Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15)

Respiratory syncytial virus (RSV) is a major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. Factors attributing to this problem are associated with an incomplete understanding of the mechanisms by which RSV modulates the host cell response to infection. In the present study, we investigate suppressor of cytokine signaling (SOCS)-1 and SOCS3 expression associated with the type I IFN and IFN-stimulated gene (ISG)-15 response following infection of mouse lung epithelial (MLE-15) cells with RSV or RSV mutant viruses lacking the G gene, or NS1 and NS2 gene deletions. Studies in MLE-15 cells are important as this cell line represents the distal bronchiolar and alveolar epithelium of mice, the most common animal model used to evaluate the host cell response to RSV infection, and exhibit morphologic characteristics of alveolar type II cells, a primary cell type targeted during RSV infection. These results show an important role for SOCS1 regulation of the antiviral host response to RSV infection, and demonstrate a novel role for RSV G protein manipulation of SOCS3 and modulation of ISG15 and IFNβ mRNA expression

Evolutionary Kuramoto Dynamics

Biological systems have a variety of time-keeping mechanisms ranging from molecular clocks within cells to a complex interconnected unit across an entire organism. The suprachiasmatic nucleus, comprising interconnected oscillatory neurons, serves as a master-clock in mammals. The ubiquity of such systems indicates an evolutionary benefit that outweighs the cost of establishing and maintaining them, but little is known about the process of evolutionary development. To begin to address this shortfall, we introduce and analyse a new evolutionary game theoretic framework modelling the behaviour and evolution of systems of coupled oscillators. Each oscillator is characterized by a pair of dynamic behavioural dimensions, a phase and a communication strategy, along which evolution occurs. We measure success of mutations by comparing the benefit of synchronization balanced against the cost of connections between the oscillators. Despite the simple set-up, this model exhibits non-trivial behaviours mimicking several different classical games—the Prisoner’s Dilemma, snowdrift games, coordination games—as the landscape of the oscillators changes over time. Across many situations, we find a surprisingly simple characterization of synchronization through connectivity and communication: if the benefit of synchronization is greater than twice the cost, the system will evolve towards complete communication and phase synchronization

Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15)

Respiratory syncytial virus (RSV) is a major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. Factors attributing to this problem are associated with an incomplete understanding of the mechanisms by which RSV modulates the host cell response to infection. In the present study, we investigate suppressor of cytokine signaling (SOCS)-1 and SOCS3 expression associated with the type I IFN and IFN-stimulated gene (ISG)-15 response following infection of mouse lung epithelial (MLE-15) cells with RSV or RSV mutant viruses lacking the G gene, or NS1 and NS2 gene deletions. Studies in MLE-15 cells are important as this cell line represents the distal bronchiolar and alveolar epithelium of mice, the most common animal model used to evaluate the host cell response to RSV infection, and exhibit morphologic characteristics of alveolar type II cells, a primary cell type targeted during RSV infection. These results show an important role for SOCS1 regulation of the antiviral host response to RSV infection, and demonstrate a novel role for RSV G protein manipulation of SOCS3 and modulation of ISG15 and IFNβ mRNA expression

Changing environment at the Late Upper Palaeolithic ite of Lynx Cave, North Wales

Lynx Cave is one of a handful of locations in North Wales that provide evidence of Late Upper Palaeolithic huntergatherers at the end of the last ice-age. With the region being recolonized at a time of rapid environmental change there is a need to develop on-site palaeoenvironmental records that are directly linked to the archaeology in order to further understanding of the environments and landscapes that these hunter-gatherer groups experienced. Through carbon (δ13C), nitrogen (δ15N) and sulphur (δ34S) stable isotope analysis of animal bones we explore the environmental conditions during the human occupation of Lynx Cave. Analysis of the data indicates the faunal isotope results cluster into three distinct groupings, which when considered in light of the species composition, radiocarbon dates, sample layer provenance and known temporal patterns in herbivore isotope data from Northern Europe, are likely to relate to GI-1cba (the Allerød period) around 13,700-13,000 cal BP, GI-1cba/GS-1 (the Late Allerød/ early Younger Dryas period) around 13,100-12,800 cal BP, and the Bronze Age. The isotope data indicates that the Late Upper Palaeolithic or Late Palaeolithic occupations occurred in an open landscape in which soils were undergoing changing hydrological conditions linked to ice sheet melt and permafrost thaw process and subsequent recovery. The evidence of butchery marks on the faunal remains from both Late Glacial isotope clusters, along with the disparate radiocarbon dates and the presence of three hearths, support the idea of very short-term episodic use of the cave over an extended time period

