Myeloid cells in vascular dementia and Alzheimer's disease: Possible therapeutic targets?

Growing evidence supports the suggestion that the peripheral immune system plays a role in different pathologies associated with cognitive impairment, such as vascular dementia (VD) or Alzheimer's disease (AD). The aim of this review is to summarize, within the peripheral immune system, the implications of different types of myeloid cells in AD and VD, with a special focus on post-stroke cognitive impairment and dementia (PSCID). We will review the contributions of the myeloid lineage, from peripheral cells (neutrophils, platelets, monocytes and monocyte-derived macrophages) to central nervous system (CNS)-associated cells (perivascular macrophages and microglia). Finally, we will evaluate different potential strategies for pharmacological modulation of pathological processes mediated by myeloid cell subsets, with an emphasis on neutrophils, their interaction with platelets and the process of immunothrombosis that triggers neutrophil-dependent capillary stall and hypoperfusion, as possible effector mechanisms that may pave the way to novel therapeutic avenues to stop dementia, the epidemic of our time. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Antarctic Soil Yeasts with Fermentative Capacity and Potential for the Wine Industry.

Low fermentation temperatures are usually employed to obtain high-quality wines. This is especially interesting for white wine production since it prevents the loss of volatile compounds and a browning appearance; however, available fermentative yeasts do not usually tolerate low temperatures. Therefore, an interesting place to find new yeasts with cryotolerance is the Antarctic continent. From soil samples collected in Antarctica, 125 yeasts were isolated, of which 25 exhibited fermentative activity at 10 °C. After a fingerprinting assay, we classified the candidates into nine isotypes and sequenced internal transcribed spacer regions for their identification. These yeasts were identified as part of the Mrakia genus. Sugar and alcohol tolerance tests showed that some of these Antarctic soil yeasts were able to grow up to 9% alcohol, and 25% sugar was reached; however, they exhibited longer latency periods compared to the control Saccharomyces cerevisiae. The optimal growing temperature for the isolated Antarctic yeasts was between 10 °C and 15 °C. A comprehensive analysis of the results obtained showed that the isolates 10M3-1, 4M3-6, and 4B1-35 could be good candidates for fermentation purposes due to their alcohol, sugar tolerance, and growth features. Our results prove that it is possible to isolate fermentative yeasts from Antarctic soil with promising characteristics for their potential use in the wine production industry.

Pangenome Reconstruction of Mycobacterium tuberculosis as a Guide to Reveal Genomic Features Associated with Strain Clinical Phenotype.

Tuberculosis (TB) is one of the leading causes of human deaths worldwide caused by infectious diseases. TB infection by Mycobacterium tuberculosis can occur in the lungs, causing pulmonary tuberculosis (PTB), or in any other organ of the body, resulting in extrapulmonary tuberculosis (EPTB). There is no consensus on the genetic determinants of this pathogen that may contribute to EPTB. In this study, we constructed the M. tuberculosis pangenome and used it as a tool to seek genomic signatures associated with the clinical presentation of TB based on its accessory genome differences. The analysis carried out in the present study includes the raw reads of 490 M. tuberculosis genomes (PTB n = 245, EPTB n = 245) retrieved from public databases that were assembled, as well as ten genomes from Mexican strains (PTB n = 5, EPTB n = 5) that were sequenced and assembled. All genomes were annotated and then used to construct the pangenome with Roary and Panaroo. The pangenome obtained using Roary consisted of 2231 core genes and 3729 accessory genes. On the other hand, the pangenome resulting from Panaroo consisted of 2130 core genes and 5598 accessory genes. Associations between the distribution of accessory genes and the PTB/EPTB phenotypes were examined using the Scoary and Pyseer tools. Both tools found a significant association between the hspR, plcD, Rv2550c, pe_pgrs5, pe_pgrs25, and pe_pgrs57 genes and the PTB genotype. In contrast, the deletion of the aceA, esxR, plcA, and ppe50 genes was significantly associated with the EPTB phenotype. Rv1759c and Rv3740 were found to be associated with the PTB phenotype according to Scoary; however, these associations were not observed when using Pyseer. The robustness of the constructed pangenome and the gene-phenotype associations is supported by several factors, including the analysis of a large number of genomes, the inclusion of the same number of PTB/EPTB genomes, and the reproducibility of results thanks to the different bioinformatic tools used. Such characteristics surpass most of previous M. tuberculosis pangenomes. Thus, it can be inferred that the deletion of these genes can lead to changes in the processes involved in stress response and fatty acid metabolism, conferring phenotypic advantages associated with pulmonary or extrapulmonary presentation of TB. This study represents the first attempt to use the pangenome to seek gene-phenotype associations in M. tuberculosis.

