The inner mucus layer (IML) is a critical barrier that protects the colonic epithelium from luminal threats and inflammatory bowel disease. Innate immune signaling is thought to regulate IML ...formation via goblet cell Nlrp6 inflammasome activity that controls secretion of the mucus structural component Muc2. We report that isolated colonic goblet cells express components of several inflammasomes; however, analysis of IML properties in multiple inflammasome-deficient mice, including littermate-controlled
, detect a functional IML barrier in all strains. Analysis of mice lacking inflammasome substrate cytokines identifies a defective IML in
mice, but this phenotype is ultimately traced to a microbiota-driven, Il18-independent effect. Analysis of phenotypic transfer between IML-deficient and IML-intact mice finds that the Bacteroidales family S24-7 (Muribaculaceae) and genus
consistently positively covary with IML barrier function. Together, our results demonstrate that baseline IML formation and function is independent of inflammasome activity and highlights the role of the microbiota in determining IML barrier function.
The intestinal mucus layer, an important element of epithelial protection, is produced by goblet cells. Intestinal goblet cells are assumed to be a homogeneous cell type. In this study, however, we ...delineated their specific gene and protein expression profiles and identified several distinct goblet cell populations that form two differentiation trajectories. One distinct subtype, the intercrypt goblet cells (icGCs), located at the colonic luminal surface, produced mucus with properties that differed from the mucus secreted by crypt-residing goblet cells. Mice with defective icGCs had increased sensitivity to chemically induced colitis and manifested spontaneous colitis with age. Furthermore, alterations in mucus and reduced numbers of icGCs were observed in patients with both active and remissive ulcerative colitis, which highlights the importance of icGCs in maintaining functional protection of the epithelium.
LA DEMOCRACIA EN EL S. XXI Abad, Beatriz
Aula (Santo Domingo),
12/2020, Letnik:
67, Številka:
1
Journal Article
Recenzirano
Odprti dostop
La democracia como forma de gobierno, ha ido ganando terreno a lo largo de la historia hasta llegar a consolidarse en el siglo XIX, como la preferida por la mayoría de las sociedades. La influencia ...del pensamiento político liberal, la revolución de la burguesía y el surgimiento de los partidos políticos son, sin duda, hechos que contribuyeron a darle el estatus preferencial del que goza actualmente. Sin embargo, resulta paradójico ver cómo, en cierta forma, las mismas razones que condujeron a la consolidación de la democracia como forma de gobierno preferida por la mayoría de las naciones del mundo, están resultando ser las razones que la están orillando a lo que algunos llaman la «crisis de la democracia».
Liquid chromatography high-resolution mass spectrometry fingerprinting together with pattern recognition techniques was used to determine the metabolites involved in the susceptibility of apple ...cultivars to rosy apple aphid (RAA). Preprocessing of ultra-high-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry raw data of resistant and susceptible apple cultivars was carried out with XCMS and CAMERA packages. Univariate statistical tools and multivariate data analysis highlighted significant different profiles of the apple metabolomes according to their tolerance to RAA. Optimized and cross-validated Partial least squares discriminant analysis and orthogonal projections to latent structures discriminant analysis models confirmed trans-4-caffeoylquinic acid and 4-p-coumaroylquinic acid as biomarkers for the identification of resistant and susceptible apple cultivars to RAA and disclosed that only hydroxycinnamic acids are involved in the disease susceptibility of cultivars. In this sense, the final steps of the biosynthesis of caffeoylquinic acid (CQA) and p-coumaroylquinic acid (p-CoQA) become decisive because the isomerization of 5-CQA to 4-CQA is favored in resistant cultivars, whereas the isomerization of 5-p-CoQA to 4-p-CoQA is favored in susceptible cultivars.
