Endogenous viruses: insights into viral evolution and impact on host biology

Recent studies have uncovered myriad viral sequences that are integrated or 'endogenized' in the genomes of various eukaryotes. Surprisingly, it appears that not just retroviruses but almost all types of viruses can become endogenous. We review how these genomic 'fossils' offer fresh insights into the origin, evolutionary dynamics and structural evolution of viruses, which are giving rise to the burgeoning field of palaeovirology. We also examine the multitude of ways through which endogenous viruses have influenced, for better or worse, the biology of their hosts. We argue that the conflict between hosts and viruses has led to the invention and diversification of molecular arsenals, which, in turn, promote the cellular co-option of endogenous viruses.     

Spliceosomal introns: new insights into their evolution

A new genome-wide analysis of spliceosomal introns indicates massive loss and gain of introns has taken place in many eukaryotic lineages. Only a small subset of the analyzed introns was present in the common ancestor of plants, fungi, animals and Plasmodium.     

Neocentromeres: new insights into centromere structure, disease development, and karyotype evolution

Since the discovery of the first human neocentromere in 1993, these spontaneous, ectopic centromeres have been shown to be an astonishing example of epigenetic change within the genome. Recent research has focused on the role of neocentromeres in evolution and speciation, as well as in disease development and the understanding of the organization and epigenetic maintenance of the centromere. Here, we review recent progress in these areas of research and the significant insights gained.     

A novel approach to pharmacodynamic assessment of antimicrobial agents: new insights to dosing regimen design

Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing regimen selection, both in the drug development and clinical settings. Killing by antimicrobial agents has been traditionally classified categorically as concentration-dependent (which would favor less fractionating regimens) or time-dependent (for which more frequent dosing is preferred). While intuitive and useful to explain empiric data, a more informative approach is necessary to provide a robust assessment of pharmacodynamic profiles in situations other than the extremes of the spectrum (e.g., agents which exhibit partial concentration-dependent killing). A quantitative approach to describe the interaction of an antimicrobial agent and a pathogen is proposed to fill this unmet need. A hypothetic antimicrobial agent with linear pharmacokinetics is used for illustrative purposes. A non-linear functional form (sigmoid Emax) of killing consisted of 3 parameters is used. Using different parameter values in conjunction with the relative growth rate of the pathogen and antimicrobial agent concentration ranges, various conventional pharmacodynamic surrogate indices (e.g., AUC/MIC, Cmax/MIC, %T>MIC) could be satisfactorily linked to outcomes. In addition, the dosing intensity represented by the average kill rate of a dosing regimen can be derived, which could be used for quantitative comparison. The relevance of our approach is further supported by experimental data from our previous investigations using a variety of gram-negative bacteria and antimicrobial agents (moxifloxacin, levofloxacin, gentamicin, amikacin and meropenem). The pharmacodynamic profiles of a wide range of antimicrobial agents can be assessed by a more flexible computational tool to support dosing selection.     

Two spinal cords in birds: novel insights into early avian evolution

Birds can be subdivided into two large superordinal assemblages based on differences in the dorsal horn of the spinal grey matter. Palaeognaths (i.e. ratites and tinamous), along with a few other orders of neognathous birds, exhibit the primitive dorsal horn state characteristic of other amniotes wherein cutaneous nerves form a single map of the body surface across the dorsal horn. In contrast, the vast majority of neognaths exhibit a novel, distinctly bifid dorsal horn wherein cutaneous nerves form not one, but two separate maps of the skin, each lying side-by-side. This unusual dorsal horn organization, which has been highly conserved and represents the derived state in birds, may identify a novel, major avian clade. These findings shed new light on historically problematic taxa and the early evolutionary branching sequence among living birds. Most notably, they reveal that the traditional orders Gruiformes, Columbiformes, Cuculiformes and Piciformes are unnatural assemblages. Further, in addition to palaeognaths, these findings suggest that most gruiforms, including buttonquails and mesites, as well as pigeons, cuckoos, woodpeckers and songbirds, represent ancient lineages whose ancestry predates the majority of ''modern'' birds. The phylogeny of living birds may thus be likened more to a dense bush than the traditional tree, with more than half of all living species arising from a basal side branch.     