UV Absorption Lines from High-Velocity Gas in the Vela Supernova Remnant: New insights from STIS Echelle Observations of HD72089

The star HD72089 is located behind the Vela supernova remnant and shows a complex array of high and low velocity interstellar absorption features arising from shocked clouds. A spectrum of this star was recorded over the wavelength range 1196.4 to 1397.2 Angstroms at a resolving power lambda/Delta lambda = 110,000 and signal-to-noise ratio of 32 by STIS on the Hubble Space Telescope. We have identified 7 narrow components of C I and have measured their relative populations in excited fine-structure levels. Broader features at heliocentric velocities ranging from -70 to +130 km/s are seen in C II, N I, O I, Si II, S II and Ni II. In the high-velocity components, the unusually low abundances of N I and O I, relative to S II and Si II, suggest that these elements may be preferentially ionized to higher stages by radiation from hot gas immediately behind the shock fronts.Comment: 11 pages, 2 figures, Latex. Submitted for the special HST ERO issue of the Astrophysical Journal Letter

Production of Potent Fully Human Polyclonal Antibodies against Ebola Zaire Virus in Transchromosomal Cattle

Polyclonal antibodies, derived from humans or hyperimmunized animals, have been used prophylactically or therapeutically as countermeasures for a variety of infectious diseases. SAB Biotherapeutics has successfully developed a transchromosomic (Tc) bovine platform technology that can produce fully human immunoglobulins rapidly, and in substantial quantities, against a variety of disease targets. In this study, two Tc bovines expressing high levels of fully human IgG were hyperimmunized with a recombinant glycoprotein (GP) vaccine consisting of the 2014 Ebola virus (EBOV) Makona isolate. Serum collected from these hyperimmunized Tc bovines contained high titers of human IgG against EBOV GP as determined by GP specific ELISA, surface plasmon resonance (SPR), and virus neutralization assays. Fully human polyclonal antibodies against EBOV were purified and evaluated in a mouse challenge model using mouse adapted Ebola virus (maEBOV). Intraperitoneal administration of the purified anti-EBOV IgG (100 mg/kg) to BALB/c mice one day after lethal challenge with maEBOV resulted in 90% protection; whereas 100% of the control animals succumbed. The results show that hyperimmunization of Tc bovines with EBOV GP can elicit protective and potent neutralizing fully human IgG antibodies rapidly and in commercially viable quantities

Dual ancestries and ecologies of the Late Glacial Palaeolithic in Britain

Genetic investigations of Upper Palaeolithic Europe have revealed a complex and transformative history of human population movements and ancestries, with evidence of several instances of genetic change across the European continent in the period following the Last Glacial Maximum (LGM). Concurrent with these genetic shifts, the post-LGM period is characterized by a series of significant climatic changes, population expansions and cultural diversification. Britain lies at the extreme northwest corner of post-LGM expansion and its earliest Late Glacial human occupation remains unclear. Here we present genetic data from Palaeolithic human individuals in the United Kingdom and the oldest human DNA thus far obtained from Britain or Ireland. We determine that a Late Upper Palaeolithic individual from Gough's Cave probably traced all its ancestry to Magdalenian-associated individuals closely related to those from sites such as El Mirón Cave, Spain, and Troisième Caverne in Goyet, Belgium. However, an individual from Kendrick's Cave shows no evidence of having ancestry related to the Gough’s Cave individual. Instead, the Kendrick’s Cave individual traces its ancestry to groups who expanded across Europe during the Late Glacial and are represented at sites such as Villabruna, Italy. Furthermore, the individuals differ not only in their genetic ancestry profiles but also in their mortuary practices and their diets and ecologies, as evidenced through stable isotope analyses. This finding mirrors patterns of dual genetic ancestry and admixture previously detected in Iberia but may suggest a more drastic genetic turnover in northwestern Europe than in the southwest

