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Biology, Volume 3, Issue 4 (December 2014) , Pages 645-927

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Open AccessCommunication
Identification of a Candidate Rad1 Subunit for the Kinetoplastid 9-1-1 (Rad9-Hus1-Rad1) Complex
Biology 2014, 3(4), 922-927; https://doi.org/10.3390/biology3040922
Received: 14 October 2014 / Revised: 5 December 2014 / Accepted: 12 December 2014 / Published: 19 December 2014
Cited by 1 | Viewed by 2591 | PDF Full-text (406 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The trimeric 9-1-1 (Rad9-Hus1-Rad1) complex plays an important role in the eukaryotic DNA damage response by recruiting DNA repair factors and checkpoint mediators to damaged sites. Extensively characterised in mammals and yeast, evidence is now emerging that 9-1-1 function is conserved beyond the [...] Read more.
The trimeric 9-1-1 (Rad9-Hus1-Rad1) complex plays an important role in the eukaryotic DNA damage response by recruiting DNA repair factors and checkpoint mediators to damaged sites. Extensively characterised in mammals and yeast, evidence is now emerging that 9-1-1 function is conserved beyond the relatively narrow evolutionary range of the Opisthokonts. Kinetoplastid Rad9 and Hus1 proteins have been identified and shown to be involved in the DNA damage response but Rad1 has remained elusive. In this study, PSI-BLAST iterative database searching, phylogenetic and structural modeling techniques are used to identify and characterise candidate Rad1 proteins in kinetoplastid organisms. Full article
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Open AccessReview
Hepatitis C Virus Life Cycle and Lipid Metabolism
Biology 2014, 3(4), 892-921; https://doi.org/10.3390/biology3040892
Received: 7 November 2014 / Revised: 4 December 2014 / Accepted: 8 December 2014 / Published: 15 December 2014
Cited by 35 | Viewed by 5988 | PDF Full-text (670 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C Virus (HCV) infects over 150 million people worldwide. In most cases HCV infection becomes chronic, causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. HCV affects the cholesterol homeostasis and at the molecular level, every step of the virus [...] Read more.
Hepatitis C Virus (HCV) infects over 150 million people worldwide. In most cases HCV infection becomes chronic, causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. HCV affects the cholesterol homeostasis and at the molecular level, every step of the virus life cycle is intimately connected to lipid metabolism. In this review, we present an update on the lipids and apolipoproteins that are involved in the HCV infectious cycle steps: entry, replication and assembly. Moreover, the result of the assembly process is a lipoviroparticle, which represents a peculiarity of hepatitis C virion. This review illustrates an example of an intricate virus-host interaction governed by lipid metabolism. Full article
(This article belongs to the Special Issue Lipid Metabolism)
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Open AccessArticle
The Human ABCG1 Transporter Mobilizes Plasma Membrane and Late Endosomal Non-Sphingomyelin-Associated-Cholesterol for Efflux and Esterification
Biology 2014, 3(4), 866-891; https://doi.org/10.3390/biology3040866
Received: 2 October 2014 / Revised: 22 November 2014 / Accepted: 26 November 2014 / Published: 4 December 2014
Cited by 9 | Viewed by 3092 | PDF Full-text (1840 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We have previously shown that GFP-tagged human ABCG1 on the plasma membrane (PM) and in late endosomes (LE) mobilizes sterol on both sides of the membrane lipid bilayer, thereby increasing cellular cholesterol efflux to lipid surfaces. In the present study, we examined ABCG1-induced [...] Read more.
