Protease research in the era of systems biology

Proteases are specific modulators of signaling molecules and their underlying pathways in addition to their degradative roles. However, proteases do not act alone, but form cascades, circuits and networks that all dynamically interconnect to form the protease web, which defines the proteolytic potential of a cell or tissue in a defined condition. To describe the protease web and its net activity several novel high-throughput proteomic techniques, in the field termed degradomics, have been developed. Emerging systems biology methods to evaluate the expression, activity and substrate discovery of proteases are presented. Understanding the protease web and its perturbations in pathology will help to develop new therapeutics for the treatment of diseases, such as cancer, arthritis and chronic obstructive pulmonary diseases.     

Peptide-mediated interactions in biological systems: new discoveries and applications

Peptide-mediated interactions play very important roles in cellular processes. Recent years have seen much activity in the discovery of new bioactive peptides, and interactions mediated by protein-peptide binding events. At the same time, computational approaches continue to be developed that allow protein-peptide interactions to be discovered with great accuracy. There are also a growing number of chemicals that can target these interactions with various applications in disease. Both new discoveries and predictions suggest that these protein-peptide interactions play greater roles in cellular processes than previously thought. We propose that projects to uncover the protein-peptide repertoire used in Nature in a systematic way will have numerous applications in molecular biology and medicine.     

The long neglect of genetic discoveries and the criterion of prematurity

Journal of the History of Biology -     

A new era in hypertension research: discussing the findings of ALLHAT

The key question in hypertension research today is, "Does it matter how elevated blood pressure is lowered?" The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) initiated in 1994 serves as a model for comparative trials. Its strengths include its independent sponsorship, scope and design. The alpha-blocker arm was stopped early; doxazosin was shown to be clearly inferior to low-dose chlorthalidone not only in preventing heart failure, but also stroke, in spite of similar blood pressure reduction. The findings have major public health implications as pointed out by Krakoff in this journal. Other commentaries by Gavras and Gavras and Hooper discuss possible mechanisms behind the excess of cardiovascular events in doxazosin-treated patients.     

Ten greatest discoveries of the 20th century in cardiovascular medicine

The Netherlands Society of Cardiology (NVVC) was founded 70 years ago on 28 April 1934. When looking back at the history of our Society on its 70th anniversary, it might be a nice opportunity to mention ten great discoveries in cardiology in the 20th century.     

Transfusion medicine in the era of proteomics

Blood components (BCs) are highly complex mixtures of plasma proteins and cells. At present, BC and blood derivatives (BDs) quality control is mainly focused on standardized quantitative assessment, providing relatively limited information about products. Unfortunately, during the production, inactivation, and storage processes there is the risk of changes in their integrity, especially at the protein level, which could cause negative effects on transfusion. It is therefore a major challenge to identify significant alterations of these products, and, in this context, proteomics can play a potentially relevant role in transfusion medicine (TM) to assess the protein composition of blood-derived therapeutics, particularly for identifying modified proteins. It can provide comprehensive information about changes occurring during processing and storage of BCs and BDs and can be applied to assess or improve them, therefore potentially enabling a global assessment of processing, inactivation and storage methods, as well as of possible contaminants and neoantigens that may influence the immunogenic capacity of blood-derived therapeutics. Thus, proteomics could become a relevant part of quality-control process to verify the identity, purity, safety, and potency of various blood therapeutics. A more detailed understanding of the proteins found in blood and blood products, and the identification of their interactions, may also yield important information for the design of new small molecule therapeutics and also for future improvements in TM.

Proteomics, together with genomics in the near future, will presumably have an impact on disease diagnosis and prognosis as well as on further advances in the production, pathogen inactivation and storage processes of blood-based therapeutics.     

Research versus practice: The dilemmas of research ethics in the era of learning health‐care systems

In this article we attempt to answer the question of how the ethical and conceptual framework (ECF) for a learning health‐care system (LHS) affects some of the main controversies in research ethics by addressing five key problems of research ethics: (a) What is the difference between practice and research? (b) What is the relationship between research ethics and clinical ethics? (c) What is the ethical relevance of the principle of clinical equipoise? (d) Does participation in research require a higher standard of informed consent than the practice of medicine? and (e) What ethical principle should take precedence in medicine? These questions allow us to construct two opposite idealized positions on the distinction between research and practice: the integration model and the segregation model of research and practice. We then compare the ECF for an LHS with these two idealized positions. We argue that the ECF for a LHS does not, in fact, solve these problems, but that it is a third, separate position in the relationship between research ethics and clinical ethics. Moreover, we suggest that the ECF for a LHS raises new ethical problems that require additional ethical analysis and justification. Our article contributes to the discussion on the relationship between research ethics and clinical ethics, revealing that although a learning health‐care system may significantly change the landscape of health care, some ethical dilemmas still require resolving on both theoretical and policy‐making levels.     

