Update on the role of T cells in cognitive impairment.

The central nervous system (CNS) has long been considered an immune-privileged site, with minimal interaction between immune cells, particularly of the adaptive immune system. Previously, the presence of immune cells in this organ was primarily linked to events involving disruption of the blood-brain barrier (BBB) or inflammation. However, current research has shown that immune cells are found patrolling CNS under homeostatic conditions. Specifically, T cells of the adaptive immune system are able to cross the BBB and are associated with ageing and cognitive impairment. In addition, T-cell infiltration has been observed in pathological conditions, where inflammation correlates with poor prognosis. Despite ongoing research, the role of this population in the ageing brain under both physiological and pathological conditions is not yet fully understood. In this review, we provide an overview of the interactions between T cells and other immune and CNS parenchymal cells, and examine the molecular mechanisms by which these interactions may contribute to normal brain function and the scenarios in which disruption of these connections lead to cognitive impairment. A comprehensive understanding of the role of T cells in the ageing brain and the underlying molecular pathways under normal conditions could pave the way for new research to better understand brain disorders.S

Chimeric NANOG repressors inhibit glioblastoma growth in vivo in a context-dependent manner

Targeting stemness promises new therapeutic strategies against highly invasive tumors. While a number of approaches are being tested, inhibiting the core transcription regulatory network of cancer stem cells is an attractive yet challenging possibility. Here we have aimed to provide the proof of principle for a strategy, previously used in developmental studies, to directly repress the targets of a salient stemness and pluripotency factor: NANOG. In doing so we expected to inhibit the expression of so far unknown mediators of pro-tumorigenic NANOG function. We chose NANOG since previous work showed the essential requirement for NANOG activity for human glioblastoma (GBM) growth in orthotopic xenografts, and it is apparently absent from many adult human tissues thus likely minimizing unwanted effects on normal cells. NANOG repressor chimeras, which we name NANEPs, bear the DNA-binding specificity of NANOG through its homeodomain (HD), and this is linked to transposable human repressor domains. We show that in vitro and in vivo, NANEP5, our most active NANEP with a HES1 repressor domain, mimics knock-down (kd) of NANOG function in GBM cells. Competition orthotopic xenografts also reveal the effectiveness of NANEP5 in a brain tumor context, as well as the specificity of NANEP activity through the abrogation of its function via the introduction of specific mutations in the HD. The transcriptomes of cells expressing NANEP5 reveal multiple potential mediators of pro-tumorigenic NANEP/NANOG action including intercellular signaling components. The present results encourage further studies on the regulation of context-dependent NANEP abundance and function, and the development of NANEP-based anti-cancer therapies.This work was supported by a James McDonnell Brain Cancer Award, Fondation Eclosion funds and by the Département d’Instruction Publique de Genève to ARA. C.M. and M.K. were fellows of the ITN-EU networks CAPPELLA and HEALING, respectively

Global patterns in the implementation of payments for environmental services

Assessing global tendencies and impacts of conditional payments for environmental services (PES) programs is challenging because of their heterogeneity, and scarcity of comparative studies. This meta-study systematizes 55 PES schemes worldwide in a quantitative database. Using categorical principal component analysis to highlight clustering patterns, we reconfirm frequently hypothesized differences between public and private PES schemes, but also identify diverging patterns between commercial and non-commercial private PES vis-à-vis their service focus, area size, and market orientation. When do these PES schemes likely achieve significant environmental additionality? Using binary logistical regression, we find additionality to be positively influenced by three theoretically recommended PES 'best design' features: spatial targeting, payment differentiation, and strong conditionality, alongside some contextual controls (activity paid for and implementation time elapsed). Our results thus stress the preeminence of customized design over operational characteristics when assessing what determines the outcomes of PES implementation. (Résumé d'auteur

Non-Destructive Identification of Woolly Peaches combining Mechanical Impact Response and NIR Spectroscopy.

