Amazonian Amphibian Diversity Is Primarily Derived from Late Miocene Andean Lineages

The Neotropics contains half of remaining rainforests and Earth's largest reservoir of amphibian biodiversity. However, determinants of Neotropical biodiversity (i.e., vicariance, dispersals, extinctions, and radiations) earlier than the Quaternary are largely unstudied. Using a novel method of ancestral area reconstruction and relaxed Bayesian clock analyses, we reconstructed the biogeography of the poison frog clade (Dendrobatidae). We rejected an Amazonian center-of-origin in favor of a complex connectivity model expanding over the Neotropics. We inferred 14 dispersals into and 18 out of Amazonia to adjacent regions; the Andes were the major source of dispersals into Amazonia. We found three episodes of lineage dispersal with two interleaved periods of vicariant events between South and Central America. During the late Miocene, Amazonian, and Central American-Chocoan lineages significantly increased their diversity compared to the Andean and Guianan-Venezuelan-Brazilian Shield counterparts. Significant percentage of dendrobatid diversity in Amazonia and Chocó resulted from repeated immigrations, with radiations at <10.0 million years ago (MYA), rather than in situ diversification. In contrast, the Andes, Venezuelan Highlands, and Guiana Shield have undergone extended in situ diversification at near constant rate since the Oligocene. The effects of Miocene paleogeographic events on Neotropical diversification dynamics provided the framework under which Quaternary patterns of endemism evolved

Marine Incursion: The Freshwater Herring of Lake Tanganyika Are the Product of a Marine Invasion into West Africa

The spectacular marine-like diversity of the endemic fauna of Lake Tanganyika, the oldest of the African Great Lakes, led early researchers to suggest that the lake must have once been connected to the ocean. Recent geophysical reconstructions clearly indicate that Lake Tanganyika formed by rifting in the African subcontinent and was never directly linked to the sea. Although the Lake has a high proportion of specialized endemics, the absence of close relatives outside Tanganyika has complicated phylogeographic reconstructions of the timing of lake colonization and intralacustrine diversification. The freshwater herring of Lake Tanganyika are members of a large group of pellonuline herring found in western and southern Africa, offering one of the best opportunities to trace the evolutionary history of members of Tanganyika's biota. Molecular phylogenetic reconstructions indicate that herring colonized West Africa 25–50MYA, at the end of a major marine incursion in the region. Pellonuline herring subsequently experienced an evolutionary radiation in West Africa, spreading across the continent and reaching East Africa's Lake Tanganyika during its early formation. While Lake Tanganyika has never been directly connected with the sea, the endemic freshwater herring of the lake are the descendents of an ancient marine incursion, a scenario which may also explain the origin of other Tanganyikan endemics

In silico toxicology protocols

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information

An Investigation of intrathymic and medullary mechanisms of butadiene metabolite-mediated toxicity to mouse thymocytes

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department ([email protected])

Regeneration of T-cell helper function in zinc-deficient adult mice

Diets deficient in zinc cause rapid atrophy of the thymus and loss of T-cell helper function in the young adult A/J mouse. Because zinc deficiency, as well as other nutritional deficiences, causes extensive damage to the immune system, the question arose as to whether zinc-deficient mice could repair the thymus and fully regenerate T-cell helper function if returned to diets containing adequate amounts of zinc. Five-week-old A/J female mice were fed either a zinc-deficient (<1 μg of Zn per g) or a zinc-adequate (50 μg of Zn per g) diet for 31 days. Histological examination of thymuses from the zinc-deficient mice revealed that the cortex was preferentially involuted and the thymus was about one-third of normal size. The direct plaque-forming cells produced per mouse spleen in response to immunization with sheep erythrocytes was 34% of normal; indirect plaque-forming cells were 18% of normal (Jerne plaque assay). After the deficient mice had been fed a zinc-adequate diet for 1 week, their response was nearly normal, except that the indirect response was 68% of controls; in this same period, the thymuses of these mice had quadrupled in size and exhibited a greatly enlarged cortex repopulated with immature thymocytes. By 2 weeks, the thymuses of the previously zinc-deficient mice were normal in size and appearance; however, there was a slight increases in numbers of indirect plaque-forming cells. By 4 weeks, the thymus weights, direct and indirect plaque-forming cell counts, and secondary response of the previously deficient mice were normal. Mice that were nearly athymic after 45 days of dietary zinc deficiency were also able to fully reconstruct the thymus and regenerate T-cell helper function. The data show that the zinc-deficient young adult mouse has the capacity to fully restore the T-cell-dependent antibody-mediated responses upon nutritional repletion