The colonic mucus layer is organized as a two-layered system providing a physical barrier against pathogens and simultaneously harboring the commensal flora. The factors contributing to the ...organization of this gel network are not well understood. In this study, the impact of transglutaminase activity on this architecture was analyzed. Here, we show that transglutaminase TGM3 is the major transglutaminase-isoform expressed and synthesized in the colon. Furthermore, intrinsic extracellular transglutaminase activity in the secreted mucus was demonstrated in vitro and ex vivo. Absence of this acyl-transferase activity resulted in faster degradation of the major mucus component the MUC2 mucin and changed the biochemical properties of mucus. Finally, TGM3-deficient mice showed an early increased susceptibility to Dextran Sodium Sulfate-induced colitis. Here, we report that natural isopeptide cross-linking by TGM3 is important for mucus homeostasis and protection of the colon from inflammation, reducing the risk of colitis.
Lipid imaging mass spectrometry (LIMS) has been tested in several pathological contexts, demonstrating its ability to segregate and isolate lipid signatures in complex tissues, thanks to the ...technique’s spatial resolution. However, it cannot yet compete with the superior identification power of high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS), and therefore, very often, the latter is used to refine the assignment of the species detected by LIMS. Also, it is not clear if the differences in sensitivity and spatial resolution between the two techniques lead to a similar panel of biomarkers for a given disease. Here, we explore the capabilities of LIMS and HPLC-MS to produce a panel of lipid biomarkers to screen nephrectomy samples from 40 clear cell renal cell carcinoma patients. The same set of samples was explored by both techniques, and despite the important differences between them in terms of the number of detected and identified species (148 by LIMS and 344 by HPLC-MS in negative-ion mode) and the presence/absence of image capabilities, similar conclusions were reached: using the lipid fingerprint, it is possible to set up classifiers that correctly identify the samples as either healthy or tumor samples. The spatial resolution of LIMS enables extraction of additional information, such as the existence of necrotic areas or the existence of different tumor cell populations, but such information does not seem determinant for the correct classification of the samples, or it may be somehow compensated by the higher analytical power of HPLC-MS. Similar conclusions were reached with two very different techniques, validating their use for the discovery of lipid biomarkers.
Transmembrane mucin MUC17 is an integral part of the glycocalyx as it covers the brush border membrane of small intestinal enterocytes and presents an extended
-glycosylated mucin domain to the ...intestinal lumen. Here, we identified two unknown phosphorylated serine residues, S4428 and S4492, in the cytoplasmic tail of human MUC17. We have previously demonstrated that MUC17 is anchored to the apical membrane domain via an interaction with the scaffolding protein PDZK1. S4492, localized in the C-terminal PDZ binding motif of MUC17, was mutated to generate phosphomimetic and phosphodeficient variants of MUC17. Using Caco-2 cells as a model system, we found that induction of an inflammatory state by long-term stimulation with the proinflammatory cytokine TNFα resulted in an increase of MUC17 protein levels and enhanced insertion of MUC17 and its two phospho-variants into apical membranes. Up-regulation and apical insertion of MUC17 was followed by shedding of MUC17-containing vesicles. Transmembrane mucins have previously been shown to play a role in the prevention of bacterial colonization by acting as sheddable decoys for encroaching bacteria. Overexpression and increased presentation at the plasma membrane of wild-type MUC17 and its phosphodeficient variant MUC17 S-4492A protected Caco-2 cells against adhesion of enteropathogenic
, indicating that C-terminal phosphorylation of MUC17 may play a functional role in epithelial cell protection. We propose a new function for MUC17 in inflammation, where MUC17 acts as a second line of defense by preventing attachment of bacteria to the epithelial cell glycocalyx in the small intestine.
Melanoma is the deadliest form of skin cancer due to its ability to colonize distant sites and initiate metastasis. Although these processes largely depend on the lipid-based cell membrane scaffold, ...our understanding of the melanoma lipid phenotype lags behind most other aspects of this tumor cell. Here, we examined a panel of normal human epidermal and nevus melanocytes and primary and metastatic melanoma cell lines to determine whether distinctive cell-intrinsic lipidomes can discern non-neoplastic from neoplastic melanocytes and define their metastatic potential. Lipidome profiles were obtained by UHPLC-ESI mass-spectrometry, and differences in the signatures were analyzed by multivariate statistical analyses. Significant and highly specific changes in more than 30 lipid species were annotated in the initiation of melanoma, whereas less numerous changes were associated with melanoma progression and the non-malignant transformation of nevus melanocytes. Notably, the "malignancy lipid signature" features marked drops in pivotal membrane lipids, like sphingomyelins, and aberrant elevation of ether-type lipids and phosphatidylglycerol and phosphatidylinositol variants, suggesting a previously undefined remodeling of sphingolipid and glycerophospholipid metabolism. Besides broadening the molecular definition of this neoplasm, the different lipid profiles identified may help improve the clinical diagnosis/prognosis and facilitate therapeutic interventions for cutaneous melanoma.
