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The rising prevalence of obesity and metabolic disorders worldwide highlights the urgent need to find new long-term and clinically meaningful weight-loss therapies. Here, we evaluate the therapeutic potential and the mechanism of action of a biomimetic cellulose-based oral superabsorbent hydrogel (OSH). Treatment with OSH exerts effects on intestinal tissue and gut microbiota composition, functioning like a protective dynamic exoskeleton. It protects from gut barrier permeability disruption and induces rapid and consistent changes in the gut microbiota composition, specifically fostering Akkermansia muciniphila expansion. The mechanobiological, physical, and chemical structures of the gel are required for A. muciniphila growth. OSH treatment induces weight loss and reduces fat accumulation, in both preventative and therapeutic settings. OSH usage also prevents liver steatosis, immune infiltration, and fibrosis, limiting the progression of non-alcoholic fatty liver disease. Our work shows the potential of using OSH as a non-systemic mechanobiological approach to treat metabolic syndrome and its comorbidities.
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Dispositivo Exoesqueleto , Enfermedad del Hígado Graso no Alcohólico , Humanos , Hidrogeles/uso terapéutico , Biomimética , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/prevención & control , Obesidad/tratamiento farmacológicoRESUMEN
Recent data have shown that gut microbiota has a major impact on the clinical response to immune checkpoint inhibitors (ICIs) in the context of solid tumors. ICI-based therapy acts by unlocking cognate cytotoxic T lymphocyte (CTL) effector responses, and increased sensitivity to ICIs is due to an enhancement of patients' tumor antigen (TA)-specific CTL responses. Cancer clearance by TA-specific CTL requires expression of relevant TAs on cancer cells' HLA class I molecules, and reduced HLA class I expression is a common mechanism used by cancer cells to evade the immune system. Here, we show that metabolites released by bacteria, in particular, phytosphingosine, can upregulate HLA class I expression on cancer cells, sensitizing them to TA-specific CTL lysis in vitro and in vivo, in combination with immunotherapy. This effect is mediated by postbiotic-induced upregulation of NLRC5 in response to upstream MYD88-NF-κB activation, thus significantly controlling tumor growth.
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The maintenance of intestinal barrier function is essential for preventing different pathologies, such as the leaky gut syndrome (LGS), which is characterized by the passage of harmful agents, like bacteria, toxins, and viruses, into the bloodstream. Intestinal barrier integrity is controlled by several players, including the gut microbiota. Various molecules, called postbiotics, are released during the natural metabolic activity of the microbiota. Postbiotics can regulate host-microbe interactions, epithelial homeostasis, and have overall benefits for our health. In this work, we used in vitro and in vivo systems to demonstrate the role of Lactobacillus paracasei CNCM I-5220-derived postbiotic (LP-PBF) in preserving intestinal barrier integrity. We demonstrated in vitro that LP-PBF restored the morphology of tight junctions (TJs) that were altered upon Salmonella typhimurium exposure. In vivo, LP-PBF protected the gut vascular barrier and blocked S. typhimurium dissemination into the bloodstream. Interestingly, we found that LP-PBF interacts not only with the host cells, but also directly with S. typhimurium blocking its biofilm formation, partially due to the presence of biosurfactants. This study highlights that LP-PBF is beneficial in maintaining gut homeostasis due to the synergistic effect of its different components. These results suggest that LP-PBF could be utilized in managing several pathologies displaying an impaired intestinal barrier function.
