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Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchymally derived, multifunctional paracrine regulator possessing mitogenic, motogenic, and morphogenetic activities in cultured epithelial cells containing its tyrosine kinase receptor, Met. c-met has been implicated in oncogenesis through correlation of expression with malignant phenotype in specific cell lines and tumors. Paradoxically, however, HGF/SF can also inhibit the growth of some tumor cells. To elucidate the oncogenic role of HGF/SF in vivo, transgenic mice were created such that HGF/SF was inappropriately targeted to a variety of tissues. HGF/SF transgenic mice developed a remarkably broad array of histologically distinct tumors of both mesenchymal and epithelial origin. Many neoplasms arose from tissues exhibiting abnormal development, including the mammary gland, skeletal muscle, and melanocytes, suggesting a functional link between mechanisms regulating morphogenesis and those promoting tumorigenesis. Most neoplasms, especially melanomas, demonstrated overexpression of both the HGF/SF transgene and endogenous c-met, and had enhanced Met kinase activity, strongly suggesting that autocrine signaling broadly promotes tumorigenesis. Thus, subversion of normal mesenchymal-epithelial paracrine regulation through the forced misdirection of HGF/SF expression induces aberrant morphogenesis and subsequent malignant transformation of cells of diverse origin.

In the current low interest-rate and highly-regulated environment investing capital efficiently is one of the most important challenges insurance companies face. Certain quantitative parts of regulatory requirements (e.g. Solvency II capital requirements) result in constraints on the investment strategies. This paper mathematically describes the implications of Solvency II constraints on the investment strategies of insurance companies in an expected utility framework with a focus on the market risk module. For this constrained expected utility problem, we define a two-step approach that leads to closed-form approximations for the optimal investment strategies. This proposal circumvents the technical difficulties encountered when applying the convex duality approach or the theory of viscosity solutions. The investment strategies found using the two-step approach can be understood as the optimal investment strategies for constraint problems according to Solvency II. The impact of such constraints on the asset allocation and the performance of these strategies is assessed in a numerical case study.

Background In Dictyostelium discoideum, vesicular transport of the adenylyl cyclase A (ACA) to the posterior of polarized cells is essential to relay exogenous 3′,5′-cyclic adenosine monophosphate (cAMP) signals during chemotaxis and for the collective migration of cells in head-to-tail arrangements called streams. Results Using fluorescence in situ hybridization (FISH), we discovered that the ACA mRNA is asymmetrically distributed at the posterior of polarized cells. Using both standard estimators and Monte Carlo simulation methods, we found that the ACA mRNA enrichment depends on the position of the cell within a stream, with the posterior localization of ACA mRNA being strongest for cells at the end of a stream. By monitoring the recovery of ACA-YFP after cycloheximide (CHX) treatment, we observed that ACA mRNA and newly synthesized ACA-YFP first emerge as fluorescent punctae that later accumulate to the posterior of cells. We also found that the ACA mRNA localization requires 3′ ACA cis-acting elements. Conclusions Together, our findings suggest that the asymmetric distribution of ACA mRNA allows the local translation and accumulation of ACA protein at the posterior of cells. These data represent a novel functional role for localized translation in the relay of chemotactic signal during chemotaxis.