Epigenetic modulation of host: new insights into immune evasion by viruses

Viruses have evolved with their hosts, which include all living species. This has been partly responsible for the development of highly advanced immune systems in the hosts. However, viruses too have evolved ways to regulate and evade the host’s immune defence. In addition to mutational mechanisms that viruses employ to mimic the host genome and undergo latency to evade the host’s recognition of the pathogen, they have also developed epigenetic mechanisms by which they can render the host’s immune responses inactive to their antigens. The epigenetic regulation of gene expression is intrinsically active inside the host and is involved in regulating gene expression and cellular differentiation. Viral immune evasion strategies are an area of major concern in modern biomedical research. Immune evasion strategies may involve interference with the host antigen presentation machinery or host immune gene expression capabilities, and viruses, in these manners, introduce and propagate infection. The aim of this review is to elucidate the various epigenetic changes that viruses are capable of bringing about in their host in order to enhance their own survivability and pathogenesis.     

A novel approach to measuring subtidal habitat complexity

Habitat complexity plays an important role in determining benthic community structure. A diverse range of methods for its measurement have been adopted but none are convenient for use underwater where access time is at a premium. We describe a novel, calibrated, tool for rapidly measuring scale-dependent habitat complexity developed, primarily, for use underwater. This tool is based on a distance-wheel with interchangeable wheels of different sizes to allow a scale-dependent measure of distance. This technique was calibrated against a profile of known complexity, at relevant scales, and then trialed on the Loch Linnhe Artificial Reef, a replicated artificial substratum offering two different scale-dependent habitat complexities. The distance-wheel was cost-effective, simple to fabricate and enabled the rapid and straightforward measurement of perceived distance over the step-length range of 133-1020 mm.     

Delayed luminescence: a novel technique to obtain new insights into water structure

Fully understanding the structure of water is a crucial point in biophysics because this liquid is essential in the operation of the engines of life. Many of its amazing anomalies seem to be tailored to support biological processes and, during about a century, several models have been developed to describe the water structuring. In particular, a theory assumes that water is a mixture of domains constituted by two distinct and inter-converting structural species, the low-density water (LDW) and the high-density water (HDW). According to this theory, by using some particular solutes or changing the water temperature, it should be possible to modify the equilibrium between the two species, changing in this way the water behavior in specific biological processes, as in governing the shape and stability of the structures of proteins. In this work, we assess the possibility of obtaining information on the structures induced in water by specific salts or by temperature by measuring the delayed luminescence (DL) of some salt solutions and of water in the super-cooled regime. Previous works have demonstrated that the delayed luminescence of a system is correlated with its dynamic ordered structures. The results show significant DL signals only when the formation of LDW domains is expected. The measurement reveals a similar activation energy for the domains both in aqueous salt solutions and super-cooled water. It is worth noting that the time trend of DL signals suggests the existence of structures unusually long-lasting in time, up to the microsecond range.     

病毒介导的细胞融合:癌症发生和发展的新视点

细胞融合(cell fusion)具有重要的生理意义。然而,病毒介导的非生理性细胞融合可能促进癌症的发生和发展。相对于基因突变等细胞癌变的传统诱因,病毒的这种致癌机制能够更合理地解释我们在癌症中发现的许多现象。病毒介导的细胞融合可能诱导癌症的观点对我们重新认识病毒相关肿瘤发生发展的机制,并依此调整癌症治疗的策略具有重要意义。     

Lifestyle evolution in symbiotic bacteria: insights from genomics

Bacteria that live only in eukaryotic cells and tissues, including chronic pathogens and mutualistic bacteriocyte associates, often possess a distinctive set of genomic traits, including reduced genome size, biased nucleotide base composition and fast polypeptide evolution. These phylogenetically diverse bacteria have lost certain functional categories of genes, including DNA repair genes, which affect mutational patterns. However, pathogens and mutualistic symbionts retain loci that underlie their unique interaction types, such as genes enabling nutrient provisioning by mutualistic bacteria-inhabiting animals. Recent genomic studies suggest that many of these bacteria are irreversibly specialized, precluding shifts between pathogenesis and mutualism.     