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Transcriptional reprogramming plays a key role in drought stress responses, preceding the onset of morphological and physiological acclimation. The best-characterized signal regulating gene expression in response to drought is the phytohormone abscisic acid (ABA). ABA-regulated gene expression, biosynthesis and signaling are highly organized in a diurnal cycle, so that ABA-regulated physiological traits occur at the appropriate time of day. The mechanisms that underpin such diel oscillations in ABA signals are poorly characterized. Here we uncover GIGANTEA (GI) as a key gatekeeper of ABA-regulated transcriptional and physiological responses. Time-resolved gene expression profiling by RNA sequencing under different irrigation scenarios indicates that gi mutants produce an exaggerated ABA response, despite accumulating wild-type levels of ABA. Comparisons with ABA-deficient mutants confirm the role of GI in controlling ABA-regulated genes, and the analysis of leaf temperature, a read-out for transpiration, supports a role for GI in the control of ABA-regulated physiological processes. Promoter regions of GI/ABA-regulated transcripts are directly targeted by different classes of transcription factors (TFs), especially PHYTOCHROME-INTERACTING FACTOR and -BINDING FACTOR, together with GI itself. We propose a model whereby diel changes in GI control oscillations in ABA responses. Peak GI accumulation at midday contributes to establishing a phase of reduced ABA sensitivity and related physiological responses, by gating DNA binding or function of different classes of TFs that cooperate or compete with GI at target regions.
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Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Sequías , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico/genéticaRESUMEN
BACKGROUND AND AIMS: The SARS-CoV-2 pandemic has overwhelmed the treatment capacity of the health care systems during the highest viral diffusion rate. Patients reaching the emergency department had to be either hospitalized (inpatients) or discharged (outpatients). Still, the decision was taken based on the individual assessment of the actual clinical condition, without specific biomarkers to predict future improvement or deterioration, and discharged patients often returned to the hospital for aggravation of their condition. Here, we have developed a new combined approach of omics to identify factors that could distinguish coronavirus disease 19 (COVID-19) inpatients from outpatients. METHODS: Saliva and blood samples were collected over the course of two observational cohort studies. By using machine learning approaches, we compared salivary metabolome of 50 COVID-19 patients with that of 270 healthy individuals having previously been exposed or not to SARS-CoV-2. We then correlated the salivary metabolites that allowed separating COVID-19 inpatients from outpatients with serum biomarkers and salivary microbiota taxa differentially represented in the two groups of patients. RESULTS: We identified nine salivary metabolites that allowed assessing the need of hospitalization. When combined with serum biomarkers, just two salivary metabolites (myo-inositol and 2-pyrrolidineacetic acid) and one serum protein, chitinase 3-like-1 (CHI3L1), were sufficient to separate inpatients from outpatients completely and correlated with modulated microbiota taxa. In particular, we found Corynebacterium 1 to be overrepresented in inpatients, whereas Actinomycetaceae F0332, Candidatus Saccharimonas, and Haemophilus were all underrepresented in the hospitalized population. CONCLUSION: This is a proof of concept that a combined omic analysis can be used to stratify patients independently from COVID-19.
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Currently, there is no therapy targeting septic cardiomyopathy (SC), a key contributor to organ dysfunction in sepsis. In this study, we used a machine learning (ML) pipeline to explore transcriptomic, proteomic, and metabolomic data from patients with septic shock, and prospectively collected measurements of high-sensitive cardiac troponin and echocardiography. The purposes of the study were to suggest an exploratory methodology to identify and characterise the multiOMICs profile of (i) myocardial injury in patients with septic shock, and of (ii) cardiac dysfunction in patients with myocardial injury. The study included 27 adult patients admitted for septic shock. Peripheral blood samples for OMICS analysis and measurements of high-sensitive cardiac troponin T (hscTnT) were collected at two time points during the ICU stay. A ML-based study was designed and implemented to untangle the relations among the OMICS domains and the aforesaid biomarkers. The resulting ML pipeline consisted of two main experimental phases: recursive feature selection (FS) assessing the stability of biomarkers, and classification to characterise the multiOMICS profile of the target biomarkers. The application of a ML pipeline to circulate OMICS data in patients with septic shock has the potential to predict the risk of myocardial injury and the risk of cardiac dysfunction.
