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Biology, Volume 1, Issue 1 (June 2012), Pages 1-115

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Editorial

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Open AccessEditorial Biology—The Path Ahead
Biology 2012, 1(1), 1-4; doi:10.3390/biology1010001
Received: 31 August 2011 / Accepted: 31 August 2011 / Published: 1 September 2011
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Abstract
There has never been a more exciting time to study the science of living systems. Contemporary biology is a vibrant field which grows stronger year on year. Biological scientists have access to powerful new tools and techniques that even recently would have seemed
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There has never been a more exciting time to study the science of living systems. Contemporary biology is a vibrant field which grows stronger year on year. Biological scientists have access to powerful new tools and techniques that even recently would have seemed like science fiction. We are enjoying ‘a wellspring of technical advancements’ [1]. The consequence is a deeper and wider understanding of living systems. Older approaches remain important and often essential, but new unbiased and often fast approaches are helping us to deploy our traditional approaches more rationally. The result of this synergy of old and new is an explosion in the field of biological sciences. It may seem daunting to consider what lies ahead and the challenges will be great, but the pace of discovery is increasingly rapid.[...] Full article

Research

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Open AccessArticle The Biology of Autoimmune Response in the Scurfy Mice that Lack the CD4+Foxp3+ Regulatory T-Cells
Biology 2012, 1(1), 18-42; doi:10.3390/biology1010018
Received: 2 March 2012 / Revised: 22 March 2012 / Accepted: 26 March 2012 / Published: 4 April 2012
Cited by 1 | PDF Full-text (866 KB) | HTML Full-text | XML Full-text
Abstract
Due to a mutation in the Foxp3 transcription factor, Scurfy mice lack regulatory T-cells that maintain self-tolerance of the immune system. They develop multi-organ inflammation (MOI) and die around four weeks old. The affected organs are skin, tail, lungs and liver. In humans,
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Due to a mutation in the Foxp3 transcription factor, Scurfy mice lack regulatory T-cells that maintain self-tolerance of the immune system. They develop multi-organ inflammation (MOI) and die around four weeks old. The affected organs are skin, tail, lungs and liver. In humans, endocrine and gastrointestinal inflammation are also observed, hence the disease is termed IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. The three week period of fatal MOI offers a useful autoimmune model in which the controls by genetics, T-cell subsets, cytokines, and effector mechanisms could be efficiently investigated. In this report, we will review published work, summarize our recent studies of Scurfy double mutants lacking specific autoimmune-related genes, discuss the cellular and cytokine controls by these genes on MOI, the organ-specificities of the MOI controlled by environments, and the effector mechanisms regulated by specific Th cytokines, including several newly identified control mechanisms for organ-specific autoimmune response. Full article
(This article belongs to the Special Issue Feature Papers)
Open AccessArticle Enhanced Macrophage Tribbles-1 Expression in Murine Experimental Atherosclerosis
Biology 2012, 1(1), 43-57; doi:10.3390/biology1010043
Received: 1 March 2012 / Revised: 13 March 2012 / Accepted: 31 March 2012 / Published: 10 April 2012
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Abstract
Development of the atherosclerotic plaque involves a complex interplay between a number of cell types and an extensive inter-cellular communication via cell bound as well as soluble mediators. The family of tribbles proteins has recently been identified as novel controllers of pro-inflammatory signal
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Development of the atherosclerotic plaque involves a complex interplay between a number of cell types and an extensive inter-cellular communication via cell bound as well as soluble mediators. The family of tribbles proteins has recently been identified as novel controllers of pro-inflammatory signal transduction. The objective of this study was to address the expression pattern of all three tribbles proteins in atherosclerotic plaques from a mouse model of atherosclerosis. Each tribbles were expressed in vascular smooth muscle cells, endothelial cells as well as in resident macrophages of mouse atherosclerotic plaques. The role of IL-1 mediated inflammatory events in controlling tribbles expression was also addressed by inducing experimental atherosclerosis in ApoE−/−IL1R1−/− (double knockout) mice. Immunohistochemical analysis of these mice showed a selective decrease in the percentage of trb-1 expressing macrophages, compared to the ApoE−/− cohort (14.7% ± 1.55 vs. 26.3% ± 1.19). The biological significance of this finding was verified in vitro where overexpression of trb-1 in macrophages led to a significant attenuation (~70%) of IL-6 production as well as a suppressed IL-12 expression induced by a proinflammatory stimulus. In this in vitro setting, expression of truncated trb-1 mutants suggests that the kinase domain of this protein is sufficient to exert this inhibitory action. Full article
Open AccessArticle Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease
Biology 2012, 1(1), 81-93; doi:10.3390/biology1010081
Received: 30 April 2012 / Revised: 23 May 2012 / Accepted: 25 May 2012 / Published: 31 May 2012
Cited by 3 | PDF Full-text (775 KB) | HTML Full-text | XML Full-text
Abstract
Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined.
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Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)

