Dreaming of a Flat Earth

Since the turn of the Millennium, it has become increasingly difficult to understand the socio-political landscape using the traditional models. Although this is a global phenomenon, it is particularly evident in the United States, which is where we will focus the majority of this article. The current era is dominated by a series of overlapping phenomena, rooted in a series of what we term “disconnections,” that bring into view a new “spherical” political reality. These disconnections describe situations where the empirical, or observable, world differs from the actual, but often hidden, reality. Deriving from these disconnections, the traditional “flat” understanding of political structures, focused on “traditional” axes of Liberal to Conservative and Libertarian to Authoritarian, ignores an important third dimension that we will examine. This third axis relates to issues of rural / nationalist / science-skeptical versus urban / globalist / science-positive. This article explores how this third axis informs, and is informed, by the three most significant issues facing the world at this moment: climate change, COVID-19, and the attempted coup of January 2021

Tidal changes in estuarine systems induced by local geomorphologic modifications

Although rising global sea levels will affect the estuarine flooded areas over the coming decades, the local and regional-scale processes will also induce important changes in these coastal systems. The main aim of this work is to investigate possible tidal changes in estuarine systems induced by local geomorphologic modifications, analysing the particular case of Ria de Aveiro which is in risk of inundation. Located in the Portuguese west coast, this tidally driven lagoon has a large area of mostly abandoned salt pans, which are in progressive degradation caused by the lack of maintenance and by the strong currents which erode their protective walls. To explore possible tidal changes the hydrodynamic model ELCIRC was applied to Ria de Aveiro to simulate and analyse the impact in the lagoon hydrodynamics of this degradation which results in the enlargement of the lagoon flooded area. A high-resolution grid (grid spacing of the order of 1 m) was developed in order to represent the narrow channels adjacent to the salt pans. The hydrodynamic model was then successfully calibrated and assessed for skill for the Aveiro lagoon through comparison between measurements and model results and quantification of the numerical accuracy. The model was subsequently used to investigate the effect of the flooded lagoon area enlargement on tidal propagation in Ria de Aveiro. Simulations were performed for three geomorphologic configurations, representing the reference or present situation and two flooded scenarios. Results were compared through the analysis of tidal currents, tidal asymmetry and tidal prism. The increase of the lagoon flooded area results in an intensification of the tidal currents, tidal prism and tidal asymmetry. Results also indicate that the tidal prism further increases when the flooding depth increases. Otherwise, changes in tidal currents and in tidal asymmetry pattern are negligible with the increase of the flooded area depth. These results indicate that modifications of the flooded area of estuarine systems will result in tidal changes, with an intensification of the actual tidal patterns induced by the enlargement of inundation areas

Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps)

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60–70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the “Rule of Three” was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity

Shaping a screening file for maximal lead discovery efficiency and effectiveness: elimination of molecular redundancy

High Throughput Screening (HTS) is a successful strategy for finding hits and leads that have the opportunity to be converted into drugs. In this paper we highlight novel computational methods used to select compounds to build a new screening file at Pfizer and the analytical methods we used to assess their quality. We also introduce the novel concept of molecular redundancy to help decide on the density of compounds required in any region of chemical space in order to be confident of running successful HTS campaigns

The Metalloprotease Meprinβ Processes E-Cadherin and Weakens Intercellular Adhesion

BACKGROUND: Meprin (EC 3.4.24.18), an astacin-like metalloprotease, is expressed in the epithelium of the intestine and kidney tubules and has been related to cancer, but the mechanistic links are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used MDCK and Caco-2 cells stably transfected with meprin alpha and or meprin beta to establish models of renal and intestinal epithelial cells expressing this protease at physiological levels. In both models E-cadherin was cleaved, producing a cell-associated 97-kDa E-cadherin fragment, which was enhanced upon activation of the meprin zymogen and reduced in the presence of a meprin inhibitor. The cleavage site was localized in the extracellular domain adjacent to the plasma membrane. In vitro assays with purified components showed that the 97-kDa fragment was specifically generated by meprin beta, but not by ADAM-10 or MMP-7. Concomitantly with E-cadherin cleavage and degradation of the E-cadherin cytoplasmic tail, the plaque proteins beta-catenin and plakoglobin were processed by an intracellular protease, whereas alpha-catenin, which does not bind directly to E-cadherin, remained intact. Using confocal microscopy, we observed a partial colocalization of meprin beta and E-cadherin at lateral membranes of incompletely polarized cells at preconfluent or early confluent stages. Meprin beta-expressing cells displayed a reduced strength of cell-cell contacts and a significantly lower tendency to form multicellular aggregates. CONCLUSIONS/SIGNIFICANCE: By identifying E-cadherin as a substrate for meprin beta in a cellular context, this study reveals a novel biological role of this protease in epithelial cells. Our results suggest a crucial role for meprin beta in the control of adhesiveness via cleavage of E-cadherin with potential implications in a wide range of biological processes including epithelial barrier function and cancer progression