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Up to 40% of patients with inflammatory bowel disease present with psychosocial disturbances. We previously identified a gut vascular barrier that controls the dissemination of bacteria from the intestine to the liver. Here, we describe a vascular barrier in the brain choroid plexus (PVB) that is modulated in response to intestinal inflammation through bacteria-derived lipopolysaccharide. The inflammatory response induces PVB closure after gut vascular barrier opening by the up-regulation of the wingless-type, catenin-beta 1 (Wnt/ß-catenin) signaling pathway, rendering it inaccessible to large molecules. In a model of genetically driven closure of choroid plexus endothelial cells, we observed a deficit in short-term memory and anxiety-like behavior, suggesting that PVB closure may correlate with mental deficits. Inflammatory bowel diseaserelated mental symptoms may thus be the consequence of a deregulated gutbrain vascular axis.
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Plexo Coroideo/irrigación sanguínea , Plexo Coroideo/fisiopatología , Colitis Ulcerosa/fisiopatología , Colitis Ulcerosa/psicología , Intestinos/fisiopatología , Trastornos de la Memoria/fisiopatología , Memoria a Corto Plazo , Animales , Ansiedad/etiología , Ansiedad/fisiopatología , Barrera Hematoencefálica/patología , Colitis Ulcerosa/complicaciones , Dextranos , Modelos Animales de Enfermedad , Humanos , Lipopolisacáridos , Trastornos de la Memoria/etiología , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Transducción de Señal , Uniones Estrechas/patología , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
Our latest advances in the field of miniaturized optical PM sensors are presented. This sensor combines a hybrid fluidic-optronic CMOS (holed retina) that is able to record a specific irradiance pattern scattered by an illuminated particle (scattering signature), while enabling the circulation of particles toward the sensing area. The holed retina is optically coupled with a monolithic, millimeter-sized, refracto-reflective optical system. The latter notably performs an optical pre-processing of signatures, with a very wide field of view of scattering angles. This improves the sensitivity of the sensors, and simplifies image processing. We report the precise design methodology for such a sensor, as well as its fabrication and characterization using calibrated polystyrene beads. Finally, we discuss its ability to characterize particles and its potential for further miniaturization and integration.
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Metastasis is facilitated by the formation of a "premetastatic niche," which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence regulator VirF. Upon GVB impairment, bacteria disseminate to the liver, boost the formation of a premetastatic niche, and favor the recruitment of metastatic cells. In training and validation cohorts of CRC patients, we find that the increased levels of PV-1, a marker of impaired GVB, is associated with liver bacteria dissemination and metachronous distant metastases. Thus, PV-1 is a prognostic marker for CRC distant recurrence and vascular impairment, leading to liver metastases.
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Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/patología , Metástasis de la Neoplasia/patología , Recurrencia Local de Neoplasia/patología , Bacterias/aislamiento & purificación , Neoplasias del Colon/irrigación sanguínea , Neoplasias del Colon/patología , Humanos , Hígado/patología , Neoplasias Hepáticas/secundarioRESUMEN
Although chemotherapeutic agents have been used for decades, the mechanisms of action, mechanisms of resistance, and the best treatment schedule remain elusive. Mitomycin C (MMC) is the gold standard treatment for non-muscle-invasive bladder cancer (NMIBC). However, it is effective only in a subset of patients, suggesting that, aside from cytotoxicity, other mechanisms could be involved in mediating the success of the treatment. Here, we showed that MMC promotes immunogenic cell death (ICD) and in vivo tumor protection. MMC-induced ICD relied on metabolic reprogramming of tumor cells toward increased oxidative phosphorylation. This favored increased mitochondrial permeability leading to the cytoplasmic release of mitochondrial DNA, which activated the inflammasome for efficient IL-1ß (interleukin-1ß) secretion that promoted dendritic cell maturation. Resistance to ICD was associated with mitochondrial dysfunction related to low abundance of complex I of the respiratory chain. Analysis of complex I in patient tumors indicated that low abundance of this mitochondrial complex was associated with recurrence incidence after chemotherapy in patients with NMIBC. The identification of mitochondria-mediated ICD as a mechanism of action of MMC offers opportunities to optimize bladder cancer management and provides potential markers of treatment efficacy that could be used for patient stratification.