Review

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Open AccessReview Biomarker Gene Signature Discovery Integrating Network Knowledge
Biology 2012, 1(1), 5-17; doi:10.3390/biology1010005
Received: 29 January 2012 / Revised: 18 February 2012 / Accepted: 21 February 2012 / Published: 27 February 2012
Cited by 10 | PDF Full-text (143 KB) | HTML Full-text | XML Full-text
Abstract
Discovery of prognostic and diagnostic biomarker gene signatures for diseases, such as cancer, is seen as a major step towards a better personalized medicine. During the last decade various methods, mainly coming from the machine learning or statistical domain, have been proposed for
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Discovery of prognostic and diagnostic biomarker gene signatures for diseases, such as cancer, is seen as a major step towards a better personalized medicine. During the last decade various methods, mainly coming from the machine learning or statistical domain, have been proposed for that purpose. However, one important obstacle for making gene signatures a standard tool in clinical diagnosis is the typical low reproducibility of these signatures combined with the difficulty to achieve a clear biological interpretation. For that purpose in the last years there has been a growing interest in approaches that try to integrate information from molecular interaction networks. Here we review the current state of research in this field by giving an overview about so-far proposed approaches. Full article
(This article belongs to the Special Issue Feature Papers)
Open AccessReview The Surprising Role of Amyloid Fibrils in HIV Infection
Biology 2012, 1(1), 58-80; doi:10.3390/biology1010058
Received: 29 April 2012 / Revised: 19 May 2012 / Accepted: 23 May 2012 / Published: 29 May 2012
Cited by 8 | PDF Full-text (850 KB) | HTML Full-text | XML Full-text
Abstract
Despite its discovery over 30 years ago, human immunodeficiency virus (HIV) continues to threaten public health worldwide. Semen is the principal vehicle for the transmission of this retrovirus and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120)
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Despite its discovery over 30 years ago, human immunodeficiency virus (HIV) continues to threaten public health worldwide. Semen is the principal vehicle for the transmission of this retrovirus and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2), assemble into amyloid fibrils that promote HIV infection. For example, PAP248-286 fibrils, termed SEVI (Semen derived Enhancer of Viral Infection), potentiate HIV infection by up to 105-fold. Fibrils enhance infectivity by facilitating virion attachment and fusion to target cells, whereas soluble peptides have no effect. Importantly, the stimulatory effect is greatest at low viral titers, which mimics mucosal transmission of HIV, where relatively few virions traverse the mucosal barrier. Devising a method to rapidly reverse fibril formation (rather than simply inhibit it) would provide an innovative and urgently needed preventative strategy for reducing HIV infection via the sexual route. Targeting a host-encoded protein conformer represents a departure from traditional microbicidal approaches that target the viral machinery, and could synergize with direct antiviral approaches. Here, we review the identification of these amyloidogenic peptides, their mechanism of action, and various strategies for inhibiting their HIV-enhancing effects. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
Open AccessReview Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages
Biology 2012, 1(1), 94-115; doi:10.3390/biology1010094
Received: 15 May 2012 / Revised: 7 June 2012 / Accepted: 11 June 2012 / Published: 15 June 2012
Cited by 5 | PDF Full-text (573 KB) | HTML Full-text | XML Full-text
Abstract
Productive transcription of the integrated HIV-1 provirus is restricted by cellular factors that inhibit RNA polymerase II elongation. The viral Tat protein overcomes this by recruiting a general elongation factor, P-TEFb, to the TAR RNA element that forms at the 5’ end of
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Productive transcription of the integrated HIV-1 provirus is restricted by cellular factors that inhibit RNA polymerase II elongation. The viral Tat protein overcomes this by recruiting a general elongation factor, P-TEFb, to the TAR RNA element that forms at the 5’ end of nascent viral transcripts. P-TEFb exists in multiple complexes in cells, and its core consists of a kinase, Cdk9, and a regulatory subunit, either Cyclin T1 or Cyclin T2. Tat binds directly to Cyclin T1 and thereby targets the Cyclin T1/P-TEFb complex that phosphorylates the CTD of RNA polymerase II and the negative factors that inhibit elongation, resulting in efficient transcriptional elongation. P-TEFb is tightly regulated in cells infected by HIV-1—CD4+ T lymphocytes and monocytes/macrophages. A number of mechanisms have been identified that inhibit P-TEFb in resting CD4+ T lymphocytes and monocytes, including miRNAs that repress Cyclin T1 protein expression and dephosphorylation of residue Thr186 in the Cdk9 T-loop. These repressive mechanisms are overcome upon T cell activation and macrophage differentiation when the permissivity for HIV-1 replication is greatly increased. This review will summarize what is currently known about mechanisms that regulate P-TEFb and how this regulation impacts HIV-1 replication and latency. Full article
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)

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