Highly Pathogenic H5N1 Avian Influenza: Entry Pathways into North America via Bird Migration

Given the possibility of highly pathogenic H5N1 avian influenza arriving in North America and monitoring programs that have been established to detect and track it, we review intercontinental movements of birds. We divided 157 bird species showing regular intercontinental movements into four groups based on patterns of movement—one of these groups (breed Holarctic, winter Eurasia) fits well with the design of the monitoring programs (i.e., western Alaska), but the other groups have quite different movement patterns, which would suggest the importance of H5N1 monitoring along the Pacific, Atlantic, and Gulf coasts of North America

Oceanic Sharks Clean at Coastal Seamount

Interactions between pelagic thresher sharks (Alopias pelagicus) and cleaner wrasse were investigated at a seamount in the Philippines. Cleaning associations between sharks and teleosts are poorly understood, but the observable interactions seen at this site may explain why these mainly oceanic sharks regularly venture into shallow coastal waters where they are vulnerable to disturbance from human activity. From 1,230 hours of observations recorded by remote video camera between July 2005 and December 2009, 97 cleaner-thresher shark events were analyzed, 19 of which were interrupted. Observations of pelagic thresher sharks interacting with cleaners at the seamount were recorded at all times of day but their frequency declined gradually from morning until evening. Cleaners showed preferences for foraging on specific areas of a thresher shark's body. For all events combined, cleaners were observed to conduct 2,757 inspections, of which 33.9% took place on the shark's pelvis, 23.3% on the pectoral fins, 22.3% on the caudal fin, 8.6% on the body, 8.3% on the head, 2.1% on the dorsal fin, and 1.5% on the gills respectively. Cleaners did not preferentially inspect thresher sharks by time of day or by shark sex, but there was a direct correlation between the amount of time a thresher shark spent at a cleaning station and the number of inspections it received. Thresher shark clients modified their behavior by “circular-stance-swimming,” presumably to facilitate cleaner inspections. The cleaner-thresher shark association reflected some of the known behavioral trends in the cleaner-reef teleost system since cleaners appeared to forage selectively on shark clients. Evidence is mounting that in addition to acting as social refuges and foraging grounds for large visiting marine predators, seamounts may also support pelagic ecology by functioning as cleaning stations for oceanic sharks and rays

Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine

Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo. The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo. Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t 1/2 = 9.7 h) relative to vincristine (t 1/2 = 18.5 h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine. These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized

Critical Transition in Tissue Homeostasis Accompanies Murine Lung Senescence

BACKGROUND: Respiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to "low pulmonary reserve", ostensibly reflecting a combination of age-related musculoskeletal, immunologic and intrinsic pulmonary dysfunction. METHODS/PRINCIPAL FINDINGS: Using a murine model of the aging lung, senescent DBA/2 mice, we correlated a longitudinal survey of airspace size and injury measures with a transcriptome from the aging lung at 2, 4, 8, 12, 16 and 20 months of age. Morphometric analysis demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age marked by an initial increase in oxidative stress, cell death and elastase activation which is soon followed by inflammatory cell infiltration, immune complex deposition and the onset of airspace enlargement. The temporally correlative transcriptome showed exuberant induction of immunoglobulin genes coincident with airspace enlargement. Immunohistochemistry, ELISA analysis and flow cytometry demonstrated increased immunoglobulin deposition in the lung associated with a contemporaneous increase in activated B-cells expressing high levels of TLR4 (toll receptor 4) and CD86 and macrophages during midlife. These midlife changes culminate in progressive airspace enlargement during late life stages. CONCLUSION/SIGNIFICANCE: Our findings establish that a tissue-specific aging program is evident during a presenescent interval which involves early oxidative stress, cell death and elastase activation, followed by B lymphocyte and macrophage expansion/activation. This sequence heralds the progression to overt airspace enlargement in the aged lung. These signature events, during middle age, indicate that early stages of the aging immune system may have important correlates in the maintenance of tissue morphology. We further show that time-course analyses of aging models, when informed by structural surveys, can reveal nonintuitive signatures of organ-specific aging pathology

Biology-driven cancer drug development: back to the future

Most of the significant recent advances in cancer treatment have been based on the great strides that have been made in our understanding of the underlying biology of the disease. Nevertheless, the exploitation of biological insight in the oncology clinic has been haphazard and we believe that this needs to be enhanced and optimized if patients are to receive maximum benefit. Here, we discuss how research has driven cancer drug development in the past and describe how recent advances in biology, technology, our conceptual understanding of cell networks and removal of some roadblocks may facilitate therapeutic advances in the (hopefully) near future

A parameter-free total Lagrangian smooth particle hydrodynamics algorithm applied to problems with free surfaces

This paper presents a new Smooth Particle Hydrodynamics computational framework for the solution of inviscid free surface flow problems. The formulation is based on the Total Lagrangian description of a system of first-order conservation laws written in terms of the linear momentum and the Jacobian of the deformation. One of the aims of this paper is to explore the use of Total Lagrangian description in the case of large deformations but without topological changes. In this case, the evaluation of spatial integrals is carried out with respect to the initial undeformed configuration, yielding an extremely efficient formulation where the need for continuous particle neighbouring search is completely circumvented. To guarantee stability from the SPH discretisation point of view, consistently derived Riemann-based numerical dissipation is suitably introduced where global numerical entropy production is demonstrated via a novel technique in terms of the time rate of the Hamiltonian of the system. Since the kernel derivatives presented in this work are fixed in the reference configuration, the non-physical clumping mechanism is completely removed. To fulfil conservation of the global angular momentum, a posteriori (least-squares) projection procedure is introduced. Finally, a wide spectrum of dedicated prototype problems is thoroughly examined. Through these tests, the SPH methodology overcomes by construction a number of persistent numerical drawbacks (e.g. hour-glassing, pressure instability, global conservation and/or completeness issues) commonly found in SPH literature, without resorting to the use of any ad-hoc user-defined artificial stabilisation parameters. Crucially, the overall SPH algorithm yields equal second order of convergence for both velocities and pressure

Connecting Planetary Composition with Formation

The rapid advances in observations of the different populations of exoplanets, the characterization of their host stars and the links to the properties of their planetary systems, the detailed studies of protoplanetary disks, and the experimental study of the interiors and composition of the massive planets in our solar system provide a firm basis for the next big question in planet formation theory. How do the elemental and chemical compositions of planets connect with their formation? The answer to this requires that the various pieces of planet formation theory be linked together in an end-to-end picture that is capable of addressing these large data sets. In this review, we discuss the critical elements of such a picture and how they affect the chemical and elemental make up of forming planets. Important issues here include the initial state of forming and evolving disks, chemical and dust processes within them, the migration of planets and the importance of planet traps, the nature of angular momentum transport processes involving turbulence and/or MHD disk winds, planet formation theory, and advanced treatments of disk astrochemistry. All of these issues affect, and are affected by the chemistry of disks which is driven by X-ray ionization of the host stars. We discuss how these processes lead to a coherent end-to-end model and how this may address the basic question.Comment: Invited review, accepted for publication in the 'Handbook of Exoplanets', eds. H.J. Deeg and J.A. Belmonte, Springer (2018). 46 pages, 10 figure

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe