Revisiting reef models in the Oligocene of northern Italy (Venetian Southern Alps)

The lower Oligocene coral communities and reefs exposed in the Lessini Shelf of northern Italy may record one of the oldest well-developed barrier reef/lagoon systems of the Cenozoic. However, the rimmed-shelf interpretation has been repeatedly challenged in favour of a ramp model with scattered corals. Based upon a re-analysis of selected localities in the Lessini Shelf, we here provide support for the barrier reef model based on four key observations: 1) systematic changes of coral growth-forms from branching in the proximal areas to massive at the platform margin; 2) a progressive increase of the hydrodynamic energy from the proximal belt towards the more distal environments in the Berici Hills; 3) the occurrence of shallow-water, euphotic conditions throughout the whole depositional system; and 4) the presence of restricted circulation in the proximal environments during sea-level lowstands, with lack of coral colonies. These features, together with the evidence of coral frameworks located on the southeastern edge of the Lessini Shelf, substantiate the occurrence of a reef-rimmed margin. The reefal rim acted as an efficient barrier, with the formation of a landward, wide lagoon protected from the action of waves and currents

Weighted Barycentric Sets and Singular Liouville Equations on Compact Surfaces

Given a closed two dimensional manifold, we prove a general existence result for a class of elliptic PDEs with exponential nonlinearities and negative Dirac deltas on the right-hand side, extending a theory recently obtained for the regular case. This is done by global methods: since the associated Euler functional is in general unbounded from below, we need to define a new model space, generalizing the so-called space of formal barycenters and characterizing (up to homotopy equivalence) its very low sublevels. As a result, the analytic problem is reduced to a topological one concerning the contractibility of this model space. To this aim, we prove a new functional inequality in the spirit of [16] and then we employ a min-max scheme based on a cone-style construction, jointly with the blow-up analysis given in [5] (after [6] and [8]). This study is motivated by abelian Chern- Simons theory in self-dual regime, or from the problem of prescribing the Gaussian curvature in presence of conical singularities (hence generalizing a problem raised by Kazdan and Warner in [26]).Comment: to appear on Journal of Functional Analysis. One proof in Section 3 has been simplified with respect to the previous version, while Section 6 (on open problems) has been substantially improved. At the end on the Introduction, the complete proof of the topological conjecture given in Section 6 (to appear in a forthcoming paper) is announce

Dendritic Cell-Based Immunotherapy for Prostate Cancer

Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display an extraordinary capacity to induce, sustain, and regulate T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Thus, clinical trials enrolling prostate cancer patients were conducted, which were based on the administration of DCs loaded with tumor-associated antigens. These clinical trials revealed that DC-based immunotherapeutic strategies represent safe and feasible concepts for the induction of immunological and clinical responses in prostate cancer patients. In this context, the administration of the vaccine sipuleucel-T consisting of autologous peripheral blood mononuclear cells including APCs, which were pre-exposed in vitro to the fusion protein PA2024, resulted in a prolonged overall survival among patients with metastatic castration-resistent prostate cancer. In April 2010, sipuleucel-T was approved by the United States Food and Drug Administration for prostate cancer therapy

Serial entrepreneurs: A review of literature and guidance for future research

Little research has been conducted regarding serial entrepreneurship compared to entrepreneurship research more broadly, despite research that suggests that asmany as 50% of all entrepreneurs are serial entrepreneurs. Entrepreneurship research shows that most new ventures fail, yet serial entrepreneurs continually exit previous ventures and start new ones. Our study explores 118 scholarly articles indexed in Web of Science and Scopus databases on serial entrepreneurship through multiple correspondence analysis. Through our analysis, we identify key areas for future research, explore and consolidate the theoretical foundations used, and provide a review of academic literature for future researchers to utilize. Our perceptual map has identified four key research areas that researchers should focus upon: heuristics in entrepreneurship, entrepreneurial capabilities, the entrepreneurial ecosystem, and technological development and resources

