology. TargetP, by Emanuelsson et al. (J. Mol. Biol., 300, 1005-1016, 2000) is a neural network based system which is currently the best predictor in the literature for N-terminal sorting signals. One drawback of neural networks, however, is that it is generally difficult to understand and interpret how and why they make such predictions. In this paper, we aim to generate simple and interpretable rules as predictors, and still achieve a practical prediction accuracy. We adopt an approach which consists of an extensive search for simple rules and various attributes which is partially guided by human intuition. RESULTS: We have succeeded in finding rules whose prediction accuracies come close to that of TargetP, while still retaining a very simple and interpretable form. We also discuss and interpret the discovered rules.     

Custom sizing of lower limb exoskeleton actuators using gait dynamic modelling of children with cerebral palsy

The use of exoskeletons as an aid for people with musculoskeletal disorder is the subject to an increasing interest in the research community. These devices are expected to meet the specific needs of users, such as children with cerebral palsy (CP) who are considered a significant population in pediatric rehabilitation. Although these exoskeletons should be designed to ease the movement of people with physical shortcoming, their design is generally based on data obtained from healthy adults, which leads to oversized components that are inadequate to the targeted users. Consequently, the objective of this study is to custom-size the lower limb exoskeleton actuators based on dynamic modeling of the human body for children with CP on the basis of hip, knee, and ankle joint kinematics and dynamics of human body during gait. For this purpose, a multibody modeling of the human body of 3 typically developed children (TD) and 3 children with CP is used. The results show significant differences in gait patterns especially in knee and ankle with respectively 0.39 and ?0.33 (Nm/kg) maximum torque differences between TD children and children with CP. This study provides the recommendations to support the design of actuators to normalize the movement of children with CP.     

Molecular modeling of the human eukaryotic translation initiation factor 5A (eIF5A) based on spectroscopic and computational analyses

The eukaryotic translation initiation factor 5A (eIF5A) is a protein ubiquitously present in archaea and eukarya, which undergoes a unique two-step post-translational modification called hypusination. Several studies have shown that hypusination is essential for a variety of functional roles for eIF5A, including cell proliferation and synthesis of proteins involved in cell cycle control. Up to now neither a totally selective inhibitor of hypusination nor an inhibitor capable of directly binding to eIF5A has been reported in the literature. The discovery of such an inhibitor might be achieved by computer-aided drug design based on the 3D structure of the human eIF5A. In this study, we present a molecular model for the human eIF5A protein based on the crystal structure of the eIF5A from Leishmania brasiliensis, and compare the modeled conformation of the loop bearing the hypusination site with circular dichroism data obtained with a synthetic peptide of this loop. Furthermore, analysis of amino acid variability between different human eIF5A isoforms revealed peculiar structural characteristics that are of functional relevance.     

Computer modeling of the human systemic arterial tree

A model of the human systemic arterial tree has been devised, based on a lumped-parameter-circuit approximate form. This model has been set up and studied on an analog computer. A feature of this simulation is the division of the arterial system into sections whose lengths are inversely proportional (approximately) to their cross-sectional area-or what is termed ‘equal-volume’ modeling.

Great care was exercised in the determination of the model parameters, using expressions for these parameters from a recent paper by Rideout and Dick on fluid flow in distensible tubes, with numerical values based on measurements reported in the medical literature.

The simulated pressure and flow waveforms obtained with the model compare favorably with data recorded from the normal adult human, and exhibit such well-known features as distal delay and peaking of pressure pulses. The aortic input impedance vs. frequency curve checks well against measurements on the human. The model also provides a simple means for determination of cardiac output, cardiac work and cardiac power under various assumed conditions such as variation of heart rate.     

Treatment of long bone defects and non-unions: from research to clinical practice

The treatment of long bone defects and non-unions is still a major clinical and socio-economical problem. In addition to the non-operative therapeutic options, such as the application of various forms of electricity, extracorporeal shock wave therapy and ultrasound therapy, which are still in clinical use, several operative treatment methods are available. No consensus guidelines are available and the treatments of such defects differ greatly. Therefore, clinicians and researchers are presently investigating ways to treat large bone defects based on tissue engineering approaches. Tissue engineering strategies for bone regeneration seem to be a promising option in regenerative medicine. Several in vitro and in vivo studies in small and large animal models have been conducted to establish the efficiency of various tissue engineering approaches. Neverthelsss, the literature still lacks controlled studies that compare the different clinical treatment strategies currently in use. However, based on the results obtained so far in diverse animal studies, bone tissue engineering approaches need further validation in more clinically relevant animal models and in clinical pilot studies for the translation of bone tissue engineering approaches into clinical practice.