Identification of antarctic soil bacteria exhibiting antiproliferative activity against a colon cancer cell line / Identificación de bacterias de suelo antártico que presentan actividad antiproliferativa sobre una línea celular de cáncer de colon

SUMMARY: Cancer is the second leading cause of death in the world and colorectal cancer is the only cancer that has shown a sustained increase in mortality in the last decade. In the search for new chemotherapeutic agents against cancer, extremophilic microorganisms have shown to be a potential source to obtain molecules of natural origin and with selective cytotoxic action towards cancer cells. In this work we analyzed the ability of a collection of Antarctic soil bacteria, isolated on Collins Glacier from the rhizosphere of Deschampsia antarctica Desv plant, to secrete molecules capable of inhibiting cell proliferation of a colorectal cancer tumor line. Our results demonstrated that culture supernatants from the Antarctic bacteria K2I17 and MI12 decreased the viability of LoVo cells, a colorectal adenocarcinoma cell line. Phenotypic and genotypic characterization of the Antarctic bacteria showed that they were taxonomically related and nucleotide identity analysis based on the 16S rRNA gene sequence identified the bacterium K2I17 as a species belonging to the genus Bacillus.

El cáncer es la segunda causa de muerte en el mundo y el cáncer colorrectal es el único que presenta un aumento sostenido de la mortalidad en la última década. En la búsqueda de nuevos agentes quimioterapeúticos contra el cáncer, se ha propuesto a los microorganismos extremófilos como una fuente potencial para obtener moléculas de origen natural y con acción citotóxica selectiva hacia las células cancerígenas. En este trabajo analizamos la capacidad de una colección de bacterias de suelo antártico, aisladas en el glaciar Collins desde rizosfera de la planta de Deschampsia antarctica Desv, de secretar moléculas capaces de inhibir la proliferación celular de una línea tumoral de cáncer colorrectal. Nuestros resultados demostraron que los sobrenadantes de cultivo de las bacterias antárticas K2I17 y MI12 disminuyeron la viabilidad de la línea celular de adenocarcinoma colorrectal LoVo, en un ensayo de reducción metabólica de MTT. La caracterización fenotípica y genotípica de las bacterias antárticas, demostró que estaban relacionadas taxonómicamente y el análisis de la identidad nucleotídica en base a la secuencia del gen ARNr 16S identificó a la bacteria K2I17 como una especie perteneciente al género Bacillus.

Tumor Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6): A Promising Immunomodulatory Target in Acute Neurodegenerative Diseases.

Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), the first soluble chemokine-binding protein to be identified in mammals, inhibits chemotaxis and transendothelial migration of neutrophils and attenuates the inflammatory response of dendritic cells, macrophages, monocytes, and T cells. This immunoregulatory protein is a pivotal mediator of the therapeutic efficacy of mesenchymal stem/stromal cells (MSC) in diverse pathological conditions, including neuroinflammation. However, TSG-6 is also constitutively expressed in some tissues, such as the brain and spinal cord, and is generally upregulated in response to inflammation in monocytes/macrophages, dendritic cells, astrocytes, vascular smooth muscle cells and fibroblasts. Due to its ability to modulate sterile inflammation, TSG-6 exerts protective effects in diverse degenerative and inflammatory diseases, including brain disorders. Emerging evidence provides insights into the potential use of TSG-6 as a peripheral diagnostic and/or prognostic biomarker, especially in the context of ischemic stroke, whereby the pathobiological relevance of this protein has also been demonstrated in patients. Thus, in this review, we will discuss the most recent data on the involvement of TSG-6 in neurodegenerative diseases, particularly focusing on relevant anti-inflammatory and immunomodulatory functions. Furthermore, we will examine evidence suggesting novel therapeutic opportunities that can be afforded by modulating TSG-6-related pathways in neuropathological contexts and, most notably, in stroke.