We have previously shown that GFP-tagged human ABCG1 on the plasma membrane (PM) and in late endosomes (LE) mobilizes sterol on both sides of the membrane lipid bilayer, thereby increasing cellular cholesterol efflux to lipid surfaces. In the present study, we examined ABCG1-induced changes in membrane cholesterol distribution, organization, and mobility. ABCG1-GFP expression increased the amount of mobile, non-sphingomyelin(SM)-associated cholesterol at the PM and LE, but not the amount of SM-associated-cholesterol or SM. ABCG1-mobilized non-SM-associated-cholesterol rapidly cycled between the PM and LE and effluxed from the PM to extracellular acceptors, or, relocated to intracellular sites of esterification. ABCG1 increased detergent-soluble pools of PM and LE cholesterol, generated detergent-resistant, non-SM-associated PM cholesterol, and increased resistance to both amphotericin B-induced (cholesterol-mediated) and lysenin-induced (SM-mediated) cytolysis, consistent with altered organization of both PM cholesterol and SM. ABCG1 itself resided in detergent-soluble membrane domains. We propose that PM and LE ABCG1 residing at the phase boundary between ordered (Lo) and disordered (Ld) membrane lipid domains alters SM and cholesterol organization thereby increasing cholesterol flux between Lo and Ld, and hence, the amount of cholesterol available for removal by acceptors on either side of the membrane bilayer for either efflux or esterification. Full article
(This article belongs to the Special Issue Lipid Metabolism)
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Open AccessReview
The Intriguing Dual Lattices of the Myosin Filaments in Vertebrate Striated Muscles: Evolution and Advantage
Biology 2014, 3(4), 846-865; https://doi.org/10.3390/biology3040846
Received: 5 September 2014 / Revised: 20 November 2014 / Accepted: 25 November 2014 / Published: 3 December 2014
Cited by 6 | Viewed by 3090 | PDF Full-text (1867 KB) | HTML Full-text | XML Full-text
Abstract
Myosin filaments in vertebrate striated muscle have a long roughly cylindrical backbone with cross-bridge projections on the surfaces of both halves except for a short central bare zone. In the middle of this central region the filaments are cross-linked by the M-band which [...] Read more.
Myosin filaments in vertebrate striated muscle have a long roughly cylindrical backbone with cross-bridge projections on the surfaces of both halves except for a short central bare zone. In the middle of this central region the filaments are cross-linked by the M-band which holds them in a well-defined hexagonal lattice in the muscle A-band. During muscular contraction the M-band-defined rotation of the myosin filaments around their long axes influences the interactions that the cross-bridges can make with the neighbouring actin filaments. We can visualise this filament rotation by electron microscopy of thin cross-sections in the bare-region immediately adjacent to the M-band where the filament profiles are distinctly triangular. In the muscles of teleost fishes, the thick filament triangular profiles have a single orientation giving what we call the simple lattice. In other vertebrates, for example all the tetrapods, the thick filaments have one of two orientations where the triangles point in opposite directions (they are rotated by 60° or 180°) according to set rules. Such a distribution cannot be developed in an ordered fashion across a large 2D lattice, but there are small domains of superlattice such that the next-nearest neighbouring thick filaments often have the same orientation. We believe that this difference in the lattice forms can lead to different contractile behaviours. Here we provide a historical review, and when appropriate cite recent work related to the emergence of the simple and superlattice forms by examining the muscles of several species ranging back to primitive vertebrates and we discuss the functional differences that the two lattice forms may have. Full article
(This article belongs to the Special Issue Muscle Structure and Function)
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Open AccessArticle
Pre- and Postsynaptic Role of Dopamine D2 Receptor DD2R in Drosophila Olfactory Associative Learning
Biology 2014, 3(4), 831-845; https://doi.org/10.3390/biology3040831
Received: 1 October 2014 / Revised: 29 October 2014 / Accepted: 12 November 2014 / Published: 21 November 2014
Cited by 2 | Viewed by 3551 | PDF Full-text (684 KB) | HTML Full-text | XML Full-text
Abstract
Dopaminergic neurons in Drosophila play critical roles in diverse brain functions such as motor control, arousal, learning, and memory. Using genetic and behavioral approaches, it has been firmly established that proper dopamine signaling is required for olfactory classical conditioning (e.g., aversive and appetitive [...] Read more.