Spinning Gland Transcriptomics from Two Main Clades of Spiders (Order: Araneae) - Insights on Their Molecular, Anatomical and Behavioral Evolution

Characterized by distinctive evolutionary adaptations, spiders provide a comprehensive system for evolutionary and developmental studies of anatomical organs, including silk and venom production. Here we performed cDNA sequencing using massively parallel sequencers (454 GS-FLX Titanium) to generate ∼80,000 reads from the spinning gland of Actinopus spp. (infraorder: Mygalomorphae) and Gasteracantha cancriformis (infraorder: Araneomorphae, Orbiculariae clade). Actinopus spp. retains primitive characteristics on web usage and presents a single undifferentiated spinning gland while the orbiculariae spiders have seven differentiated spinning glands and complex patterns of web usage. MIRA, Celera Assembler and CAP3 software were used to cluster NGS reads for each spider. CAP3 unigenes passed through a pipeline for automatic annotation, classification by biological function, and comparative transcriptomics. Genes related to spider silks were manually curated and analyzed. Although a single spidroin gene family was found in Actinopus spp., a vast repertoire of specialized spider silk proteins was encountered in orbiculariae. Astacin-like metalloproteases (meprin subfamily) were shown to be some of the most sampled unigenes and duplicated gene families in G. cancriformis since its evolutionary split from mygalomorphs. Our results confirm that the evolution of the molecular repertoire of silk proteins was accompanied by the (i) anatomical differentiation of spinning glands and (ii) behavioral complexification in the web usage. Finally, a phylogenetic tree was constructed to cluster most of the known spidroins in gene clades. This is the first large-scale, multi-organism transcriptome for spider spinning glands and a first step into a broad understanding of spider web systems biology and evolution

Le intersezioni stradali a raso. Illustrazione del DM 19.4.2006, n.1699

Il Decreto Ministeriale n. 1699 \u201cNorme funzionali e geometriche per la costruzione delle intersezioni stradali\u201d, dopo quello sulle \u201cNorme geometriche e funzionali per la costruzione delle strade\u201d del 2001, ha reso cogente le direttive per la progettazione delle intersezioni stradali con l\u2019obiettivo di migliorare la sicurezza in questo campo. E\u2019 noto che l\u2019incidentalit\ue0 nelle intersezioni stradali si attesta intorno al 50 % dell\u2019incidentalit\ue0 totale, con valori ancora maggiori in ambito urbano. Anche se il decreto ha valore cogente solo per le nuove realizzazioni, esso rappresenta un fondamentale punto di riferimento per la riqualificazione di quelle esistenti. La presente nota ha l\u2019obiettivo di evidenziare le importanti novit\ue0 del Decreto soprattutto per le intersezioni pi\uf9 diffuse in ambito urbano: le intersezioni a raso lineari e a rotatoria. Fondamentale per una corretta progettazione \ue8 la classificazione delle intersezioni prevista dal decreto in relazione alle tipologie di strade connesse dal nodo. Nelle intersezioni lineari, la geometria degli elementi viene scelta attraverso la valutazione puntuale delle velocit\ue0 di progetto nell\u2019intersezione (diagramma delle velocit\ue0). Una particolare attenzione \ue8 rivolta alle intersezioni a rotatoria, oggi molto diffuse, sia in ambito urbano sia in quello extraurbano. Nella scelta di questa soluzione, soprattutto negli interventi di riqualifica di intersezioni esistenti, pu\uf2 diventare decisiva l\u2019analisi del comportamento degli utenti, con il rilievo delle traiettorie e velocit\ue0 praticate