Frecuencia de y cesáreas en establecimientos públicos y privados de la Provincia de Concepción, Chile, 2001-2019 / Caesareans section frequency in public and private establishments of the Province of Concepción, Chile, 2001-2019

Introducción: El porcentaje nacional de cesárea supera las recomendaciones internacionales, alcanzando altos niveles, con consecuencias significativas en la salud de la mujer. Por esta razón es un problema necesario de analizar. Objetivo: Describir la situación epidemiológica de las cesáreas en la Provincia de Concepción, periodo 2001-2019, según establecimiento y previsión. Material y métodos: Estudio observacional, descriptivo, ecológico, transversal. Incluye universo de partos en la Provincia de Concepción 2001-2019, datos del Departamento de Estadísticas e Información de Salud (DEIS). Recopilación y análisis según técnicas descriptivas en Microsoft Excel® Resultados: En establecimientos públicos, el número de partos disminuyó un 60.6%. En establecimientos privados aumentó 4.8 veces, junto al 39% de incremento en las cesáreas. Las pacientes pertenecientes al grupo A de menores ingresos de la aseguradora de salud pública, Fondo Nacional de Salud (FONASA), presentaron un porcentaje estable de cesáreas, en torno al 25%, mientras que el grupo D (de mayores ingresos) aumentó un 47.8% entre los años 2005 y 2009. Entre 2002 y 2019 el porcentaje promedio de cesáreas de pacientes pertenecientes a las aseguradoras privadas, Instituciones de Salud Previsional (ISAPRE), fue del 66.5%. Conclusiones: Se observó un aumento de cesáreas muy especialmente en recintos privados. La previsión de salud es un factor que considerar, particularmente el grupo FONASA-D, que presentó la mayor alza en las cesáreas, incluso más que las gestantes de ISAPRE. El porcentaje alarmante de cesáreas, especialmente en establecimientos privados, debe ser preocupación prioritaria para nuestro sistema de salud.

Introduction: The national caesarean section rate exceeds international recommendations, reaching elevated levels, with significant consequences on women's health. For this reason it is a necessary problem to analyze. Objective: To describe the epidemiological situation of caesarean sections in the Province of Concepción, period 2001-2019, according to establishment and forecast. Material and methods: Observational, descriptive, ecological, longitudinal study. Includes universe of births in the Province of Concepción 2001-2019, data from the Department of Statistics and Health Information (DEIS). Collection and analysis according to descriptive techniques in Microsoft Excel®. Results: In public establishments, the number of deliveries decreased by 60.6%. In private establishments it increased 4.8 times, together with the 39% increase in cesarean sections. Patients belonging to group A with the lowest income of the public health insurer, National Health Fund (FONASA), presented a stable percentage of caesarean sections, around 25%, while group D (with the highest income) increased 47.8% between 2005 and 2009. Between 2002 and 2019, the average percentage of caesarean sections of patients belonging to private insurers, Institutions of Social Security (ISAPRE), was 66.5%. Conclusions: An increase in caesarean sections was observed, especially in private facilities. Health insurance is a factor to consider, particularly the FONASA-D group, which presented the highest increase in cesarean sections, even more than ISAPRE pregnant women. The alarming percentage of caesarean sections, especially in private establishments, should be a priority concern for our health system.

Citotoxicidad in vitro del polipéptido antimicrobiano nisina sobre células tumorales sanguíneas / In vitro cytotoxicity of the antimicrobial polypeptide nisin on blood tumor cells

RESUMEN: Las bacteriocinas son péptidos antimicrobianos de síntesis ribosomal secretadas por bacterias. Dentro de estas destaca nisina que posee potenciales usos en terapias antibióticas, como biopreservante de alimentos y probióticos. También se ha descrito que nisina posee citotoxicidad sobre líneas celulares neoplásicas, pero existe poca información de su efecto sobre células tumorales sanguíneas. Debido al potencial uso que presenta nisina, es relevante determinar la toxicidad que presenta sobre líneas celulares tumorales del tipo sanguíneo. Para esto, se realizaron ensayos de actividad hemolítica sobre eritrocitos humanos y de toxicidad sobre células mononucleares de sangre periférica humanas, determinándose que nisina no posee efecto citotóxico sobre este tipo de células normales humanas sanguíneas. Se realizaron también, ensayos de citotoxicidad con líneas celulares tumorales (K562 y U937), con el fin de determinar dosis, tiempo de exposición y selectividad en el efecto tóxico de nisina sobre las células tumorales humanas. Estos ensayos muestran que nisina presenta actividad citotóxica sobre líneas celulares K562 y U937 a las 72 h de exposición, a una concentración de 40 µg/mL, que corresponde a 100 veces la concentración mínima inhibitoria (MIC) usada para su acción sobre bacterias. Al comparar el efecto de nisina sobre células mononucleares de sangre periférica humanas con las líneas tumorales linfoides y mieloides (K562 y U937 respectivamente), se observa un efecto selectivo de nisina sobre las células tumorales sanguíneas.