Adenylyl cyclases and their product, 3'-5'-cyclic adenosine monophosphate (cAMP), are critical signaling molecules fundamental to many signaling pathways found throughout eukaryotes and mammals. This importance arises from the ability to not only transduce signals from receptors to downstream effectors but also to amplify the initial signaling response. In Dictyostelium, the binding of the chemoattractant cAMP to its G protein coupled receptor activates a variety of effectors including the adenylyl cyclase A (ACA). We demonstrate using the gene fusion product ACA-YFP (ACA and yellow fluorescent protein) that ACA is enriched at the back of chemotaxing cells and propose that this enrichment provides a compartment from which cAMP is released, relaying the chemotactic signal to neighboring cells and allowing the cells to align head-to-tail, forming streams during chemotaxis. Interestingly, we find that this enrichment of ACA is composed of many smaller vesicles containing ACA and that ACA containing vesicles are observed rapidly moving throughout the cell. We investigated the role of ACA vesicle trafficking in the enrichment of ACA at the back of cells. Using Fluorescence Recovery After Photobleaching (FRAP), we find that vesicle delivery of ACA-YFP to the plasma membrane is required for the asymmetric enrichment of ACA at the back of cells. When actin fibers and microtubules are disrupted with latrunculin A or nocodazole, respectively, ACA vesicle trafficking is strongly inhibited resulting in the loss of ACA enrichment at the back of cells. We find that ACA vesicles co-localize with microtubules and that nocodazole-treated cells have streaming defects. Together, these findings suggest that vesicle trafficking is required for cAMP release. Intriguingly, we also observe that migrating cells leave behind trails containing ACA. Since migrating cells maintain a polarized distribution of ACA, we reason that ACA must be replenished by protein synthesis to maintain its asymmetric distribution. To investigate this, we completely bleached migrating ACA-YFP expressing cells and monitored the fluorescence recovery over time. We observe a 40% recovery within 7 minutes, presumably due to protein synthesis. Indeed, we find that cycloheximide treatment reduces ACA levels, abolishes its enrichment specifically at the back of migrating cells and prevents streaming. Our findings provide a novel model to explain group cell migration, where vesicles containing de novo enzymes involved in the synthesis of chemoattractants are delivered to the back of migrating cells, thereby creating a compartment from which chemoattractants are specifically released. We propose that similar methods of enzyme compartmentalization exist in mammalian cells allowing for cells to migrate collectively to sites of inflammation, to metastasize to new tissues and to form neural networks.

Aberrant communication among growth factors and cytokines that regulate tissue homeostasis often results in malignancy. Among the many cell types that participate in this process, stromal fibroblasts communicate in a paracrine and juxtracrine manner with cells of epithelial, endothelial, and hematopoietic origin. For fibroblasts, platelet-derived growth factor (PDGF) is a major proliferative and differentiation agent. Interleukin-4 (IL-4), however, possesses only modulating functions in this cell type. Here, we investigated the consequences of deleting Stat6 on PDGF and IL-4 signaling, proliferation, and transcriptional activation by establishing and characterizing early passage fibroblasts from wild-type and Stat6 null mice. Both wild-type and Stat6-/- fibroblasts showed nearly identical PDGFR and IL-4R activation, gross substrate tyrosine phosphorylation, PI 3-kinase activation, as well as Stat1, 3 and 5 DNA binding activities. Unexpectedly, IL-4's enhancement of PDGF-induced [3H]thymidine incorporation was greatly diminished in Stat6-/-, but not wild-type fibroblasts. PDGF-induced [3H]thymidine uptake was largely unaffected. Strikingly, IL-4, but not PDGF induction of the proinflammatory gene products, IL-6 and MCP-1 was markedly reduced in Stat6-/- fibroblasts. Thus, Stat6 is an important and specific mediator of IL-4-enhanced PDGF-induced proliferation as well as IL-4's transcriptional activation of IL-6 and MCP-1.

Increasing evidence supports the association of periodontitis with rheumatoid arthritis. Even though a prominent role has been postulated for Porphyromonas gingivalis , many bacterial species contribute to the pathogenesis of periodontal disease. We therefore investigated the impact of Porphyromonas gingivalis as well as other major pathobionts on the development of both, periodontitis and arthritis in the mouse. Pathobionts used - either alone or in combination - were Porphyromonas gingivalis , Fusobacterium nucleatum and Aggregatibacter actinomycetemcomintans . Periodontitis was induced via oral gavage in SKG, DBA/1 and F1 (DBA/1 × B10.Q) mice and collagen-induced arthritis was provoked via immunization and boost with bovine collagen type II. Alveolar bone loss was quantified via micro computed tomography, arthritis was evaluated macroscopically and histologically and serum antibodies were assessed. Among the strains tested, only F1 mice were susceptible to P. gingivalis induced periodontitis and showed significant alveolar bone loss. Bone loss was paralleled by antibody titers against P. gingivalis . Of note, mice inoculated with the mix of all three pathobionts showed less alveolar bone loss than mice inoculated with P. gingivalis alone. However, oral inoculation with either F. nucleatum or A. actinomycetemcomintans alone accelerated subsequent arthritis onset and progression. This is the first report of a triple oral inoculation of pathobionts combined with collagen-induced arthritis in the mouse. In this interplay and this particular genetic setting, F. nucleatum and A. actinomycetemcomitans exerted a protective impact on P. gingivalis induced alveolar bone loss. By themselves they did not induce periodontitis yet accelerated arthritis onset and progression.