Disruption to routines is an increasingly common part of everyday life. With the roots of some disruptions in the interconnectedness of the world and environmental and socio-political instability, ...there is good reason to believe that conditions that cause widespread disruption will persist. Individuals, communities, and systems are thus challenged to engage in resilience practices to deal with both acute and chronic disruption. Our interest is in chronic, everyday resilience, and the role of both technology and non-technical adaptation practices engaged by individuals and communities, with a specific focus on practices centered in nature. Foregrounding nature's role allows close examination of environmental adversity and nature as part of adaptivity. We add to the CSCW and HCI literature on resilience by examining long-distance hikers, for whom both the sources of adversity and the mitigating resilience processes cut across the social, the technical, and the environmental. In interviews with 12 long-distance hikers we find resilience practices that draw upon technology, writ large, and nature in novel assemblages, and leverage fluid configurations of the individual and the community. We place our findings in the context of a definition for resilience that emphasizes a systems view at multiple scales of social organization. We make three primary contributions: (1) we contribute an empirical account of resilience in a contextual setting that complements prior CSCW resilience studies, (2) we add nuance to existing models for resilience to reflect the role of technology as both a resilience tool and a source of adversity, and (3) we identify the need for new designs that integrate nature into systems as a way to foster collaborative resilience. This nuanced understanding of the role of technology in individual and community resilience in and with nature provides direction for technology design that may be useful for everyday disrupted life.
Background
Information is lacking regarding long-term survival and predictive factors for mortality in patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19) and ...undergoing invasive mechanical ventilation. We aimed to estimate 180-day mortality of patients with COVID-19 requiring invasive ventilation, and to develop a predictive model for long-term mortality.
Methods
Retrospective, multicentre, national cohort study between March 8 and April 30, 2020 in 16 intensive care units (ICU) in Spain. Participants were consecutive adults who received invasive mechanical ventilation for COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection detected in positive testing of a nasopharyngeal sample and confirmed by real time reverse-transcriptase polymerase chain reaction (rt-PCR). The primary outcomes was 180-day survival after hospital admission. Secondary outcomes were length of ICU and hospital stay, and ICU and in-hospital mortality. A predictive model was developed to estimate the probability of 180-day mortality.
Results
868 patients were included (median age, 64 years interquartile range IQR, 56–71 years; 72% male). Severity at ICU admission, estimated by SAPS3, was 56 points IQR 50–63. Prior to intubation, 26% received some type of noninvasive respiratory support. The unadjusted overall 180-day survival rates was 59% (95% CI 56–62%). The predictive factors measured during ICU stay, and associated with 180-day mortality were: age Odds Ratio OR per 1-year increase 1.051, 95% CI 1.033–1.068)), SAPS3 (OR per 1-point increase 1.027, 95% CI 1.011–1.044), diabetes (OR 1.546, 95% CI 1.085–2.204), neutrophils to lymphocytes ratio (OR per 1-unit increase 1.008, 95% CI 1.001–1.016), failed attempt of noninvasive positive pressure ventilation prior to orotracheal intubation (OR 1.878 (95% CI 1.124–3.140), use of selective digestive decontamination strategy during ICU stay (OR 0.590 (95% CI 0.358–0.972) and administration of low dosage of corticosteroids (methylprednisolone 1 mg/kg) (OR 2.042 (95% CI 1.205–3.460).
Conclusion
The long-term survival of mechanically ventilated patients with severe COVID-19 reaches more than 50% and may help to provide individualized risk stratification and potential treatments.
Trial registration
: ClinicalTrials.gov Identifier:
NCT04379258.
Registered 10 April 2020 (retrospectively registered)
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