SUMMARY: Bacteriocins are antimicrobial peptides of ribosomal synthesis secreted by bacteria. Among these, nisin stands out, which has potential uses in antibiotic therapies, as a food bio preservative and probiotics. Nisin has also been reported to have cytotoxicity on neoplastic cell lines, but there is little information on its effect on blood tumor cells. Due to the potential use that nisin presents, it is relevant to determine the toxicity it presents on tumor cell lines of the blood type. For this, hemolytic activity tests were carried out on human erythrocytes and toxicity on human peripheral blood mononuclear cells, determining that nisin does not have a toxic effect on this type of normal human blood cells. Cytotoxicity tests were also carried out with tumor cell lines (K562 and U937), to determine dose, exposure time and selectivity in the toxic effect of nisin on human tumor cells. These tests show that nisin shows cytotoxic activity on K562 and U937 cell lines at 72 h of exposure, at a concentration of 40 µg / mL, which corresponds to 100 times the minimum inhibitory concentration (MIC) used for its action on bacteria. When comparing the effect of nisin on human peripheral blood mononuclear cells with lymphoid and myeloid tumor lines (K562 and U937 respectively), a selective effect of nisin on blood tumor cells is observed.

Incidence, risk factors, prognosis, and health-related quality of life after stroke in a low-resource community in Chile (ÑANDU): a prospective population-based study.

BACKGROUND: Stroke is a leading cause of disability and death worldwide. The best estimates of local, national, and global burden of stroke are derived from prospective population-based studies. We aimed to investigate the incidence, risk factors, long-term prognosis, care, and quality of life after stroke in the Ñuble region of Chile. METHODS: We did a prospective community-based study with use of multiple overlapping sources of hospitalised, ambulatory, and deceased cases. Standardised diagnostic criteria were used to identify and follow up all cases occurring in the resident population of the Ñuble region, Chile (in a low-income rural-urban population including predominantly people of Indigenous-European heritage), for 1 year. Participants were included if they had a clinical diagnosis of stroke confirmed according to the study criteria. All cases were adjudicated by vascular neurologists. Incidence rates of first-ever stroke were calculated from the population of Ñuble according to the 2017 national census. FINDINGS: From April 1, 2015, to March 31, 2016, we ascertained 1103 stroke cases, of which 890 (80·7%) were first-ever incident cases. The mean age of patients with first-ever stroke was 70·3 years (SD 14·1) and 443 (49·8%) were women. A CT scan was obtained in 801 (90%) of 890 patients (mean time from symptom onset to scan of 13·4 h (SD 29·8). The incidence of first-ever stroke age-adjusted to the world population was 121·7 (95% CI 113·7-130·1) per 100 000. The age-adjusted incidence rates, per 100 000 inhabitants, by main pathological subtypes were as follows: ischaemic stroke (101·5 [95% CI 90·9-113·0]); intracerebral haemorrhage (17·9 [13·5-23·4]), and subarachnoid haemorrhage (4·2 [2·1-7·3]). The 30-day case-fatality rate was 24·6% (21·9-27·6). At 6 months after the stroke, 55·9% (432 of 773) of cases had died or were disabled, which increased to 61·0% (456 of 747) at 12 months. Health-related quality of life in survivors was low at 6 months, improving slightly at 12 months after the stroke. INTERPRETATION: The incidence of stroke in this low-resource population was higher than our previous finding in northern Chile and within the mid-range of most population-based stroke studies. This result was due mainly to a higher incidence of ischaemic stroke, probably associated with increasing age and a high prevalence of cardiometabolic risk factors in the population studied. Our findings suggest that more should be done for the prevention and care of stroke in communities like the Ñuble population. FUNDING: The National Agency for Research and Development and the Technology-Health Research Fund, Clínica Alemana de Santiago, Boehringer Ingelheim, Bristol Meyers Squibb, The Herminda Martin Clinical Hospital of Chillán, Universidad Mayor, and Universidad de Concepción.