Data from: Behavioral and biomaterial coevolution in spider orb webs

Mechanical performance of biological structures, such as tendons, byssal threads, muscles, and spider webs, is determined by a complex interplay between material quality (intrinsic material properties, larger scale morphology) and proximate behavior. Spider orb webs are a system in which fibrous biomaterials―silks―are arranged in a complex design resulting from stereotypical behavioral patterns, to produce effective energy absorbing traps for flying prey. Orb webs show an impressive range of designs, some effective at capturing tiny and flimsy insects, others that can stop even small birds in mid flight. Here, we test whether material quality and behavior (web design) co-evolve to fine-tune web function. We quantify the intrinsic material properties of the sticky capture silk and radial support threads, as well as their architectural arrangement in webs, across diverse species of orb weaving spiders to estimate the maximum potential performance of orb webs as energy absorbing traps. We find a dominant pattern of material and behavioral coevolution where evolutionary shifts to larger body sizes, a common result of fecundity selection in spiders, is repeatedly accompanied by improved web performance due to changes in both silk material and web spinning behaviors. Large spiders produce silk with improved material properties, and also use more silk, to make webs with superior stopping potential. After controlling for spider size, spiders spinning higher quality silk used it more sparsely in webs. This implies that improvements in silk quality enables “sparser” architectural designs, or alternatively that spiders spinning lower quality silk compensate architecturally for the inferior material quality of their silk. In summary, spider silk material properties are fine-tuned to the architectures of webs across millions of years of diversification, a coevolutionary pattern not yet clearly identified for other important biomaterials such as tendon, mollusk byssal threads, and keratin

Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: A case study using aromatic amine mutagenicity

Statistical-based and expert rule-based models built using public domain mutagenicity knowledge and data are routinely used for computational (Q)SAR assessments of pharmaceutical impurities in line with the approach recommended in the ICH M7 guideline. Knowledge from proprietary corporate mutagenicity databases could be used to increase the predictive performance for selected chemical classes as well as expand the applicability domain of these (Q)SAR models. This paper outlines a mechanism for sharing knowledge without the release of proprietary data. Primary aromatic amine mutagenicity was selected as a case study because this chemical class is often encountered in pharmaceutical impurity analysis and mutagenicity of aromatic amines is currently difficult to predict. As part of this analysis, a series of aromatic amine substructures were defined and the number of mutagenic and non-mutagenic examples for each chemical substructure calculated across a series of public and proprietary mutagenicity databases. This information was pooled across all sources to identify structural classes that activate or deactivate aromatic amine mutagenicity. This structure activity knowledge, in combination with newly released primary aromatic amine data, was incorporated into Leadscope's expert rule-based and statistical-based (Q)SAR models where increased predictive performance was demonstrated.JRC.I.5-Systems Toxicolog

In silico approaches in organ toxicity hazard assessment: Current status and future needs in predicting liver toxicity

Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed. The biological mechanisms and processes underpinning hepatotoxicity are summarized and experimental approaches to support the prediction of hepatotoxicity are described, including toxicokinetic considerations. The paper describes the increasingly important role of in silico approaches and highlights challenges to the adoption of these methods including the lack of a commonly agreed upon protocol for performing such an assessment and the need for in silico solutions that take dose into consideration. A proposed framework for the integration of in silico and experimental information is provided along with a case study describing how computational methods have been used to successfully respond to a regulatory question concerning non-genotoxic impurities in chemically synthesized pharmaceuticals