Canonical Solution of Classical Magnetic Models with Long-Range Couplings

We study the canonical solution of a family of classical $n-vector$ spin models on a generic $d$-dimensional lattice; the couplings between two spins decay as the inverse of their distance raised to the power $\alpha$, with $\alpha<d$. The control of the thermodynamic limit requires the introduction of a rescaling factor in the potential energy, which makes the model extensive but not additive. A detailed analysis of the asymptotic spectral properties of the matrix of couplings was necessary to justify the saddle point method applied to the integration of functions depending on a diverging number of variables. The properties of a class of functions related to the modified Bessel functions had to be investigated. For given $n$, and for any $\alpha$, $d$ and lattice geometry, the solution is equivalent to that of the $\alpha=0$ model, where the dimensionality $d$ and the geometry of the lattice are irrelevant.Comment: Submitted for publication in Journal of Statistical Physic

Citizen Science Terminology Matters: Exploring Key Terms

Much can be at stake depending on the choice of words used to describe citizen science, because terminology impacts how knowledge is developed. Citizen science is a quickly evolving field that is mobilizing people’s involvement in information development, social action and justice, and large-scale information gathering. Currently, a wide variety of terms and expressions are being used to refer to the concept of ‘citizen science’ and its practitioners. Here, we explore these terms to help provide guidance for the future growth of this field. We do this by reviewing the theoretical, historical, geopolitical, and disciplinary context of citizen science terminology; discussing what citizen science is and reviewing related terms; and providing a collection of potential terms and definitions for ‘citizen science’ and people participating in citizen science projects. This collection of terms was generated primarily from the broad knowledge base and on-the-ground experience of the authors, by recognizing the potential issues associated with various terms. While our examples may not be systematic or exhaustive, they are intended to be suggestive and invitational of future consideration. In our collective experience with citizen science projects, no single term is appropriate for all contexts. In a given citizen science project, we suggest that terms should be chosen carefully and their usage explained; direct communication with participants about how terminology affects them and what they would prefer to be called also should occur. We further recommend that a more systematic study of terminology trends in citizen science be conducted

Catálogo de las plantas vasculares de Chile

A catalog of vascular plants growing in Chile is presented. It is organized by divisions, Pteridophyta (Lycopodiopsida and Polypodiopsida), Pinophyta (Gnetopsida and Pinopsida) and Magnoliophyta (Liliopsida and Magnoliopsida), and within each group, the taxonomic hierarchies (Family, Genus, Species and infraspecific taxa) are arranged alphabetically. In accordance with this catalogue, the flora of vascular plants of Chile comprise 186 families, 1121 genera and 5471 species, 4655 species are native, 2145 of these are endemic to Chile and 816 species are introduced.Se presenta un catálogo de las plantas vasculares que crecen en Chile. Está organizado por divisiones, Pteridophyta (Lycopodiopsida y Polypodiopsida), Pinophyta (Gnetopsida y Pinopsida) y Magnoliophyta (Liliopsida y Magnoliopsida), y dentro de cada grupo, las jerarquías taxonómicas (Familia, Género, Especies y taxones infraespecíficos) están ordenados alfabéticamente. Se incluye además un índice alfabético de géneros con indicación de la familia y grupo a que pertenecen. De acuerdo a este catálogo la flora de las plantas vasculares que crecen en Chile, comprende 186 familias, 1121 géneros y especies, de éstas, 4655 corresponden a especies nativas, de las cuales 2145 son endémicas de Chile y 816 las especies introducidas