Dopaminergic neurons in Drosophila play critical roles in diverse brain functions such as motor control, arousal, learning, and memory. Using genetic and behavioral approaches, it has been firmly established that proper dopamine signaling is required for olfactory classical conditioning (e.g., aversive and appetitive learning). Dopamine mediates its functions through interaction with its receptors. There are two different types of dopamine receptors in Drosophila: D1-like (dDA1, DAMB) and D2-like receptors (DD2R). Currently, no study has attempted to characterize the role of DD2R in Drosophila learning and memory. Using a DD2R-RNAi transgenic line, we have examined the role of DD2R, expressed in dopamine neurons (i.e., the presynaptic DD2R autoreceptor), in larval olfactory learning. The function of postsynaptic DD2R expressed in mushroom body (MB) was also studied as MB is the center for Drosophila learning, with a function analogous to that of the mammalian hippocampus. Our results showed that suppression of presynaptic DD2R autoreceptors impairs both appetitive and aversive learning. Similarly, postsynaptic DD2R in MB neurons appears to be involved in both appetitive and aversive learning. The data confirm, for the first time, that DD2R plays an important role in Drosophila olfactory learning. Full article
(This article belongs to the Special Issue Neural Mechanisms of Learning and Memory)
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Open AccessReview
Glycerophosphate/Acylglycerophosphate Acyltransferases
Biology 2014, 3(4), 801-830; https://doi.org/10.3390/biology3040801
Received: 12 September 2014 / Revised: 2 November 2014 / Accepted: 5 November 2014 / Published: 19 November 2014
Cited by 24 | Viewed by 4060 | PDF Full-text (445 KB) | HTML Full-text | XML Full-text
Abstract
Acyl-CoA:glycerol-3-phosphate acyltransferase (GPAT) and acyl-CoA: 1-acyl-glycerol-3-phosphate acyltransferase (AGPAT) are involved in the de novo synthesis of triacylglycerol (TAG) and glycerophospholipids. Many enzymes belonging to the GPAT/AGPAT family have recently been identified and their physiological or pathophysiological roles have been proposed. The roles of [...] Read more.
Acyl-CoA:glycerol-3-phosphate acyltransferase (GPAT) and acyl-CoA: 1-acyl-glycerol-3-phosphate acyltransferase (AGPAT) are involved in the de novo synthesis of triacylglycerol (TAG) and glycerophospholipids. Many enzymes belonging to the GPAT/AGPAT family have recently been identified and their physiological or pathophysiological roles have been proposed. The roles of GPAT/AGPAT in the synthesis of TAG and obesity-related diseases were revealed through the identification of causative genes of these diseases or analyses of genetically manipulated animals. Recent studies have suggested that some isoforms of GPAT/AGPAT family enzymes are involved in the fatty acid remodeling of phospholipids. The enzymology of GPAT/AGPAT and their physiological/ pathological roles in the metabolism of glycerolipids have been described and discussed in this review. Full article
(This article belongs to the Special Issue Lipid Metabolism)
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Open AccessArticle
Cellular Localization and Trafficking of the Human ABCG1 Transporter
Biology 2014, 3(4), 781-800; https://doi.org/10.3390/biology3040781
Received: 2 October 2014 / Revised: 23 October 2014 / Accepted: 28 October 2014 / Published: 14 November 2014
Cited by 7 | Viewed by 3039 | PDF Full-text (1968 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We have developed a suitable heterologous cell expression system to study the localization, trafficking, and site(s) of function of the human ABCG1 transporter. Increased plasma membrane (PM) and late endosomal (LE) cholesterol generated by ABCG1 was removed by lipoproteins and liposomes, but not [...] Read more.