In June, 2022, 25 scientists from eight countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to finalise their evaluation of the carcinogenicity of occupational exposure as a firefighter. Firefighters can be exposed to combustion products from fires (eg, polycyclic aromatic hydrocarbons [PAHs] and particulates), building materials (eg, asbestos), chemicals in firefighting foams (eg, perfluorinated and polyfluorinated substances [PFAS]), flame retardants, diesel exhaust, and other hazards (eg, night shift work and ultraviolet or other radiation). Dermal absorption of chemicals can occur even in firefighters wearing PPE due to limitations of its design, fit, maintenance, or decontamination. Since the previous classification of firefighting (as “possibly carcinogenic to humans,” Group 2B) by the IARC Monographs in 2007,2 many new studies have investigated the association between occupational exposure as a firefighter and cancer risk in humans. Airway and systemic inflammatory markers, such as IL-6 and IL-8, were associated with firefighting-related exposures. [...]declines in lung function associated with changes in inflammatory markers and exposure-associated bronchial hyperreactivity were reported in firefighters.

The goal of phylogenetic comparative methods (PCMs) is to study the distribution of quantitative traits among related species. The observed traits are often seen as the result of a Brownian Motion (BM) along the branches of a phylogenetic tree. Reticulation events such as hybridization, gene flow or horizontal gene transfer, can substantially affect a species’ traits, but are not modeled by a tree. Phylogenetic networks have been designed to represent reticulate evolution. As they become available for downstream analyses, new models of trait evolution are needed, applicable to networks. One natural extension of the BM is to use a weighted average model for the trait of a hybrid, at a reticulation point. We develop here an efficient recursive algorithm to compute the phylogenetic variance matrix of a trait on a network, in only one preorder traversal of the network. We then extend the standard PCM tools to this new framework, including phylogenetic regression with covariates (or phylogenetic ANOVA), ancestral trait reconstruction, and Pagel’s λ test of phylogenetic signal. The trait of a hybrid is sometimes outside of the range of its two parents, for instance because of hybrid vigor or hybrid depression. These two phenomena are rather commonly observed in present-day hybrids. Transgressive evolution can be modeled as a shift in the trait value following a reticulation point. We develop a general framework to handle such shifts and take advantage of the phylogenetic regression view of the problem to design statistical tests for ancestral transgressive evolution in the evolutionary history of a group of species. We study the power of these tests in several scenarios and show that recent events have indeed the strongest impact on the trait distribution of present-day taxa. We apply those methods to a data set of Xiphophorus fishes, to confirm and complete previous analysis in this group. All the methods developed here are available in the Julia package PhyloNetworks.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition. © 2018 The Author(s).

Environmental scientists play a key role in society's responses to environmental problems, and many of the studies they perform are intended ultimately to affect policy. The precautionary principle, proposed as a new guideline in environmental decision making, has four central components: taking preventive action in the face of uncertainty; shifting the burden of proof to the proponents of an activity; exploring a wide range of alternatives to possibly harmful actions; and increasing public participation in decision making. In this paper we examine the implications of the precautionary principle for environmental scientists, whose work often involves studying highly complex, poorly understood systems, while at the same time facing conflicting pressures from those who seek to balance economic growth and environmental protection. In this complicated and contested terrain, it is useful to examine the methodologies of science and to consider ways that, without compromising integrity and objectivity, research can be more or less helpful to those who would act with precaution. We argue that a shift to more precautionary policies creates opportunities and challenges for scientists to think differently about the ways they conduct studies and communicate results. There is a complicated feedback relation between the discoveries of science and the setting of policy. While maintaining their objectivity and focus on understanding the world, environmental scientists should be aware of the policy uses of their work and of their social responsibility to do science that protects human health and the environment. The precautionary principle highlights this tight, challenging linkage between science and policy.