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Neoplasias de la Vejiga Urinaria , Administración Intravesical , Antibióticos Antineoplásicos/uso terapéutico , Humanos , Muerte Celular Inmunogénica , Mitocondrias , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
PURPOSE: The dogma that urine is sterile has been overturned and dysbiosis of the urinary microbiome has been linked to many urological disorders. We tested the hypothesis that the urinary microbial composition may be different between men with or without bladder cancer in catheter collected urines, bladder washouts and midstream voided urines, and may be dependent on tumor staging. MATERIALS AND METHODS: Liquid samples were collected from male patients with bladder cancer, and sex and age matched nonneoplastic controls. Total DNA was extracted and processed for 16S rRNA gene sequencing. Bioinformatic analysis for microbial classification was performed to assess diversity and variations. RESULTS: The urinary microbiome associated with catheter collected urine samples of patients with bladder cancer was characterized by a significantly increased abundance of Veillonella (p=0.04) and Corynebacterium (p=0.03), and decreased Ruminococcus (p=0.03) compared to controls, with differences exacerbating with disease progression. Compared to catheterized urines, bladder cancer washouts showed the specific increase of some taxa, like Burkholderiaceae (p=0.014), whereas midstream urines were enriched in Streptococcus (p <0.0001), Enterococcus (p <0.0001), Corynebacterium (p=0.038) and Fusobacterium (p <0.0001). CONCLUSIONS: The bladder is colonized by endogenous bacteria and microbial modifications characterize the microbiome of patients with bladder cancer. Different microbial compositions can be characterized by changing sampling strategy. These results pave the way for exploring new diagnostic and therapeutic options based on the manipulation of the bacterial community.
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Disbiosis/diagnóstico , Microbiota/genética , Neoplasias de la Vejiga Urinaria/orina , Vejiga Urinaria/microbiología , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , ADN Bacteriano/aislamiento & purificación , Disbiosis/microbiología , Disbiosis/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , ARN Ribosómico 16S/genética , Urinálisis/métodos , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/microbiología , Neoplasias de la Vejiga Urinaria/patología , Cateterismo Urinario/métodosRESUMEN
Mother's milk is the best choice for infants nutrition, however when it is not available or insufficient to satisfy the needs of the infant, formula is proposed as an effective substitute. Here, we report the results of a randomized controlled clinical trial (NCT03637894) designed to evaluate the effects of two different dietary regimens (standard formula and Lactobacillus paracasei CBA L74-fermented formula) versus breastfeeding (reference group) on immune defense mechanisms (primary endpoint: secretory IgA, antimicrobial peptides), the microbiota and its metabolome (secondary outcomes), in healthy full term infants according to the type of delivery (n = 13/group). We show that the fermented formula, safe and well tolerated, induces an increase in secretory IgA (but not in antimicrobial peptides) and reduces the diversity of the microbiota, similarly, but not as much as, breastmilk. Metabolome analysis allowed us to distinguish subjects based on their dietary regimen and mode of delivery. Together, these results suggest that a fermented formula favors the maturation of the immune system, microbiota and metabolome.