Woolliness (mealiness in other fruits) is a negative attribute of peach sensory texture that is a physiological disorder associated with inadequate cold storage. It is characterised by lack of crispness and juiciness without variation in the tissue water content (Harker and Hallet, 1992). Many attempts have been made to develop destructive instrumental procedures to detect mealiness and woolliness. Non-destructive procedures attempted include using nuclear magnetic resonance (Sonego et al., 1995). However, this technique has economical limitations and is not practical at present. Non-destructive impact tests and NIR are non-destructive techniques which have been used to assess internal characteristics of fruits (Chen and Sun, 1991). The objective of this study was to develop a novel non-destructive procedure to identify woolly peaches by combining impact and NIR approaches

Woolliness assessment in peaches (Cv. Springcrest) by sensory and instrumental means.

Mealiness is a negative attribute of sensory texture, characterised by the lack of juiciness without variation of total water content in the tissues. In peaches, mealiness is also known as "woolliness" and "leatheriness". This internal disorder is characterised by the lack of juiciness and flavour. In peaches, it is associated with interna browning near the stone and the incapacity of ripening although there is externa ripe appearance. Woolliness is associated with inadequate cold storage and is considered as a physiological disorder that appears in stone fruits when an unbalanced pectolitic enzyme activity during storage occurs (Kailasapathy and Melton, 1992). Many attempts have been carried out to identify and measure mealiness and woolliness in fruits. The texture of a food product is composed by a wide spectrum of sensory attributes. Consumer defines the texture integrating simultaneously all the sensory attributes. However, an instrument assesses one or several parameters related to a fraction of the texture spectrum (Kramer, 1973). The complexity of sensory analysis by means of trained panels to assess the quality of some producing processes, supports the attempt to estimate texture characteristics by instrumental means. Some studies have been carried out comparing sensory and instrumental methods to assess mealiness and woolliness. The current study is centered on analysis and evaluation of woolliness in peaches and is part of the European project FAIR CT95 0302 "Mealiness in fruits: consumer perception and means for detection". The main objective of this study was to develop procedures to detect woolly peaches by sensory and by instrumental means, as well as to compare both measuring procedures

Propuesta didáctica para promover el desarrollo de las competencias del área de personal social en estudiantes de cuarto grado de educación primaria de una institución educativa pública de San Pedro de Lloc, La Libertad

El presente trabajo de suficiencia profesional que a continuación se presenta tiene como propósito diseñar el desarrollo de las competencias en el área de Personal Social en estudiantes del cuarto grado de educación primaria de una institución educativa pública de San Pedro de Lloc, La Libertad, teniendo como fundamento el paradigma sociocognitivo- humanista y del paradigma sociocultural-contextual, los cuáles sostienen un conjunto teorías que son utilizan de manera práctica en las diversas actividades. En esta propuesta se considera el modelo T, el cual integra competencias, capacidades y destrezas, ya que no sólo obtiene conocimientos, sino que desarrolla habilidades y capacidades de manera autónoma y así el estudiante pueda enfrentar a los cambios actuales. Mediante esta propuesta se orientará a los estudiantes a ser ciudadanos democráticos con sentido crítico, reflexivo, investigadores, que valoren su propia cultura y la de los demás, que asuman responsablemente su rol dentro de la sociedad siendo agentes de cambio social. Por último, se indica que dicha propuesta tiene la siguiente estructura: en el primer capítulo la planificación del trabajo de suficiencia profesional, en el segundo capítulo el marco teórico y como tercer capítulo la programación curricular.The present work of professional sufficiency that is presented below has the purpose of designing the development of competences in the area of Social Personnel in students of the fourth grade of primary education of a public educational institution in San Pedro de Lloc, La Libertad, having as I base the sociocognitive-humanist paradigm and the sociocultural-contextual paradigm, which support a set of theories that are used practically in various activities. In this proposal, the T model is considered, which integrates competencies, abilities and skills, since it not only obtains knowledge, but also develops abilities and abilities autonomously so that the student can face current changes. Through this proposal, students will be oriented to be democratic citizens with a critical, reflective sense, researchers, who value their own culture and that of others, who responsibly assume their role within society as agents of social change. Finally, it is indicated that said proposal has the following structure: in the first chapter the planning of the work of professional sufficiency, in the second chapter the theoretical framework and as the third chapter the curricular programming.Trabajo de suficiencia profesiona

Effectiveness of Blood Flow Restriction on Functionality, Quality of Life and Pain in Patients with Neuromusculoskeletal Pathologies: A Systematic Review

