Cathelicidin Antimicrobial Peptides Block Dendritic Cell TLR4 Activation and Allergic Contact Sensitization

Abstract Cathelicidins are antimicrobial peptides of the innate immune system that establish an antimicrobial barrier at epithelial interfaces and have been proposed to have a proinflammatory function. We studied the role of cathelicidin in allergic contact dermatitis, a model requiring dendritic cells of the innate immune response and T cells of the adaptive immune response. Deletion of the murine cathelicidin gene Cnlp enhanced an allergic contact response, whereas local administration of cathelicidin before sensitization inhibited the allergic response. Cathelicidins inhibited TLR4 but not TLR2 mediated induction of dendritic cell maturation and cytokine release, and this inhibition was associated with an alteration of cell membrane function and structure. Further analysis in vivo connected these observations because inhibition of sensitization by exogenous cathelicidin was dependent on the presence of functional TLR4. These observations provide evidence that cathelicidin antimicrobial peptides mediate an anti-inflammatory response in part by their activity at the membrane

Message in a Bottle -- An Update to the Golden Record

Communication is an essential asset enabling humankind to forge an advanced civilization. Using approximately 31,000 languages from the Stone Age to our present digital information society, humans have connected and collaborated to accomplish remarkable feats. As the newly dawned Space Age progresses, we are attempting to communicate with intelligent species beyond our world, on distant planets and in Earth's far future. Absent mutually understood signs, symbols, and semiotic conventions, this study, the "Message in a Bottle", uses scientific methods to assess and design a means of communication encapsulating the story of humanity, conveying our thoughts, emotions, ingenuity, and aspirations. The message will be structured to provide a universal yet contextual understanding of modern human society, evolution of life on Earth, and challenges for the future. In assembling this space and time capsule, we aim to energize and unite current generations to celebrate and preserve humanity

Genome-Wide DNA Methylation Maps in Follicular Lymphoma Cells Determined by Methylation-Enriched Bisulfite Sequencing

BACKGROUND: Follicular lymphoma (FL) is a form of non-Hodgkin's lymphoma (NHL) that arises from germinal center (GC) B-cells. Despite the significant advances in immunotherapy, FL is still not curable. Beyond transcriptional profiling and genomics datasets, there currently is no epigenome-scale dataset or integrative biology approach that can adequately model this disease and therefore identify novel mechanisms and targets for successful prevention and treatment of FL. METHODOLOGY/PRINCIPAL FINDINGS: We performed methylation-enriched genome-wide bisulfite sequencing of FL cells and normal CD19(+) B-cells using 454 sequencing technology. The methylated DNA fragments were enriched with methyl-binding proteins, treated with bisulfite, and sequenced using the Roche-454 GS FLX sequencer. The total number of bases covered in the human genome was 18.2 and 49.3 million including 726,003 and 1.3 million CpGs in FL and CD19(+) B-cells, respectively. 11,971 and 7,882 methylated regions of interest (MRIs) were identified respectively. The genome-wide distribution of these MRIs displayed significant differences between FL and normal B-cells. A reverse trend in the distribution of MRIs between the promoter and the gene body was observed in FL and CD19(+) B-cells. The MRIs identified in FL cells also correlated well with transcriptomic data and ChIP-on-Chip analyses of genome-wide histone modifications such as tri-methyl-H3K27, and tri-methyl-H3K4, indicating a concerted epigenetic alteration in FL cells. CONCLUSIONS/SIGNIFICANCE: This study is the first to provide a large scale and comprehensive analysis of the DNA methylation sequence composition and distribution in the FL epigenome. These integrated approaches have led to the discovery of novel and frequent targets of aberrant epigenetic alterations. The genome-wide bisulfite sequencing approach developed here can be a useful tool for profiling DNA methylation in clinical samples

Rate-Induced Transitions in Networked Complex Adaptive Systems: Exploring Dynamics and Management Implications Across Ecological, Social, and Socioecological Systems