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Dieta , Sistema Inmunológico/fisiología , Metaboloma/fisiología , Microbiota/fisiología , Péptidos Catiónicos Antimicrobianos/metabolismo , Lactancia Materna , Método Doble Ciego , Heces/microbiología , Femenino , Fermentación , Humanos , Inmunoglobulina A Secretora/metabolismo , Fórmulas Infantiles , Recién Nacido , Lacticaseibacillus paracasei/metabolismo , Masculino , Leche Humana , beta-Defensinas/metabolismo , CatelicidinasRESUMEN
Rubinstein-Taybi syndrome (RSTS) is a rare multisystem developmental disorder with moderate to severe intellectual disability caused by heterozygous mutations of either CREBBP or EP300 genes encoding CBP/p300 chromatin regulators. We explored the gene programs and processes underlying the morphological and functional alterations shown by iPSC-derived neurons modeling RSTS to bridge the molecular changes resulting from defective CBP/p300 to cognitive impairment. By global transcriptome analysis, we compared the differentially expressed genes (DEGs) marking the transition from iPSC-derived neural progenitors to cortical neurons (iNeurons) of five RSTS patients carrying private CREBBP/EP300 mutations and manifesting differently graded neurocognitive signs with those of four healthy controls. Our data shows a defective and altered neuroprogenitor to neuron transcriptional program in the cells from RSTS patients. First, transcriptional regulation is weaker in RSTS as less genes than in controls are modulated, including genes of key processes of mature functional neurons, such as those for voltage-gated channels and neurotransmitters and their receptors. Second, regulation is subverted as genes acting at pre-terminal stages of neural differentiation in cell polarity and adhesive functions (members of the cadherin family) and axon extension/guidance (members of the semaphorins and SLIT receptors families) are improperly upregulated. Impairment or delay of RSTS neuronal differentiation program is also evidenced by decreased modulation of the overall number of neural differentiation markers, significantly impacting the initial and final stages of the differentiation cascade. Last, extensive downregulation of genes for RNA/DNA metabolic processes confirms that RSTS is a global transcription disorder, consistent with a syndrome driven by chromatin dysregulation. Interestingly, the morphological and functional alterations we have previously appointed as biomarkers of RSTS iNeurons provide functional support to the herein designed transcriptome profile pointing to key dysregulated neuronal genes as main contributors to patients' cognitive deficit. The impact of RSTS transcriptome may go beyond RSTS as comparison of dysregulated genes across modeled neurodevelopmental disorders could unveil convergent genes of cognitive impairment.
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Diferenciación Celular/genética , Perfilación de la Expresión Génica , Células Madre Pluripotentes Inducidas/patología , Neuronas/metabolismo , Neuronas/patología , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patología , Animales , Biomarcadores/metabolismo , Estudios de Casos y Controles , Línea Celular , Corteza Cerebral/patología , Regulación de la Expresión Génica , Ontología de Genes , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Modelos Biológicos , Donantes de TejidosRESUMEN
Semiconductor nanoplatelets exhibit spectrally pure, directional fluorescence. To make polarized light emission accessible and the charge transport effective, nanoplatelets have to be collectively oriented in the solid state. We discovered that the collective nanoplatelets orientation in monolayers can be controlled kinetically by exploiting the solvent evaporation rate in self-assembly at liquid interfaces. Our method avoids insulating additives such as surfactants, making it ideally suited for optoelectronics. The monolayer films with controlled nanoplatelets orientation (edge-up or face-down) exhibit long-range ordering of transition dipole moments and macroscopically polarized light emission. Furthermore, we unveil that the substantial in-plane electronic coupling between nanoplatelets enables charge transport through a single nanoplatelets monolayer, with an efficiency that strongly depends on the orientation of the nanoplatelets. The ability to kinetically control the assembly of nanoplatelets into ordered monolayers with tunable optical and electronic properties paves the way for new applications in optoelectronic devices.
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BACKGROUND: Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock. METHODS: We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock. RESULTS: In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend. CONCLUSIONS: This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02141607. Registered 19 May 2014.