Low Pathogenic Avian Influenza Isolates from Wild Birds Replicate and Transmit via Contact in Ferrets without Prior Adaptation

Direct transmission of avian influenza viruses to mammals has become an increasingly investigated topic during the past decade; however, isolates that have been primarily investigated are typically ones originating from human or poultry outbreaks. Currently there is minimal comparative information on the behavior of the innumerable viruses that exist in the natural wild bird host. We have previously demonstrated the capacity of numerous North American avian influenza viruses isolated from wild birds to infect and induce lesions in the respiratory tract of mice. In this study, two isolates from shorebirds that were previously examined in mice (H1N9 and H6N1 subtypes) are further examined through experimental inoculations in the ferret with analysis of viral shedding, histopathology, and antigen localization via immunohistochemistry to elucidate pathogenicity and transmission of these viruses. Using sequence analysis and glycan binding analysis, we show that these avian viruses have the typical avian influenza binding pattern, with affinity for cell glycoproteins/glycolipids having terminal sialic acid (SA) residues with α 2,3 linkage [Neu5Ac(α2,3)Gal]. Despite the lack of α2,6 linked SA binding, these AIVs productively infected both the upper and lower respiratory tract of ferrets, resulting in nasal viral shedding and pulmonary lesions with minimal morbidity. Moreover, we show that one of the viruses is able to transmit to ferrets via direct contact, despite its binding affinity for α 2,3 linked SA residues. These results demonstrate that avian influenza viruses, which are endemic in aquatic birds, can potentially infect humans and other mammals without adaptation. Finally this work highlights the need for additional study of the wild bird subset of influenza viruses in regard to surveillance, transmission, and potential for reassortment, as they have zoonotic potential

The Energy Landscapes of Repeat-Containing Proteins: Topology, Cooperativity, and the Folding Funnels of One-Dimensional Architectures

Repeat-proteins are made up of near repetitions of 20– to 40–amino acid stretches. These polypeptides usually fold up into non-globular, elongated architectures that are stabilized by the interactions within each repeat and those between adjacent repeats, but that lack contacts between residues distant in sequence. The inherent symmetries both in primary sequence and three-dimensional structure are reflected in a folding landscape that may be analyzed as a quasi–one-dimensional problem. We present a general description of repeat-protein energy landscapes based on a formal Ising-like treatment of the elementary interaction energetics in and between foldons, whose collective ensemble are treated as spin variables. The overall folding properties of a complete “domain” (the stability and cooperativity of the repeating array) can be derived from this microscopic description. The one-dimensional nature of the model implies there are simple relations for the experimental observables: folding free-energy (ΔGwater) and the cooperativity of denaturation (m-value), which do not ordinarily apply for globular proteins. We show how the parameters for the “coarse-grained” description in terms of foldon spin variables can be extracted from more detailed folding simulations on perfectly funneled landscapes. To illustrate the ideas, we present a case-study of a family of tetratricopeptide (TPR) repeat proteins and quantitatively relate the results to the experimentally observed folding transitions. Based on the dramatic effect that single point mutations exert on the experimentally observed folding behavior, we speculate that natural repeat proteins are “poised” at particular ratios of inter- and intra-element interaction energetics that allow them to readily undergo structural transitions in physiologically relevant conditions, which may be intrinsically related to their biological functions