A novel approach to measuring heat flux in swimming animals

We present a design for long-term or removable attachment of heat flux sensors (HFSs) to stationary or swimming animals in water that enables collection of heat flux data on both captive and free-ranging pinnipeds. HFSs were modified to allow for independent, continuous, and long-term or removable attachment to study animals. The design was tested for effects of HFSs and the attachment mechanism on resultant heat flux. Effects were insulative and consistent across water temperatures and flow speeds, resulting in a correction factor of 3.42. This correction factor was applied to all measurements of heat flux from animal experiments to account for the thermal resistance of HFSs and insulative effects of the attachment mechanism. Heat flux and skin temperature data were collected from two captive Steller sea lions (Eumetopias jubatus) as they swam in a large habitat tank over time periods ranging from approximately 4 to 9 min. Of the 72 HFSs deployed using the attachment mechanism, data were successfully retrieved from 70. The HFS attachment mechanism was also used on two wild free-ranging Weddell seals (Leptonychotes weddellii) off Ross Island, Antarctica, for up to 7 days. Heat flux data were retrieved from all eight sensors deployed. These results, along with those from Steller sea lions, suggest that HFSs can be deployed with success on captive and wild animals using the designed attachment mechanism.     

A systems biology approach: new insights into fetal growth restriction using Bayesian Networks

IL-6, IGF-II and IGFBP-2 concentrations in placental lysates were previously shown to be associated with foetal growth. This study aimed to apply a Bayesian Network (BN) model in order to investigate complex dependencies among biochemical and clinical factors and fetal growth outcome. Twenty-one Intra-Uterine Growth Restricted (IUGR) and 25 Appropriate for Gestational Age (AGA) pregnancies were followed throughout pregnancy. Information was collected on maternal and gestational age, neonatal gender, previous gynaecological history. Total protein content, IGF-II, IGFBP-1, IGFBP-2, IL-6, and TNF-alpha concentrations in placental lysates were measured, and IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IL-6 relative gene expression in placenta assessed. A BN and a hybrid forecasting system were implemented: BN revealed a key role of maternal age and TNF-alpha on IUGR and confirmed a close relationship among IGF-II, IL-6 and foetal growth. A relationship between duration of gestation, appropriateness for gestational age, and placental IL-6 concentration was also confirmed. Compared with other techniques, BN showed a better accuracy. Findings confirmed a major role of maternal age in addition to IGF-II, IL-6 and TNF-alpha in IUGR. A direct role of IGFBP-2 was not shown. BN confirmed to be useful in understanding the system's biology and graphically representing variable relationships and hierarchy, particularly where, as in IUGR, many interactions among predictors exist.     

Neurotransmission by ATP: new insights, novel mechanisms

Purines have long been known for their roles in extracellular signaling. One of the most interesting functions to come to light recently has been the involvement, particularly of adenosine 5'-triphosphate (ATP), as a neurotransmitter in the central and the sympathetic nervous system. ATP is stored in and released from synaptic nerve terminals, like other neurotransmitters, and is known to act post-synaptically via specific rapidly-conducting, ligand-gated ion channels, the P2x receptors. Another interesting feature is the discovery that ATP is widely found to be a "co-transmitter" at the same synapses in combination with other neurotransmitters such as noradrenaline, acetylcholine, and GABA, altering our picture of the biophysics and biochemistry of neurotransmission at these synapses. We describe here these and other aspects of neurotransmission by ATP being investigated vigorously today, including recent findings on P2x receptors and those on the synaptic inactivation of ATP by ecto-ATPase. We conclude by pointing out possible pharmacological and clinical implications of neurotransmission by ATP.     

A comparative genomics approach to the evolution of eukaryotes and their mitochondria.

The Organelle Genome Megasequencing Program (OGMP) investigates mitochondrial genome diversity and evolution by systematically determining the complete mitochondrial DNA (mtDNA) sequences of a phylogenetically broad selection of protists. The mtDNAs of lower fungi and choanoflagellates are being analyzed by the Fungal Mitochondrial Genome Project (FMGP), a sister project to the OGMP. Some of the most interesting protists include the jakobid flagellates Reclinomonas americana, Malawimonas jakobiformis, and Jakoba libera, which share ultrastructural similarities with amitochondriate retortamonads, and harbor mitochondrial genes not seen before in mtDNAs of other organisms. In R. americana and J. libera, gene clusters are found that resemble, to an unprecedented degree, the contiguous ribosomal protein operons str, S10, spc, and alpha of eubacteria. In addition, their mtDNAs code for an RNase P RNA that displays all the elements of a bacterial minimum consensus structure. This structure has been instrumental in detecting the rnpB gene in additional protists. Gene repertoire and gene order comparisons as well as multiple-gene phylogenies support the view of a single endosymbiotic origin of mitochondria, whose closest extant relatives are Rickettsia-type alpha-Proteobacteria.