The macroecology of infectious diseases: a new perspective on global‐scale drivers of pathogen distributions and impacts

Identifying drivers of infectious disease patterns and impacts at the broadest scales of organisation is one of the most crucial challenges for modern science, yet answers to many fundamental questions remain elusive. These include what factors commonly facilitate transmission of pathogens to novel host species, what drives variation in immune investment among host species, and more generally what drives global patterns of parasite diversity and distribution? Here we consider how the perspectives and tools of macroecology, a field that investigates patterns and processes at broad spatial, temporal and taxonomic scales, are expanding scientific understanding of global infectious disease ecology. In particular, emerging approaches are providing new insights about scaling properties across all living taxa, and new strategies for mapping pathogen biodiversity and infection risk. Ultimately, macroecology is establishing a framework to more accurately predict global patterns of infectious disease distribution and emergence.     

Tumor-infiltrating lymphocytes: Streamlining a complex manufacturing process

Adoptive cell therapy of tumor-infiltrating lymphocytes has shown promise for treatment of refractory melanoma and other solid malignancies; however, challenges to manufacturing have limited its widespread use. Traditional manufacturing efforts were lengthy, cumbersome and used open culture systems. We describe changes in testing and manufacturing that decreased the process cycle time, enhanced the robustness of critical quality attribute testing and facilitated a functionally closed system. These changes have enabled export of the manufacturing process to support multi-center clinical trials.     

A nuclear lamina‐chromatin‐Ran GTPase axis modulates nuclear import and DNA damage signaling

The Ran GTPase regulates nuclear import and export by controlling the assembly state of transport complexes. This involves the direct action of RanGTP, which is generated in the nucleus by the chromatin‐associated nucleotide exchange factor, RCC1. Ran interactions with RCC1 contribute to formation of a nuclear:cytoplasmic (N:C) Ran protein gradient in interphase cells. In previous work, we showed that the Ran protein gradient is disrupted in fibroblasts from Hutchinson–Gilford progeria syndrome (HGPS) patients. The Ran gradient disruption in these cells is caused by nuclear membrane association of a mutant form of Lamin A, which induces a global reduction in heterochromatin marked with Histone H3K9me3 and Histone H3K27me3. Here, we have tested the hypothesis that heterochromatin controls the Ran gradient. Chemical inhibition and depletion of the histone methyltransferases (HMTs) G9a and GLP in normal human fibroblasts reduced heterochromatin levels and caused disruption of the Ran gradient, comparable to that observed previously in HGPS fibroblasts. HMT inhibition caused a defect in nuclear localization of TPR, a high molecular weight protein that, owing to its large size, displays a Ran‐dependent import defect in HGPS. We reasoned that pathways dependent on nuclear import of large proteins might be compromised in HGPS. We found that nuclear import of ATM requires the Ran gradient, and disruption of the Ran gradient in HGPS causes a defect in generating nuclear γ‐H2AX in response to ionizing radiation. Our data suggest a lamina–chromatin–Ran axis is important for nuclear transport regulation and contributes to the DNA damage response.     

Causes and consequences of ontogenetic dietary shifts: a global synthesis using fish models

Ontogenetic dietary shifts (ODSs), the changes in diet utilisation occurring over the life span of an individual consumer, are widespread in the animal kingdom. Understanding ODSs provides fundamental insights into the biological and ecological processes that function at the individual, population and community levels, and is critical for the development and testing of hypotheses around key concepts in trophic theory on model organisms. Here, we synthesise historic and contemporary research on ODSs in fishes, and identify where further research is required. Numerous biotic and abiotic factors can directly or indirectly influence ODSs, but the most influential of these may vary spatially, temporally and interspecifically. Within the constraints imposed by prey availability, we identified competition and predation risk as the major drivers of ODSs in fishes. These drivers do not directly affect the trophic ontogeny of fishes, but may have an indirect effect on diet trajectories through ontogenetic changes in habitat use and concomitant changes in prey availability. The synthesis provides compelling evidence that ODSs can have profound ecological consequences for fish by, for example, enhancing individual growth and lifetime reproductive output or reducing the risk of mortality. ODSs may also influence food‐web dynamics and facilitate the coexistence of sympatric species through resource partitioning, but we currently lack a holistic understanding of the consequences of ODSs for population, community and ecosystem processes and functioning. Studies attempting to address these knowledge gaps have largely focused on theoretical approaches, but empirical research under natural conditions, including phylogenetic and evolutionary considerations, is required to test the concepts. Research focusing on inter‐individual variation in ontogenetic trajectories has also been limited, with the complex relationships between individual behaviour and environmental heterogeneity representing a particularly promising area for future research.     