Programmed cell death and new discoveries in the genetics of parkinsonism

The concept that activation of cellular pathways of programmed cell death (PCD) may lead to the death of neurons has been an important hypothesis for adult neurodegenerative diseases. For Parkinson's disease (PD), up until now, the evidence for this hypothesis has largely been of two types: clear evidence of a role for PCD in neurotoxin models of the disease, and somewhat controversial evidence from human postmortem studies. With the rapid pace of discoveries in recent years of the genetic basis of PD, a new form of evidence has emerged. The prevailing concept of the role for PCD in PD has been that its mediators are 'downstream' effectors of more proximate and specific causes related to genetic or environmental factors. However, recent studies of three genes which cause autosomal recessive forms of parkinsonism, parkin, PTEN-induced kinase, and DJ-1, suggest that they may have more intimate relationships with the mediators of PCD and that loss-of-function mutations may result in an increased propensity for neurons to die. Intriguingly, independent studies of the function of these genes have suggested that they may share roles in regulating survival signaling pathways, such as those mediated by the survival signaling kinase Akt. Further elucidation of these relationships will have implications for the pathogenesis and neuroprotective treatment of PD.     

Precision genetic modifications: a new era in molecular biology and crop improvement

Recently, the use of programmable DNA-binding proteins such as ZFP/ZFNs, TALE/TALENs and CRISPR/Cas has produced unprecedented advances in gene targeting and genome editing in prokaryotes and eukaryotes. These advances allow researchers to specifically alter genes, reprogram epigenetic marks, generate site-specific deletions and potentially cure diseases. Unlike previous methods, these precision genetic modification techniques (PGMs) are specific, efficient, easy to use and economical. Here we discuss the capabilities and pitfalls of PGMs and highlight the recent, exciting applications of PGMs in molecular biology and crop genetic engineering. Further improvement of the efficiency and precision of PGM techniques will enable researchers to precisely alter gene expression and biological/chemical pathways, probe gene function, modify epigenetic marks and improve crops by increasing yield, quality and tolerance to limiting biotic and abiotic stress conditions.     

Disability and genetics in the era of genomic medicine

Genomic medicine offers a growing number of methods to diagnose, cure or prevent disability. Although many disabled people welcome these advances, others have reservations about the impact of genetic knowledge on disabled people's lives, arguing that genetic science might exacerbate the deep ambivalence that society as a whole has towards physical difference and anomaly. It is also possible, however, that being able to specify the genetic bases of disability, and distinguish them from other causative factors, will contribute to a fuller understanding of disability and a better response to disabled people.     

2K09 and thereafter : the coming era of integrative bioinformatics, systems biology and intelligent computing for functional genomics and personalized medicine research

Significant interest exists in establishing synergistic research in bioinformatics, systems biology and intelligent computing. Supported by the United States National Science Foundation (NSF), International Society of Intelligent Biological Medicine (http://www.ISIBM.org), International Journal of Computational Biology and Drug Design (IJCBDD) and International Journal of Functional Informatics and Personalized Medicine, the ISIBM International Joint Conferences on Bioinformatics, Systems Biology and Intelligent Computing (ISIBM IJCBS 2009) attracted more than 300 papers and 400 researchers and medical doctors world-wide. It was the only inter/multidisciplinary conference aimed to promote synergistic research and education in bioinformatics, systems biology and intelligent computing. The conference committee was very grateful for the valuable advice and suggestions from honorary chairs, steering committee members and scientific leaders including Dr. Michael S. Waterman (USC, Member of United States National Academy of Sciences), Dr. Chih-Ming Ho (UCLA, Member of United States National Academy of Engineering and Academician of Academia Sinica), Dr. Wing H. Wong (Stanford, Member of United States National Academy of Sciences), Dr. Ruzena Bajcsy (UC Berkeley, Member of United States National Academy of Engineering and Member of United States Institute of Medicine of the National Academies), Dr. Mary Qu Yang (United States National Institutes of Health and Oak Ridge, DOE), Dr. Andrzej Niemierko (Harvard), Dr. A. Keith Dunker (Indiana), Dr. Brian D. Athey (Michigan), Dr. Weida Tong (FDA, United States Department of Health and Human Services), Dr. Cathy H. Wu (Georgetown), Dr. Dong Xu (Missouri), Drs. Arif Ghafoor and Okan K Ersoy (Purdue), Dr. Mark Borodovsky (Georgia Tech, President of ISIBM), Dr. Hamid R. Arabnia (UGA, Vice-President of ISIBM), and other scientific leaders. The committee presented the 2009 ISIBM Outstanding Achievement Awards to Dr. Joydeep Ghosh (UT Austin), Dr. Aidong Zhang (Buffalo) and Dr. Zhi-Hua Zhou (Nanjing) for their significant contributions to the field of intelligent biological medicine.     

MS and GTO proprioceptor subtypes in the molecular genetic era: Opportunities for new advances and perspectives

Proprioceptive feedback from skeletal muscle is an integral element of motor control, yet the precise physiological roles of muscle spindle (MS) and Golgi tendon organ (GTO) sensory receptors have remained difficult to disentangle due to technical limitations. New insights into the molecular basis of MS and GTO afferent subtypes offers genetic opportunities to further our understanding of the distinct functional features of these proprioceptor classes, while at the same time revealing additional layers of complexity in the regulation of coordinated motor output.     

Gene delivery system: a developing arena of study for the new era of medicine

Gene therapy concept has been being overcome massive challenges from 1972 in ethical, socio-economical and developmental issues. In this review, we have attempted to go through almost all the arenas and described in a methodical way that reflects not only the initial ethical and scientific thoughts but also adorned a solid depiction of gene therapy related physico-chemical barriers, approaches and strategies till to date.