In Situ Rhizosphere Microbiome in Antarctic Vascular Plants, Modulated by Soil Condition.

Antarctic soils are considered young soils; therefore, the microbiota associated with Antarctic vascular plants play a critical role in their productivity. In this research, we compared the microbiota from three different soil conditions using a 16S rRNA and internal transcribed spacer rRNA gene amplicon approach for bacterial and fungal communities.

Decoding Gene Networks Modules That Explain the Recovery of Hymenoglossum cruentum Cav. After Extreme Desiccation.

Hymenoglossum cruentum (Hymenophyllaceae) is a poikilohydric, homoiochlorophyllous desiccation-tolerant (DT) epiphyte fern. It can undergo fast and frequent dehydration-rehydration cycles. This fern is highly abundant at high-humidity/low-light microenvironments within the canopy, although rapid changes in humidity and light intensity are frequent. The objective of this research is to identify genes associated to desiccation-rehydration cycle in the transcriptome of H. cruentum to better understand the genetic dynamics behind its desiccation tolerance mechanism. H. cruentum plants were subjected to a 7 days long desiccation-rehydration process and then used to identify key expressed genes associated to its capacity to dehydrate and rehydrate. The relative water content (RWC) and maximum quantum efficiency (F v/F m) of H. cruentum fronds decayed to 6% and 0.04, respectively, at the end of the desiccation stage. After re-watering, the fern showed a rapid recovery of RWC and F v/F m (ca. 73% and 0.8, respectively). Based on clustering and network analysis, our results reveal key genes, such as UBA/TS-N, DYNLL, and LHC, orchestrating intracellular motility and photosynthetic metabolism; strong balance between avoiding cell death and defense (CAT3, AP2/ERF) when dehydrated, and detoxifying pathways and stabilization of photosystems (GST, CAB2, and ELIP9) during rehydration. Here we provide novel insights into the genetic dynamics behind the desiccation tolerance mechanism of H. cruentum.

A comparative gene co-expression analysis using self-organizing maps on two congener filmy ferns identifies specific desiccation tolerance mechanisms associated to their microhabitat preference.

BACKGROUND: Filmy-ferns (Hymenophyllaceae) are poikilohydric, homoiochlorophyllous desiccation-tolerant (DT) epiphytes. They can colonize lower and upper canopy environments of humid forest. Filmy-ferns desiccate rapidly (hours), contrasting with DT angiosperms (days/weeks). It has been proposed that desiccation tolerance in filmy-ferns would be associated mainly with constitutive features rather than induced responses during dehydration. However, we hypothesize that the inter-specific differences in vertical distribution would be associated with different dynamics of gene expression within the dehydration or rehydration phases. A comparative transcriptomic analysis with an artificial neural network was done on Hymenophyllum caudiculatum (restricted to lower canopy) and Hymenophyllum dentatum (reach upper canopy) during a desiccation/rehydration cycle. RESULTS: Raw reads were assembled into 69,599 transcripts for H. dentatum and 34,726 transcripts for H. caudiculatum. Few transcripts showed significant changes in differential expression (DE). H. caudiculatum had ca. twice DE genes than H. dentatum and higher proportion of increased-and-decreased abundance of genes occurs during dehydration. In contrast, the abundance of genes in H. dentatum decreased significantly when transitioning from dehydration to rehydration. According to the artificial neural network results, H. caudiculatum enhanced osmotic responses and phenylpropanoid related pathways, whilst H. dentatum enhanced its defense system responses and protection against high light stress. CONCLUSIONS: Our findings provide a deeper understanding of the mechanisms underlying the desiccation tolerance responses of two filmy ferns and the relationship between the species-specific response and the microhabitats these ferns occupy in nature.

A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation.

Histone deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron-containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5'-terminal noncoding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1+ ) vascular progenitor cells (VPCs). A 7-amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1+ -VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen-activated protein kinase MEKK1 and transfer it to 14-3-3 gamma protein, forming an MEKK1-7A-14-3-3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1+ -VPCs cell migration, re-endothelialization in the femoral artery injury, and angiogenesis in hind limb ischemia. A Hd7-7sFLAG transgenic mice line was generated as the loss-of-function model, in which the 7A peptide was replaced by a FLAG-tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1+ -VPCs cell migration, re-endothelialization of the injured femoral artery, and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling.

Delayed Effects of Acute Reperfusion on Vascular Remodeling and Late-Phase Functional Recovery After Stroke.

Tissue perfusion is a necessary condition for vessel survival that can be compromised under ischemic conditions. Following stroke, delayed effects of early brain reperfusion on the vascular substrate necessary for remodeling, perfusion and maintenance of proper peri-lesional hemodynamics are unknown. Such aspects of ischemic injury progression may be critical for neurological recovery in stroke patients. This study aims to describe the impact of early, non-thrombolytic reperfusion on the vascular brain component and its potential contribution to tissue remodeling and long-term functional recovery beyond the acute phase after stroke in 3-month-old male C57bl/6 mice. Permanent (pMCAO) and transient (60 min, tMCAO) brain ischemia mouse models were used for characterizing the effect of early, non-thrombolytic reperfusion on the brain vasculature. Analysis of different vascular parameters (vessel density, proliferation, degeneration and perfusion) revealed that, while early middle cerebral artery recanalization was not sufficient to prevent sub-acute vascular degeneration within the ischemic brain regions, brain reperfusion promoted a secondary wave of vascular remodeling in the peri-lesional regions, which led to improved perfusion of the ischemic boundaries and late-phase neurological recovery. This study concluded that acute, non-thrombolytic artery recanalization following stroke favors late-phase vascular remodeling and improves peri-lesional perfusion, contributing to secondary functional recovery.

Role of TLR4 (Toll-Like Receptor 4) in N1/N2 Neutrophil Programming After Stroke.

Background and Purpose- After stroke, the population of infiltrated neutrophils in the brain is heterogeneous, including a population of alternative neutrophils (N2) that express M2 phenotype markers. We explored the role of TLR4 (toll-like receptor 4) on neutrophil infiltration and polarization in this setting. Methods- Focal cerebral ischemia was induced by occlusion of the middle cerebral artery occlusion in TLR4-KO and WT (wild type) mice. Infarct size was measured by Nissl staining and magnetic resonance imaging. Leukocyte infiltration was quantified 48 hours after middle cerebral artery occlusion by immunofluorescence and flow cytometry. To elucidate mechanisms underlying TLR4-mediated N2 phenotype, a cDNA microarray analysis was performed in neutrophils isolated from blood 48 hours after stroke in WT and TLR4-KO mice. Results- As demonstrated previously, TLR4-deficient mice presented lesser infarct volumes than WT mice. TLR4-deficient mice showed higher density of infiltrated neutrophils 48 hours after stroke compared with WT mice, concomitantly to neuroprotection. Furthermore, cytometric and stereological analyses revealed an increased number of N2 neutrophils (YM1+ cells) into the ischemic core in TLR4-deficient mice, suggesting a protective effect of this neutrophil subset that was corroborated by depleting peripheral neutrophils or using mice with TLR4 genetically ablated in the myeloid lineage. Finally, cDNA microarray analysis in neutrophils, confirmed by quantitative polymerase chain reaction, showed that TLR4 modulates several pathways associated with ischemia-induced inflammation, migration of neutrophils into the parenchyma, and their functional priming, which might explain the opposite effect on outcome of the different neutrophil subsets. Conclusions- TLR4 deficiency increased the levels of alternative neutrophils (N2)-an effect associated with neuroprotection after stroke-supporting that modulation of neutrophil polarization is a major target of TLR4 and highlighting the crucial role of TLR4 at the peripheral level after stroke. Visual Overview- An online visual overview is available for this article.

Toll-like receptor 4 regulates subventricular zone proliferation and neuroblast migration after experimental stroke.