Investigative safety strategies to improve success in drug development

Understanding and reducing attrition rate remains a key challenge in drug development. Preclinical and clinical safety issues still represent about 40% of drug discontinuation, of which cardiac and liver toxicities are the leading reasons. Reducing attrition rate can be achieved by various means, starting with a comprehensive evaluation of the potential safety issues associated to the primary target followed by an evaluation of undesirable secondary targets. To address these risks, a risk mitigation plan should be built at very early development stages, using a panel of in silico, in vitro, and in vivo models. While most pharmaceutical companies have developed robust safety strategies to de-risk genotoxicity and cardiotoxicity issues, partly driven by regulatory requirements; safety issues affecting other organs or systems, such as the central nervous system, liver, kidney, or gastro-intestinal system are less commonly addressed during early drug development. This paper proposes some de-risking strategies that can be applied to these target organ systems, including the use of novel biomarkers that can be easily integrated in both preclinical and clinical studies. Experiments to understand the mechanisms’ underlying toxicity are also important. Two examples are provided to demonstrate how such mechanistic studies can impact drug development. Novel trends in investigative safety are reviewed, such as computational modeling, mitochondrial toxicity assessment, and imaging technologies. Ultimately, understanding the predictive value of non-clinical safety testing and its translatability to humans will enable to optimize assays in order to address the key objectives of the drug discovery process, i.e., hazard identification, risk assessment, and mitigation

Evaluation of in vitro Assays to Assess the Modulation of Dendritic Cells Functions by Therapeutic Antibodies and Aggregates

Therapeutic antibodies have the potential to induce immunogenicity leading to the development of anti-drug antibodies (ADA) that consequently may result in reduced serum drug concentrations, a loss of efficacy or potential hypersensitivity reactions. Among other factors, aggregated antibodies have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are the most efficient antigen-presenting cell population and are crucial for the initiation of T cell responses and the subsequent generation of an adaptive immune response. This work focuses on the development of predictive in vitro assays that can monitor DC maturation, in order to determine whether drug products have direct DC stimulatory capabilities. To this end, four independent laboratories aligned a common protocol to differentiate human monocyte-derived DC (moDC) that were treated with either native or aggregated preparations of infliximab, natalizumab, adalimumab, or rituximab. These drug products were subjected to different forms of physical stress, heat and shear, resulting in aggregation and the formation of subvisible particles. Each partner developed and optimized assays to monitor diverse end-points of moDC maturation: measuring the upregulation of DC activation markers via flow cytometry, analyzing cytokine, and chemokine production via mRNA and protein quantification and identifying cell signaling pathways via quantification of protein phosphorylation. These study results indicated that infliximab, with the highest propensity to form aggregates when heat-stressed, induced a marked activation of moDC as measured by an increase in CD83 and CD86 surface expression, IL-1β, IL-6, IL-8, IL-12, TNFα, CCL3, and CCL4 transcript upregulation and release of respective proteins, and phosphorylation of the intracellular signaling proteins Syk, ERK1/2, and Akt. In contrast, natalizumab, which does not aggregate under these stress conditions, induced no DC activation in any assay system, whereas adalimumab or rituximab aggregates induced only slight parameter variation. Importantly, the data generated in the different assay systems by each partner site correlated and supported the use of these assays to monitor drug-intrinsic propensities to drive maturation of DC. This moDC assay is also a valuable tool as an in vitro model to assess the intracellular mechanisms that drive DC activation by aggregated therapeutic proteins

Sin3b interacts with Myc and decreases Myc levels

Myc expression is deregulated in many human cancers. A yeast two-hybrid screen has revealed that the transcriptional repressor Sin3b interacts with Myc protein. Endogenous Myc and Sin3b co-localize and interact in the nuclei of human and rat cells, as assessed by co-immunoprecipitation, immunofluorescence, and proximity ligation assay. The interaction is Max-independent. A conserved Myc region (amino acids 186-203) is required for the interaction with Sin3 proteins. Histone deacetylase 1 is recruited to Myc-Sin3b complexes, and its deacetylase activity is required for the effects of Sin3b on Myc. Myc and Sin3a/b co-occupied many sites on the chromatin of human leukemia cells, although the presence of Sin3 was not associated with gene down-regulation. In leukemia cells and fibroblasts, Sin3b silencing led to Myc up-regulation, whereas Sin3b overexpression induced Myc deacetylation and degradation. An analysis of Sin3b expression in breast tumors revealed an association between low Sin3b expression and disease progression. The data suggest that Sin3b decreases Myc protein levels upon Myc deacetylation. As Sin3b is also required for transcriptional repression by Mxd-Max complexes, our results suggest that, at least in some cell types, Sin3b limits Myc activity through two complementary activities: Mxd-dependent gene repression and reduction of Myc levels