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Perfilación de la Expresión Génica/métodos , Choque Cardiogénico/sangre , Choque Séptico/sangre , APACHE , Anciano , Anciano de 80 o más Años , Alarminas/análisis , Alarminas/sangre , Análisis de Varianza , Bélgica , Replicación del ADN/fisiología , Femenino , Perfilación de la Expresión Génica/instrumentación , Humanos , Inflamasomas/análisis , Inflamasomas/sangre , Unidades de Cuidados Intensivos/organización & administración , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Receptores de Interleucina/análisis , Receptores de Interleucina/sangre , Receptores de Reconocimiento de Patrones/análisis , Receptores de Reconocimiento de Patrones/sangre , Análisis de Secuencia de ARN/métodos , Choque Cardiogénico/fisiopatología , Choque Séptico/fisiopatología , SuizaRESUMEN
BACKGROUND: Septic shock is the most severe complication of sepsis and this syndrome is associated with high mortality. Treatment of septic shock remains largely supportive of hemodynamics and tissue perfusion. Early changes in organ function assessed by the Sequential Organ Function Assessment (SOFA) score are highly predictive of the outcome. However, the individual patient's response to supportive therapy is very heterogeneous, and the mechanisms underlying this variable response remain elusive. The aim of the study was to investigate the transcriptome of whole blood in septic shock patients with different responses to early supportive hemodynamic therapy assessed by changes in SOFA scores within the first 48 h from intensive care unit (ICU) admission. METHODS: We performed whole blood RNA sequencing in 31 patients: 17 classified as responders (R) and 14 as non-responders (NR). Gene expression was investigated at ICU admission (time point 1, or T1), comparing R with NR [padj < 0.01; Benjamini-Hochberg (BH)] and over time from T1 to T2 (48 h later) in R and NR independently (paired analysis, padj < 0.01; BH). Then the differences in gene expression trends over time were evaluated (Mann-Whitney, P <0.01). To identify enriched biological processes, we performed an over-representation analysis based on a right-sided hypergeometric test with Bonferroni step-down as multiple testing correction (padj < 0.05). RESULTS: At ICU admission, we did not identify differentially expressed genes (DEGs) between the two groups. In the transition from T1 to T2, the activation of genes involved in T cell-mediated immunity, granulocyte and natural killer (NK) cell functions, and pathogen lipid clearance was noted in the R group. Genes involved in acute inflammation were downregulated in both groups. CONCLUSIONS: Within the limits of a small sample size, our results could suggest that early activation of genes of the adaptive immune response is associated with an improvement in organ function.
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Choque Séptico/terapia , Transcriptoma/fisiología , APACHE , Adulto , Anciano , Anciano de 80 o más Años , Bélgica , Femenino , Humanos , Unidades de Cuidados Intensivos/organización & administración , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Choque Séptico/fisiopatología , Estadísticas no Paramétricas , SuizaRESUMEN
Upconversion is a photon-management process especially suited to water-splitting cells that exploit wide-bandgap photocatalysts. Currently, such catalysts cannot utilize 95% of the available solar photons. We demonstrate here that the energy-conversion yield for a standard photocatalytic water-splitting device can be enhanced under solar irradiance by using a low-power upconversion system that recovers part of the unutilized incident sub-bandgap photons. The upconverter is based on a sensitized triplet-triplet annihilation mechanism (sTTA-UC) obtained in a dye-doped elastomer and boosted by a fluorescent nanocrystal/polymer composite that allows for broadband light harvesting. The complementary and tailored optical properties of these materials enable efficient upconversion at subsolar irradiance, allowing the realization of the first prototype water-splitting cell assisted by solid-state upconversion. In our proof-of concept device the increase of the performance is 3.5%, which grows to 6.3% if concentrated sunlight (10 sun) is used. Our experiments show how the sTTA-UC materials can be successfully implemented in technologically relevant devices while matching the strict requirements of clean-energy production.
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Beyond the physiology of reproduction, estrogen controls the homeostasis of several tissues. Although macrophages play a key role in tissue remodeling, the interplay with estrogen is still ill defined. Using a transcriptomic approach we first obtained a comprehensive list of genes that are differentially expressed in peritoneal macrophages in response to physiological levels of 17ß-estradiol (E2) injected in intact female mice. Our data also showed the dynamic nature of the macrophage response to E2 and pointed to specific biological programs induced by the hormone, with cell proliferation, immune response and wound healing being the most prominent functional categories. Indeed, the exogenous administration of E2 and, more importantly, the endogenous hormonal surge proved to support macrophage proliferation in vivo, as shown by cell cycle gene expression, BrdU incorporation and cell number. Furthermore, E2 promoted an anti-inflammatory and pro-resolving macrophage phenotype, which converged on the induction of genes related to macrophage alternative activation and on IL-10 expression in vivo. Hormone action was maintained in an experimental model of peritoneal inflammation based on zymosan injection. These findings highlight a direct effect of estrogen on macrophage expansion and phenotypic adaptation in homeostatic conditions and suggest a role for this interplay in inflammatory pathologies.