We have developed a suitable heterologous cell expression system to study the localization, trafficking, and site(s) of function of the human ABCG1 transporter. Increased plasma membrane (PM) and late endosomal (LE) cholesterol generated by ABCG1 was removed by lipoproteins and liposomes, but not apoA-I. Delivery of ABCG1 to the PM and LE was required for ABCG1-mediated cellular cholesterol efflux. ABCG1 LEs frequently contacted the PM, providing a collisional mechanism for transfer of ABCG1-mobilized cholesterol, similar to ABCG1-mediated PM cholesterol efflux to lipoproteins. ABCG1-mobilized LE cholesterol also trafficked to the PM by a non-vesicular pathway. Transfer of ABCG1-mobilized cholesterol from the cytoplasmic face of LEs to the PM and concomitant removal of cholesterol from the outer leaflet of the PM bilayer by extracellular acceptors suggests that ABCG1 mobilizes cholesterol on both sides of the lipid bilayer for removal by acceptors. ABCG1 increased uptake of HDL into LEs, consistent with a potential ABCG1-mediated cholesterol efflux pathway involving HDL resecretion. Thus, ABCG1 at the PM mobilizes PM cholesterol and ABCG1 in LE/LYS generates mobile pools of cholesterol that can traffic by both vesicular and non-vesicular pathways to the PM where it can also be transferred to extracellular acceptors with a lipid surface. Full article
(This article belongs to the Special Issue Lipid Metabolism)
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Open AccessReview
High Throughput Screening in Duchenne Muscular Dystrophy: From Drug Discovery to Functional Genomics
Biology 2014, 3(4), 752-780; https://doi.org/10.3390/biology3040752
Received: 8 September 2014 / Revised: 28 October 2014 / Accepted: 30 October 2014 / Published: 14 November 2014
Cited by 6 | Viewed by 4087 | PDF Full-text (807 KB) | HTML Full-text | XML Full-text
Abstract
Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to [...] Read more.
Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD), the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS) technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
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Open AccessReview
Mammalian Non-CpG Methylation: Stem Cells and Beyond
Biology 2014, 3(4), 739-751; https://doi.org/10.3390/biology3040739
Received: 9 June 2014 / Revised: 4 November 2014 / Accepted: 5 November 2014 / Published: 11 November 2014
Cited by 17 | Viewed by 3836 | PDF Full-text (89 KB) | HTML Full-text | XML Full-text
Abstract
Although CpG dinucleotides remain the primary site for DNA methylation in mammals, there is emerging evidence that DNA methylation at non-CpG sites (CpA, CpT and CpC) is not only present in mammalian cells, but may play a unique role in the regulation of [...] Read more.
Although CpG dinucleotides remain the primary site for DNA methylation in mammals, there is emerging evidence that DNA methylation at non-CpG sites (CpA, CpT and CpC) is not only present in mammalian cells, but may play a unique role in the regulation of gene expression. For some time it has been known that non-CpG methylation is abundant in plants and present in mammalian embryonic stem cells, but non-CpG methylation was thought to be lost upon cell differentiation. However, recent publications have described a role for non-CpG methylation in adult mammalian somatic cells including the adult mammalian brain, skeletal muscle, and hematopoietic cells and new interest in this field has been stimulated by the availability of high throughput sequencing techniques that can accurately measure this epigenetic modification. Genome wide assays indicate that non-CpG methylation is negligible in human fetal brain, but abundant in human adult brain tissue. Genome wide measurement of non-CpG methylation coupled with RNA-Sequencing indicates that in the human adult brain non-CpG methylation levels are inversely proportional to the abundance of mRNA transcript at the associated gene. Additionally specific examples where alterations in non-CpG methylation lead to changes in gene expression have been described; in PGC1α in human skeletal muscle, IFN-γ in human T-cells and SYT11 in human brain, all of which contribute to the development of human disease. Full article
(This article belongs to the Special Issue DNA Methylation)
Open AccessArticle
Scaling the Feeding Mechanism of Captive Alligator mississippiensis from Hatchling to Juvenile
Biology 2014, 3(4), 724-738; https://doi.org/10.3390/biology3040724
Received: 12 September 2014 / Revised: 25 October 2014 / Accepted: 28 October 2014 / Published: 10 November 2014
Cited by 2 | Viewed by 2687 | PDF Full-text (472 KB) | HTML Full-text | XML Full-text
Abstract
Small changes in size can lead to potential performance consequences and may influence an organism’s ability to utilize resources in its environment. As the American alligator (Alligator mississippiensis) transitions between neonate, juvenile and adult habitats (ontogenetic niche shifts), there are inevitably [...] Read more.