Ischemic stroke is one of the leading causes of death and disability with an urgent need for innovative therapies, especially targeting the chronic phase. New evidence has emerged showing that Toll-Like Receptor 4 (TLR4), a key mediator of brain damage after stroke, may be involved in brain repair by neurogenesis modulation. The aim of this study is to analyze the role of TLR4 in the different stages of neurogenesis initiated in the subventricular zone (SVZ) over time after stroke in mice. Wildtype and TLR4-deficient mice underwent experimental ischemia, and neural stem/progenitor cells (NSPCs) proliferation and migration were analyzed by using FACS analysis, fluorescence densitometry, RT-qPCR and in vitro assays. Our results show that both groups, wildtype and knock-out animals, present a similar pattern of bilateral cell proliferation at the SVZ, with a decrease in NSPCs proliferation in the acute phase of stroke. We also show that TLR4 activation, very likely mediated by ligands such as HMGB1 released to CSF after stroke, is necessary to keep an increased proliferation of NSCs as well as to promote differentiation from type C cells into neuroblasts promoting their migration. TLR4 activation was also implicated in earlier expression of SDF-1α and faster recovery of BDNF expression after stroke. These results support TLR4 as an important therapeutic target in the modulation of neurogenesis after stroke.

Histone Deacetylase 7-Derived Peptides Play a Vital Role in Vascular Repair and Regeneration.

Cardiovascular disease is a leading cause of morbidity and mortality globally. Accumulating evidence indicates that local resident stem/progenitor cells play an important role in vascular regeneration. Recently, it is demonstrated that a histone deacetylase 7-derived 7-amino acid peptide (7A, MHSPGAD) is critical in modulating the mobilization and orientated differentiation of these stem/progenitor cells. Here, its therapeutic efficacy in vascular repair and regeneration is evaluated. In vitro functional analyses reveal that the 7A peptide, in particular phosphorylated 7A (7Ap, MH[pSer]PGAD), could increase stem cell antigen-1 positive (Sca1+) vascular progenitor cell (VPC) migration and differentiation toward an endothelial cell lineage. Furthermore, local delivery of 7A as well as 7Ap could enhance angiogenesis and ameliorate vascular injury in ischaemic tissues; these findings are confirmed in a femoral artery injury model and a hindlimb ischaemia model, respectively. Importantly, sustained delivery of 7A, especially 7Ap, from tissue-engineered vascular grafts could attract Sca1+-VPC cells into the grafts, contributing to endothelialization and intima/media formation in the vascular graft. These results suggest that this novel type of peptides has great translational potential in vascular regenerative medicine.

TLR4-Binding DNA Aptamers Show a Protective Effect against Acute Stroke in Animal Models.

Since Toll-like receptor 4 (TLR4) mediates brain damage after stroke, development of TLR4 antagonists is a promising therapeutic strategy for this disease. Our aim was to generate TLR4-blocking DNA aptamers to be used for stroke treatment. From a random oligonucleotide pool, we identified two aptamers (ApTLR#1R, ApTLR#4F) with high affinity for human TLR4 by systematic evolution of ligands by exponential enrichment (SELEX). Optimized truncated forms (ApTLR#1RT, ApTLR#4FT) were obtained. Our data demonstrate specific binding of both aptamers to human TLR4 as well as a TLR4 antagonistic effect. ApTLR#4F and ApTLR#4FT showed a long-lasting protective effect against brain injury induced by middle cerebral artery occlusion (MCAO), an effect that was absent in TLR4-deficient mice. Similar effects were obtained in other MCAO models, including in rat. Additionally, efficacy of ApTLR#4FT in a model of brain ischemia-reperfusion in rat supports the use of this aptamer in patients undergoing artery recanalization induced by pharmacological or mechanical interventions. The absence of major toxicology aspects and the good safety profile of the aptamers further encourage their future clinical positioning for stroke therapy and possibly other diseases in which TLR4 plays a deleterious role.

Cobalt (II) ions and nanoparticles induce macrophage retention by ROS-mediated down-regulation of RhoA expression.