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Estradiol/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Peritonitis/tratamiento farmacológico , Transcriptoma , Proteína 4 Similar a la Angiopoyetina/genética , Proteína 4 Similar a la Angiopoyetina/inmunología , Animales , Arginasa/genética , Arginasa/inmunología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/inmunología , Proliferación Celular/efectos de los fármacos , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Inmunidad Innata , Interleucina-10/genética , Interleucina-10/inmunología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/patología , Ratones , Ratones Endogámicos C57BL , Ovariectomía , Peritonitis/inducido químicamente , Peritonitis/inmunología , Peritonitis/patología , Fenotipo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/inmunología , ZimosanRESUMEN
Myofibrillar myopathies (MFMs) are genetically heterogeneous dystrophies characterized by the disintegration of Z-disks and myofibrils and are associated with mutations in genes encoding Z-disk or Z-disk-related proteins. The c.626 C > T (p.P209L) mutation in the BAG3 gene has been described as causative of a subtype of MFM. We report a sporadic case of a 26-year-old Italian woman, affected by MFM with axonal neuropathy, cardiomyopathy, rigid spine, who carries the c.626 C > T mutation in the BAG3 gene. The patient and her non-consanguineous healthy parents and brother were studied with whole exome sequencing (WES) to further investigate the genetic basis of this complex phenotype. In the patient, we found that the BAG3 mutation is associated with variants in the NRAP and FHL1 genes that encode muscle-specific, LIM domain containing proteins. Quantitative real time PCR, immunohistochemistry and Western blot analysis of the patient's muscular biopsy showed the absence of NRAP expression and FHL1 accumulation in aggregates in the affected skeletal muscle tissue. Molecular dynamic analysis of the mutated FHL1 domain showed a modification in its surface charge, which could affect its capability to bind its target proteins. To our knowledge this is the first study reporting, in a BAG3 MFM, the simultaneous presence of genetic variants in the BAG3 and FHL1 genes (previously described as independently associated with MFMs) and linking the NRAP gene to MFM for the first time.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas con Dominio LIM/genética , Proteínas Musculares/genética , Miopatías Estructurales Congénitas/genética , Adulto , Exoma , Femenino , Humanos , Italia , TransfecciónRESUMEN
BACKGROUND: Paraoxonase 1 (PON1) gene polymorphisms and polyphenols intake have been reported independently associated to lipid profile and susceptibility to atherosclerosis and cardiovascular disease. However, the interaction between these factors remains to be investigated. We performed an observational nutrigenetic study to examine whether the interaction between polyphenols and anthocyanins intake and PON1 genetic variants can modulate biomarkers of cardiovascular health in an Italian healthy population. METHODS: We recruited 443 healthy volunteers who participated in the EC funded ATHENA project (AnThocyanin and polyphenols bioactive for Health Enhancement through Nutritional Advancement). Data collection included detailed demographic, clinical, dietary, lifestyle, biochemical and genetic data. Polyphenols and anthocyanins intake was measured by 24 h dietary recall repeated three times a year in order to get seasonal variations. We tested the interaction between 18 independent tagging SNPs in PON1 gene and polyphenols intake on HDL, LDL, cholesterol, triglycerides and atherogenic index of plasma. RESULTS: Without considering the genetic background, we could not observe significant differences in the lipid profile between high and low polyphenols and anthocyanins intake. Using a nutrigenetic approach, we identified protective genotypes in four independent polymorphisms that, at Bonferroni level (p ≤ 0.0028), present a significant association with increased HDL level under high polyphenols and anthocyanins intake, compared to risk genotypes (rs854549, Beta = 4.7 per C allele; rs854552, Beta = 5.6 per C allele; rs854571, Beta = 3.92 per T allele; rs854572, Beta = 3.94 per C allele). CONCLUSIONS: We highlight the protective role of genetic variants in PON1 towards cardiovascular risk under high polyphenols and anthocyanins consumption. PON1 variants could represent novel biomarkers to stratify individuals who might benefit from targeted dietary recommendation for health promotion and strategies of preventive medicine.