The protist Trichomonas vaginalis harbors multiple lineages of transcriptionally active Mutator-like elements

<p>Abstract</p> <p>Background</p> <p>For three decades the <it>Mutator </it>system was thought to be exclusive of plants, until the first homolog representatives were characterized in fungi and in early-diverging amoebas earlier in this decade.</p> <p>Results</p> <p>Here, we describe and characterize four families of <it>Mutator</it>-like elements in a new eukaryotic group, the Parabasalids. These <b><it>T</it></b><it>richomonas </it><b><it>v</it></b><it>aginalis </it><it><b>Mu</b>tator- <b>l</b>ike </it><it><b>e</b>lements</it>, or <it>TvMULEs</it>, are active in <it>T. vaginalis </it>and patchily distributed among 12 trichomonad species and isolates. Despite their relatively distinctive amino acid composition, the inclusion of the repeats <it>TvMULE1</it>, <it>TvMULE2</it>, <it>TvMULE3 </it>and <it>TvMULE4 </it>into the <it>Mutator </it>superfamily is justified by sequence, structural and phylogenetic analyses. In addition, we identified three new <it>TvMULE</it>-related sequences in the genome sequence of <it>Candida albicans</it>. While <it>TvMULE1 </it>is a member of the <it>MuDR </it>clade, predominantly from plants, the other three <it>TvMULEs</it>, together with the <it>C. albicans </it>elements, represent a new and quite distinct <it>Mutator </it>lineage, which we named <it>TvCaMULEs</it>. The finding of <it>TvMULE1 </it>sequence inserted into other putative repeat suggests the occurrence a novel TE family not yet described.</p> <p>Conclusion</p> <p>These findings expand the taxonomic distribution and the range of functional motif of <it>MULEs </it>among eukaryotes. The characterization of the dynamics of <it>TvMULEs </it>and other transposons in this organism is of particular interest because it is atypical for an asexual species to have such an extreme level of TE activity; this genetic landscape makes an interesting case study for causes and consequences of such activity. Finally, the extreme repetitiveness of the <it>T. vaginalis </it>genome and the remarkable degree of sequence identity within its repeat families highlights this species as an ideal system to characterize new transposable elements.</p

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

BACKGROUND & AIMS: The liver, being the major site of iron storage, is particularly exposed to the toxic effects of iron. Transcription factor NRF2 is critical for protecting the liver against disease by activating the transcription of genes encoding detoxification/antioxidant enzymes. We aimed to determine if the NRF2 pathway plays a significant role in the protection against hepatic iron overload.METHODS: Wild-type and Nrf2(-/-) mouse primary hepatocytes were incubated with ferric ammonium citrate. Wild-type and Nrf2(-/-) mice were fed standard rodent chow or iron-rich diet for 2weeks, with or without daily injection of the antioxidant mito-TEMPOL.RESULTS: In mouse hepatocytes, iron induced the nuclear translocation of NRF2 and the expression of cytoprotective genes in an NRF2-dependent manner. Moreover, Nrf2(-/-) hepatocytes were highly susceptible to iron-induced cell death. Wild-type and Nrf2(-/-) mice fed iron-rich diet accumulated similar amounts of iron in the liver and were equally able to increase the expression of hepatic hepcidin and ferritin. Nevertheless, in Nrf2-null mice the iron loading resulted in progressive liver injury, ranging from mild confluent necrosis to severe necroinflammatory lesions. Hepatocytic cell death was associated with gross ultrastructural damage to the mitochondria. Notably, liver injury was prevented in iron-fed animals that received mito-TEMPOL.CONCLUSIONS: NRF2 protects the mouse liver against the toxicity of dietary iron overload by preventing hepatocytic cell death. We identify NRF2 as a potential modifier of liver disease in iron overload pathology and show the beneficial effect of the antioxidant mito-TEMPOL in a mouse model of dietary iron-induced liver injury.This work is funded by FEDER Funds through the Operational Competitiveness Programme - COMPETE and by National Funds through FCT - Fundacao para a Ciencia e a Tecnologia under the project FCOMP-01-0124-FEDER-011062 (PTDC/SAU-FCF/101177/2008). TLD is supported by "Programa Ciencia - financiado pelo POPH - QREN - Tipologia 4.2 - Promocao do Emprego Cientifico, comparticipado pelo Fundo Social Europeu e por fundos nacionais do MCTES''

SARS-CoV-2 inhibition in human airway epithelial cells using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray

There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of −3 to −4 at a concentration of 10 – 100 μg/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 μg/ mL (p < 0.05 compared to untreated controls). GCPQ is currently being developed as a pharmaceutical excipient in nasal and ocular formulations. GCPQ’s electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/ kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 hours after nasal dosing. With a no observed adverse effect level of 18 mg/ kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted

Grounding language in perception for scene conceptualization in autonomous robots

In order to behave autonomously, it is desirable for robots to have the ability to use human supervision and learn from different input sources (perception, gestures, verbal and textual descriptions etc). In many machine learning tasks, the supervision is directed specifically towards machines and hence is straight forward clearly annotated examples. But this is not always very practical and recently it was found that the most preferred interface to robots is natural language. Also the supervision might only be available in a rather indirect form, which may be vague and incomplete. This is frequently the case when humans teach other humans since they may assume a particular context and existing world knowledge. We explore this idea here in the setting of conceptualizing objects and scene layouts. Initially the robot undergoes training from a human in recognizing some objects in the world and armed with this acquired knowledge it sets out in the world to explore and learn more higher level concepts like static scene layouts and environment activities. Here it has to exploit its learned knowledge and ground language into perception to use inputs from different sources that might have overlapping as well as novel information. When exploring, we assume that the robot is given visual input, without explicit type labels for objects, and also that it has access to more or less generic linguistic descriptions of scene layout. Thus our task here is to learn the spatial structure of a scene layout and simultaneously visual object models it was not trained on. In this paper, we present a cognitive architecture and learning framework for robot learning through natural human supervision and using multiple input sources by grounding language in perception

SARS-CoV-2 inhibition using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray

There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of - 3 to - 4 at a concentration of 10-100 μg/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 μg/ mL (p < 0.05 compared to untreated controls). In vivo studies using transgenic mice expressing the ACE-2 receptor, dosed nasally with SARS-COV-2 (426,000 TCID50/mL) showed a trend for nasal GCPQ (20 mg/kg) to inhibit viral load in the respiratory tract and brain, although the study was not powered to detect statistical significance. GCPQ's electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 h after nasal dosing. With a no observed adverse effect level of 18 mg/kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted

Consensus Document on Coding of Cardiac Magnetic Resonance Examinations in Portugal

Um dos obstáculos a uma utilização mais frequente e apropriada da ressonância magnética cardíaca (RMC) em Portugal tem sido a ausência de códigos específicos que descrevam adequadamente os exames tal como são efetuados actualmente. Este documento de consenso fornece recomendações para a atualização e uniformização dos códigos empregues na RMC. São igualmente feitas recomendações quanto às técnicas e códigos a utilizar nas indicações clínicas mais frequentes

Leflunomide/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sjögren's syndrome that show potential to predict and monitor clinical response

OBJECTIVES: To assess to what extent leflunomide (LEF) and hydroxychloroquine (HCQ) therapy in patients with primary Sjögren's syndrome (RepurpSS-I) targets type I IFN-associated responses and to study the potential of several interferon associated RNA-based and protein-based biomarkers to predict and monitor treatment. METHODS: In 21 patients treated with LEF/HCQ and 8 patients treated with placebo, blood was drawn at baseline, 8, 16 and 24 weeks. IFN-signatures based on RNA expression of five IFN-associated genes were quantified in circulating mononuclear cells and in whole blood. MxA protein levels were measured in whole blood, and protein levels of CXCL10 and Galectin-9 were quantified in serum. Differences between responders and non-responders were assessed and receiver operating characteristic analysis was used to determine the capacity of baseline expression and early changes (after 8 weeks of treatment) in biomarkers to predict treatment response at the clinical endpoint. RESULTS: IFN-signatures in peripheral blood mononuclear cell and whole blood decreased after 24 weeks of LEF/HCQ treatment, however, changes in IFN signatures only poorly correlated with changes in disease activity. In contrast to baseline IFN signatures, baseline protein concentrations of galectin-9 and decreases in circulating MxA and Galectin-9 were robustly associated with clinical response. Early changes in serum Galectin-9 best predicted clinical response at 24 weeks (area under the curve 0.90). CONCLUSIONS: LEF/HCQ combination therapy targets type-I IFN-associated proteins that are associated with strongly decreased B cell hyperactivity and disease activity. IFN-associated Galectin-9 is a promising biomarker for treatment prediction and monitoring in pSS patients treated with LEF/HCQ.</p

The RACE Project: Robustness by Autonomous Competence Enhancement

This paper reports on the aims, the approach, and the results of the European project RACE. The project aim was to enhance the behavior of an autonomous robot by having the robot learn from conceptualized experiences of previous performance, based on initial models of the domain and its own actions in it. This paper introduces the general system architecture; it then sketches some results in detail regarding hybrid reasoning and planning used in RACE, and instances of learning from the experiences of real robot task execution. Enhancement of robot competence is operationalized in terms of performance quality and description length of the robot instructions, and such enhancement is shown to result from the RACE system