Small changes in size can lead to potential performance consequences and may influence an organism’s ability to utilize resources in its environment. As the American alligator (Alligator mississippiensis) transitions between neonate, juvenile and adult habitats (ontogenetic niche shifts), there are inevitably dynamic changes in their feeding performance. This study sought to investigate the scaling of the feeding mechanism and its performance from hatchling to juvenile size classes in A. mississippiensis. Feeding events were recorded during March 2011 at Rockefeller Wildlife Refuge (Grand Chenier, Louisiana). Thirty-six captive individuals were randomly sampled, ranging from 30.5 cm to 91.5 cm total length, and feeding events were recorded using a high speed camera at a rate of 300 fps. Results indicated that many linear, angular and timing kinematic variables scale allometrically with cranium length; whereas maximum gape velocity and duration of feeding bout do not scale with cranium length and remain constant between these size classes. Although it has been shown that there is an isometric relationship between cranial elements and body size in A. mississippiensis, this relationship is not transferred to linear and timing variables of prey-capture events. These allometric relationships echo other investigations of scaling relationships such as bite-force production and terrestrial locomotion. Full article
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Open AccessReview
DNA Modifications: Function and Applications in Normal and Disease States
Biology 2014, 3(4), 670-723; https://doi.org/10.3390/biology3040670
Received: 15 July 2014 / Revised: 22 September 2014 / Accepted: 24 September 2014 / Published: 22 October 2014
Cited by 30 | Viewed by 6036 | PDF Full-text (1803 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetics refers to a variety of processes that have heritable effects on gene expression programs without changes in DNA sequence. Key players in epigenetic control are chemical modifications to DNA, histone, and non-histone chromosomal proteins, which establish a complex regulatory network that controls [...] Read more.
Epigenetics refers to a variety of processes that have heritable effects on gene expression programs without changes in DNA sequence. Key players in epigenetic control are chemical modifications to DNA, histone, and non-histone chromosomal proteins, which establish a complex regulatory network that controls genome function. Methylation of DNA at the fifth position of cytosine in CpG dinucleotides (5-methylcytosine, 5mC), which is carried out by DNA methyltransferases, is commonly associated with gene silencing. However, high resolution mapping of DNA methylation has revealed that 5mC is enriched in exonic nucleosomes and at intron-exon junctions, suggesting a role of DNA methylation in the relationship between elongation and RNA splicing. Recent studies have increased our knowledge of another modification of DNA, 5-hydroxymethylcytosine (5hmC), which is a product of the ten-eleven translocation (TET) proteins converting 5mC to 5hmC. In this review, we will highlight current studies on the role of 5mC and 5hmC in regulating gene expression (using some aspects of brain development as examples). Further the roles of these modifications in detection of pathological states (type 2 diabetes, Rett syndrome, fetal alcohol spectrum disorders and teratogen exposure) will be discussed. Full article
(This article belongs to the Special Issue DNA Methylation)
Open AccessArticle
A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain
Biology 2014, 3(4), 645-669; https://doi.org/10.3390/biology3040645
Received: 23 May 2014 / Revised: 24 September 2014 / Accepted: 24 September 2014 / Published: 17 October 2014
Cited by 16 | Viewed by 4693 | PDF Full-text (2067 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2- (5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). [...] Read more.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2- (5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS) to search for novel ligands. Here, we have developed an “agonist-optimized” homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307–329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand. Full article
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
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