Complex adaptive systems (CASs), from ecosystems to economies, are open systems and inherently dependent on external conditions. While a system can transition from one state to another based on the magnitude of change in external conditions, the rate of change -- irrespective of magnitude -- may also lead to system state changes due to a phenomenon known as a rate-induced transition (RIT). This study presents a novel framework that captures RITs in CASs through a local model and a network extension where each node contributes to the structural adaptability of others. Our findings reveal how RITs occur at a critical environmental change rate, with lower-degree nodes tipping first due to fewer connections and reduced adaptive capacity. High-degree nodes tip later as their adaptability sources (lower-degree nodes) collapse. This pattern persists across various network structures. Our study calls for an extended perspective when managing CASs, emphasizing the need to focus not only on thresholds of external conditions but also the rate at which those conditions change, particularly in the context of the collapse of surrounding systems that contribute to the focal system's resilience. Our analytical method opens a path to designing management policies that mitigate RIT impacts and enhance resilience in ecological, social, and socioecological systems. These policies could include controlling environmental change rates, fostering system adaptability, implementing adaptive management strategies, and building capacity and knowledge exchange. Our study contributes to the understanding of RIT dynamics and informs effective management strategies for complex adaptive systems in the face of rapid environmental change.Comment: 25 pages, 4 figures, 1 box, supplementary informatio

Regional and scale-specific effects of land use on amphibian diversity [poster]

Background/Question/Methods Habitat loss and degradation influence amphibian distributions and are important drivers of population declines. Our previous research demonstrated that road disturbance, development and wetland area consistently influence amphibian richness across regions of the U.S. Here, we examined the relative importance of these factors in different regions and at multiple spatial scales. Understanding the scales at which habitat disturbance may be affecting amphibian distributions is important for conservation planning. Specifically, we asked: 1) Over what spatial scales do distinct landscape features affect amphibian richness? and 2) Do road types (non-rural and rural) have similar effects on amphibian richness? This is the second year of a collaborative, nationwide project involving 11 U.S. colleges integrated within undergraduate biology curricula. We summarized North American Amphibian Monitoring Program data in 13 Eastern and Central U.S states and used geographic information systems to extract landscape data for 471 survey locations. We developed models to quantify the influence of landscape variables on amphibian species richness and site occupancy across five concentric buffers ranging from 300m to 10,000m. Results/Conclusions Across spatial scales, development, road density and agriculture were the best predictors of amphibian richness and site occupancy by individual species. Across regions, we found that scale did not exert a large influence on how landscape features influenced amphibian richness as effects were largely comparable across buffers. However, development and percent impervious surface had stronger influence on richness at smaller spatial scales. Richness was lower at survey locations with higher densities of non-rural and rural roads, and non-rural road density had a larger negative effect at smaller scales. Within regions, landscape features driving patterns of species richness varied. The scales at which these factors were associated with richness were highly variable within regions, suggesting the scale effects may be region specific. Our project demonstrates that networks of undergraduate students can collaborate to compile and analyze large ecological data sets, while engaging students in authentic and inquiry-based learning in landscape-scale ecology

Hypermethylation of the DLC1 CpG island does not alter gene expression in canine lymphoma

<p>Abstract</p> <p>Background</p> <p>This study is a comparative epigenetic evaluation of the methylation status of the <it>DLC1 </it>tumor suppressor gene in naturally-occurring canine lymphoma. Canine non-Hodgkin's lymphoma (NHL) has been proposed to be a relevant preclinical model that occurs spontaneously and may share causative factors with human NHL due to a shared home environment. The canine <it>DLC1 </it>mRNA sequence was derived from normal tissue. Using lymphoid samples from 21 dogs with NHL and 7 normal dogs, the methylation status of the promoter CpG island of the gene was defined for each sample using combined bisulfite restriction analysis (COBRA), methylation-specific PCR (MSP), and bisulfite sequencing methods. Relative gene expression was determined using real-time PCR.</p> <p>Results</p> <p>The mRNA sequence of canine <it>DLC1 </it>is highly similar to the human orthologue and contains all protein functional groups, with 97% or greater similarity in functional regions. Hypermethylation of the 5' and 3' flanking regions of the promoter was statistically significantly associated with the NHL phenotype, but was not associated with silencing of expression or differences in survival.</p> <p>Conclusion</p> <p>The canine <it>DLC1 </it>is constructed highly similarly to the human gene, which has been shown to be an important tumor suppressor in many forms of cancer. As in human NHL, the promoter CpG island of <it>DLC1 </it>in canine NHL samples is abnormally hypermethylated, relative to normal lymphoid tissue. This study confirms that hypermethylation occurs in canine cancers, further supporting the use of companion dogs as comparative models of disease for evaluation of carcinogenesis, biomarker diagnosis, and therapy.</p

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin