Colorectal cancer is the fourth worldwide cause of death and even if some dietary habits are consider risk factors, the contribution of food additives including foodgrade titanium dioxide (TiO2), ...designated as E171, has been poorly investigated. We hypothesized that oral E171 intake could have impact on the enhancement of colorectal tumor formation and we aimed to investigate if E171 administration could enhance tumor formation in a colitis associated cancer (CAC) model. BALB/c male mice were grouped as follows: a) control, b) E171, c) CAC and d) CAC + E171 group (n = 6). E171 used in this study formed agglomerates of 300 nm in water. E171 intragastric administration (5 mg/kg body weight/5 days/10 weeks) was unable to induce tumor formation but dysplastic alterations were observed in the distal colon but enhanced the tumor formation in distal colon (CAC + E171 group) measured by tumor progression markers. Some E171 particles were internalized in colonic cells of the E171 and CAC + E171 groups and both groups showed a decrease in goblet cells in the distal colon. However the CAC + E171 group showed a higher decrease of these cells that act as protection barrier in colon. These results suggest that E171 could worsen pre-existent intestinal diseases.
•Food-grade titanium dioxide, known as E171, exacerbated colon tumor formation in mice.•E171 intragastric exposure (5 mg/kg/10weeks) decreased goblet cells in distal colon.•E171 particles were internalized in colonic cells and retained between daughter cells.
Myocardial infarction is a leading cause of death worldwide
. Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness ...of therapies to reduce late-stage mortality
. Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.
Breast cancer (BC) is the most frequent form of malignancy and second only to lung cancer as cause of deaths in women. Notwithstanding many progresses made in the field, metastatic BC has a very poor ...prognosis. As therapies are becoming more personalized to meet the needs of patients, a better knowledge of the molecular biology leading to the disease unfolds the possibility to project more precise compounds or antibodies targeting definite alteration at the molecular level and functioning on such cancer-causing molecules expressed in cancer cells of patients, or present as antigens on the surface of cancer cell membranes. Fibroblast growth factor receptor (FGFR) is one of such druggable targets, activated by its own ligands -namely the Fibroblast Growth Factors (FGFs). This pathway provides a vast range of interesting molecular targets pursued at different levels of clinical investigation. Herein we provide an update on the knowledge of genetic alterations of the receptors in breast cancer, their role in tumorigenesis and the most recent drugs against this particular receptor for the treatment of the disease.
The growing availability of single-cell data, especially transcriptomics, has sparked an increased interest in the inference of cell-cell communication. Many computational tools were developed for ...this purpose. Each of them consists of a resource of intercellular interactions prior knowledge and a method to predict potential cell-cell communication events. Yet the impact of the choice of resource and method on the resulting predictions is largely unknown. To shed light on this, we systematically compare 16 cell-cell communication inference resources and 7 methods, plus the consensus between the methods' predictions. Among the resources, we find few unique interactions, a varying degree of overlap, and an uneven coverage of specific pathways and tissue-enriched proteins. We then examine all possible combinations of methods and resources and show that both strongly influence the predicted intercellular interactions. Finally, we assess the agreement of cell-cell communication methods with spatial colocalisation, cytokine activities, and receptor protein abundance and find that predictions are generally coherent with those data modalities. To facilitate the use of the methods and resources described in this work, we provide LIANA, a LIgand-receptor ANalysis frAmework as an open-source interface to all the resources and methods.
Food‐grade titanium dioxide labeled as E171 has been approved for human consumption by the Food and Drug Administration (USA) and by the European Union for five decades. However, titanium dioxide has ...been classified as a possible carcinogen for humans by the International Agency of Research in Cancer raising concerns of its oral intake and the translocation to bloodstream, which could disturb barriers such as the blood‐testis barrier. There is evidence that titanium dioxide by intragastric/intraperitoneal/intravenous administration induced alterations on testosterone levels, testicular function and architecture, but studies of the E171 effects on the testicle structure and blood‐testis barrier are limited. E171 is contained not only in foods in liquid matrix but also in solid ones, which can exert different biological effects. We aimed to compare the effects of E171 consumption in a solid matrix (0.1%, 0.5% and 1% in pellets) and liquid suspension (5 mg/kg body weight) on testis structure, inflammation infiltrate and blood‐testis barrier disruption of male BALB/c mice. Results showed that none of the administration routes had influence on body weight but an increase in germ cell sloughing and the infiltrate of inflammatory cells in seminiferous tubules, together with disruption of the blood‐testis barrier were similar in testis of both groups even if the dose received in mice in liquid matrix was 136 or 260 times lower than the dose reached by oral intake in solid E171 pellets in 0.5% E171 and 1% E171, respectively. This study highlights the attention on matrix food containing E171 and possible adverse effects on testis when E171 is consumed in a liquid matrix.
Food‐grade titanium dioxide (E171) is a widely used additive in solid and liquid food products. After oral exposure, E171 reaches blood stream and other organs such as the testicles, in which toxic effects are under research. Additionally, it is unknown if the administration of E171 by solid or liquid matrix induces differences in the biological responses. We compared the effects of E171 administration by solid or liquid matrix on testis structure, inflammatory markers and blood‐testis barrier integrity in mice. Results showed an increase in germ cells sloughing, inflammation and disruption of blood‐testis barrier after E171 administration by solid or liquid matrix; however the liquid matrix exhibited higher toxicity in those parameters than solid matrix. This study points out the relevance of E171 effects on testis and the impact of matrix containing E171 in biological responses.
La sarcoidosis es un trastorno inflamatorio multisistémico de causa desconocida que se caracteriza por la formación de granulomas pleomórficos, no caseificantes, con afectación predominantemente ...pulmonar. Aunque la sarcoidosis abdominal representa el 30% de las manifestaciones extrapulmonares, la afectación peritoneal es extremadamente rara. Describiremos un caso poco frecuente de sarcoidosis peritoneal simulando carcinomatosis en una paciente joven con dolor abdominal sometida a exploración laparoscópica.
The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics to define how the transcriptomic ...landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we mapped transcriptomics modules associated with human diseases demonstrating the translational potential of our dataset. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses.
Multilevel societies, containing hierarchically nested social levels, are remarkable social structures whose origins are unclear. The social relationships of sperm whales are organized in a ...multilevel society with an upper level composed of clans of individuals communicating using similar patterns of clicks (codas). Using agent-based models informed by an 18-year empirical study, we show that clans are unlikely products of stochastic processes (genetic or cultural drift) but likely originate from cultural transmission via biased social learning of codas. Distinct clusters of individuals with similar acoustic repertoires, mirroring the empirical clans, emerge when whales learn preferentially the most common codas (conformism) from behaviourally similar individuals (homophily). Cultural transmission seems key in the partitioning of sperm whales into sympatric clans. These findings suggest that processes similar to those that generate complex human cultures could not only be at play in non-human societies but also create multilevel social structures in the wild.
Abstract
Gene regulation plays a critical role in the cellular processes that underlie human health and disease. The regulatory relationship between transcription factors (TFs), key regulators of ...gene expression, and their target genes, the so called TF regulons, can be coupled with computational algorithms to estimate the activity of TFs. However, to interpret these findings accurately, regulons of high reliability and coverage are needed. In this study, we present and evaluate a collection of regulons created using the CollecTRI meta-resource containing signed TF–gene interactions for 1186 TFs. In this context, we introduce a workflow to integrate information from multiple resources and assign the sign of regulation to TF–gene interactions that could be applied to other comprehensive knowledge bases. We find that the signed CollecTRI-derived regulons outperform other public collections of regulatory interactions in accurately inferring changes in TF activities in perturbation experiments. Furthermore, we showcase the value of the regulons by examining TF activity profiles in three different cancer types and exploring TF activities at the level of single-cells. Overall, the CollecTRI-derived TF regulons enable the accurate and comprehensive estimation of TF activities and thereby help to interpret transcriptomics data.
Graphical Abstract
Graphical Abstract
The influence that the kinematics of pitching and heaving 2D airfoils has on the aerodynamic forces is investigated using direct numerical simulations and a force decomposition algorithm. ...Large-amplitude motions are considered (of the order of one chord), with moderate Reynolds numbers and reduced frequencies of order
$O(1)$
, varying the mean pitch angle and the phase shift between the pitching and heaving motions. Our results show that the surface vorticity contribution (viscous effect) to the aerodynamic force is negligible compared with the contributions from the body motion (fluid inertia) and the vorticity within the flow (circulation). For the range of parameters considered here, the latter tends to be instantaneously oriented in the direction normal to the chord of the airfoil. Based on the results discussed in this paper, a reduced-order model for the instantaneous aerodynamic force is proposed, taking advantage of the force decomposition and the chord-normal orientation of the contribution from vorticity within the flow to the total aerodynamic force. The predictions of the proposed model are compared with those of a similar model from the literature, showing a noticeable improvement in the prediction of the mean thrust, and a smaller improvement in the prediction of the mean lift and the instantaneous force coefficients.
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