Integration of biological networks and gene expression data using Cytoscape

Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.     

Interventions to prevent or treat obesity in preschool children: a review of evaluated programs

Objective: To identify effective programs to prevent or treat overweight among 2‐ to <6‐year‐old children. Research Methods and Procedures: We searched six databases to identify evaluated intervention programs assessing changes in weight status or body fat and systematically summarized study attributes and outcomes. Results: Four of the seven studies (two intervention, two prevention) documented significant reductions in weight status or body fat. Among these, three sustained reductions at 1 or 2 years after program initiation, three incorporated a framework/theory, two actively and one passively involved parents, three included multicomponent strategies, and all four monitored behavioral changes. Of the three (prevention) studies that did not show reduction in weight or fat status, all performed assessments between 4 and 9 months after program initiation, and one used a multicomponent strategy. Other significant changes reported were reductions in television viewing, cholesterol, and parental restriction of child feeding. Discussion: The paucity of studies limits our ability to generalize findings. Among the available studies, multicomponent programs with 1‐ to 2‐year follow‐up in clinics or child care settings were successful in their impact on weight; they were likely enhanced by parental involvement. Both treatment programs and two of five prevention programs reduced weight/fat status. Our review highlights the need to evaluate more programs, advocate for use of a framework/behavioral theory and objective behavioral measures, further examine the impact of involving parents and the impact of intervention duration and follow‐up time, strengthen prevention programs, and further evaluate successful programs in other settings and among other racial/ethnic groups.     

Epidemiological Panel Studies of Older Adults: New Frontiers in the Research on Human– Animal Interaction

ABSTRACT

This paper discusses epidemiological studies of older adults and human–animal interaction (HAI), and potential relevance to future research on HAI and animal-assisted interventions (AAI) in aging populations. Key issues in epidemiological work are discussed, including target populations, treatment/exposures, follow up, and endpoint measures as they relate to interacting with or owning companion animals. In outlining the limits in our current state of knowledge, we also make recommendations for the design and analysis of epidemiological studies to advance research on HAI and aging.     

The mechanism of Mycobacterium tuberculosis alkylhydroperoxidase AhpD as defined by mutagenesis,crystallography, and kinetics

AhpD, a protein with two cysteine residues, is required for physiological reduction of the Mycobacterium tuberculosis alkylhydroperoxidase AhpC. AhpD also has an alkylhydroperoxidase activity of its own. The AhpC/AhpD system provides critical antioxidant protection, particularly in the absence of the catalase-peroxidase KatG, which is suppressed in most isoniazid-resistant strains. Based on the crystal structure, we proposed recently a catalytic mechanism for AhpD involving a proton relay in which the Glu118 carboxylate group, via His137 and a water molecule, deprotonates the catalytic residue Cys133 (Nunn, C. M., Djordjevic, S., Hillas, P. J., Nishida, C., and Ortiz de Montellano, P. R. (2002) J. Biol. Chem. 277, 20033-20040). A possible role for His132 in subsequent formation of the Cys133-Cys130 disulfide bond was also noted. To test this proposed mechanism, we have expressed the H137F, H137Q, H132F, H132Q, E118F, E118Q, C133S, and C130S mutants of AhpD, determined the crystal structures of the H137F and H132Q mutants, estimated the pKa values of the cysteine residues, and defined the kinetic properties of the mutant proteins. The collective results strongly support the proposed catalytic mechanism for AhpD.     

Detailed analysis of the CD8+ T-cell response following adenovirus vaccination

We examined CD8(+) T-cell expansion and function following intramuscular immunization with a recombinant adenovirus. This study has identified a number of properties which may explain the strong immunogenicity of adenovirus vectors: (i) the ability to deliver large amounts of antigen into the lymphoid tissues, (ii) the ability to induce rapid expansion and migration of CD8(+) T cells throughout the lymphatics, and (iii) the ability to produce a sustained, high-level CD8(+) T-cell response.