Histological assessments of synovial tissues from patients with failed CoCr alloy hip prostheses demonstrate extensive infiltration and accumulation of macrophages, often loaded with large quantities of particulate debris. The resulting adverse reaction to metal debris (ARMD) frequently leads to early joint revision. Inflammatory response starts with the recruitment of immune cells and requires the egress of macrophages from the inflamed site for resolution of the reaction. Metal ions (Co2+ and Cr3+) have been shown to stimulate the migration of T lymphocytes but their effects on macrophages motility are still poorly understood. To elucidate this, we studied in vitro and in vivo macrophage migration during exposure to cobalt and chromium ions and nanoparticles. We found that cobalt but not chromium significantly reduces macrophage motility. This involves increase in cell spreading, formation of intracellular podosome-type adhesion structures and enhanced cell adhesion to the extracellular matrix (ECM). The formation of podosomes was also associated with the production and activation of matrix metalloproteinase-9 (MMP9) and enhanced ECM degradation. We showed that these were driven by the down-regulation of RhoA signalling through the generation of reactive oxygen species (ROS). These novel findings reveal the key mechanisms driving the wear/corrosion metallic byproducts-induced inflammatory response at non-toxic concentrations. STATEMENT OF SIGNIFICANCE: Adverse tissue responses to metal wear and corrosion products from CoCr alloy implants remain a great challenge to surgeons and patients. Macrophages are the key regulators of these adverse responses to the ions and debris generated. We demonstrated that cobalt, rather than chromium, causes macrophage retention by restructuring the cytoskeleton and inhibiting cell migration via ROS production that affects Rho Family GTPase. This distinctive effect of cobalt on macrophage behaviour can help us understand the pathogenesis of ARMD and the cellular response to cobalt based alloys, which provide useful information for future implant design and biocompatibility testing.

Gestión de espacios de participación con personas con trastorno mental grave: primeras jornadas de participación de usuarios de la linea de rehabilitación psicosocial de hermanas hospitalarias / No disponible

El Modelo de Recuperación para personas con Trastorno Mental grave (TMG), es un modelo centrado en la persona, que enfatiza la atención sobre las potencialidades y fortalezas, más allá de la enfermedad. Se fundamenta en la necesidad de construcción de un proyecto vital y se promueve, entre otras cosas, mediante la educación y empoderamiento, para que asuman el cuidado de sí mismos y reivindiquen sus derechos de ciudadanía e inclusión social. El modelo de recuperación no se entiende si no se trabaja con las personas con TMG en alcanzar una participación plena y responsable, para lo que se hace necesaria la capacitación y la autodeterminación de las personas implicadas. Por lo tanto, uno de los elementos claves de la recuperación es la formalización de Espacios para la Participación. En este trabajo presentamos cómo surgieron y se organizaron las I Jornadas de Participación de usuarios de la LRHP, a partir de un proyecto de colaboración con usuarios y profesionales de la ciudad de París

The Recovery Model for people with severe mental disorders (TMD) is a person-centered model that emphasizes attention to potential and strengths, beyond the disease. It is based on the need to build a vital project and is promoted, among other things, through education and empowerment, so that they take care of themselves and claim their rights of citizenship and social inclusion. The recovery model is not understood if you do not work with people with SMI to achieve full and responsible participation, for which the training and self-determination of the people involved is necessary. Therefore, one of the key elements of the recovery is the formalization of Spaces for Participation. In this paper, we present how the 1st Conference of Participation of users of the LRHP, from a collaboration project with users and professionals from the city of Paris

A Tricin Derivative from Deschampsia antarctica Desv. Inhibits Colorectal Carcinoma Growth and Liver Metastasis through the Induction of a Specific Immune Response.

In colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina in colorectal carcinoma models. We used human and murine colorectal carcinoma cell lines for investigating proliferation, apoptosis, and cell-cycle effects of Antartina therapy in vitro Avatar and immunocompetent colorectal carcinoma animal models were applied for evaluating the effects of Antartina in vivo Immune response against colorectal carcinoma model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T-cell subpopulation, and by tumor rechallenge experiments. Antartina inhibits in vitro human colorectal carcinoma cell proliferation; however, in vivo experiments in Avatar colorectal carcinoma model Antartina display a limited antitumor effect. In an immunocompetent colorectal carcinoma mice model, Antartina potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in >30% of mice and increased animal survival. In addition, Antartina induced a potent specific cytotoxic T-cell response against colorectal carcinoma and a long-lasting antitumor immunity. Interestingly, Antartina increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina has the ability to induce antitumor immunity against colorectal carcinoma and can be used to develop new tools for the treatment of colorectal carcinoma. Mol Cancer Ther; 17(5); 966-76. ©2018 AACR.