Background: Blood flow restriction is characterized as a method used during exercise at low loads of around 20–40% of a repetition maximum, or at a low-moderate intensity of aerobic exercise, in which cuffs that occlude the proximal part of the extremities can partially reduce arterial flow and fully restrict the venous flow of the musculature in order to achieve the same benefits as high-load exercise. Objective: The main objective of this systematic literature review was to analyze the effects of BFR intervention on pain, functionality, and quality of life in subjects with neuromusculoskeletal pathologies. Methods: The search to carry out was performed in PubMed, Cochrane, EMBASE, PEDro, CINHAL, SPORTDiscus, Trip Medical Database, and Scopus: “kaatsu” OR “ischemic training” OR “blood flow restriction” OR “occlusion resistance training” OR “vascular occlusion” OR “vascular restriction”. Results: After identifying 486 papers and eliminating 175 of them due to duplication and 261 after reading the title and abstract, 50 papers were selected. Of all the selected articles, 28 were excluded for not presenting a score equal to or higher than 6 points on the PEDro scale and 8 for not analyzing the target outcome variables. Finally, 14 papers were selected for this systematic review. Conclusions: The data collected indicate that the blood flow restriction tool is a therapeutic alternative due to its effectiveness under different exercise modalities. The benefits found include decreases in pain thresholds and improvement in the functionality and quality of life of the neuro-musculoskeletal patient during the first six weeks. However, the results provided by this tool are still not clear for medium- and long-term interventions.Partial funding for open access charge: Universidad de Málag

TWEAK Activates the Non-Canonical NFκB Pathway in Murine Renal Tubular Cells: Modulation of CCL21

TWEAK is a member of the TNF superfamily of cytokines that contribute to kidney tubulointerstitial injury. It has previously been reported that TWEAK induces transient nuclear translocation of RelA and expression of RelA-dependent cytokines in renal tubular cells. Additionally, TWEAK induced long-lasting NFκB activation suggestive of engagement of the non-canonical NFκB pathway. We now explore TWEAK-induced activation of NFκB2 and RelB, as well as expression of CCL21, a T-cell chemotactic factor, in cultured murine tubular epithelial cells and in healthy kidneys in vivo. In cultured tubular cells, TWEAK and TNFα activated different DNA-binding NFκB complexes. TWEAK-induced sustained NFκB activation was associated with NFκB2 p100 processing to p52 via proteasome and nuclear translocation and DNA-binding of p52 and RelB. TWEAK, but not TNFα used as control), induced a delayed increase in CCL21a mRNA (3.5±1.22-fold over control) and CCL21 protein (2.5±0.8-fold over control), which was prevented by inhibition of the proteasome, or siRNA targeting of NIK or RelB, but not by RelA inhibition with parthenolide. A second NFκB2-dependent chemokine, CCL19, was upregulates by TWEAK, but not by TNFα. However, both cytokines promoted chemokine RANTES expression (3-fold mRNA at 24 h). In vivo, TWEAK induced nuclear NFκB2 and RelB translocation and CCL21a mRNA (1.5±0.3-fold over control) and CCL21 protein (1.6±0.5-fold over control) expression in normal kidney. Increased tubular nuclear RelB and tubular CCL21 expression in acute kidney injury were decreased by neutralization (2±0.9 vs 1.3±0.6-fold over healthy control) or deficiency of TWEAK (2±0.9 vs 0.8±0.6-fold over healthy control). Moreover, anti-TWEAK treatment prevented the recruitment of T cells to the kidney in this model (4.1±1.4 vs 1.8±1-fold over healthy control). Our results thus identify TWEAK as a regulator of non-canonical NFκB activation and CCL21 expression in tubular cells thus promoting lymphocyte recruitment to the kidney during acute injury

A novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia

A high proportion of patients with acute myeloid leukemia who achieve minimal residual disease negative status ultimately relapse because a fraction of pathological clones remains undetected by standard methods. We designed and validated a high-throughput sequencing method for minimal residual disease assessment of cell clonotypes with mutations of NPM1, IDH1/2 and/or FLT3-single nucleotide variants. For clinical validation, 106 follow-up samples from 63 patients in complete remission were studied by sequencing, evaluating the level of mutations detected at diagnosis. The predictive value of minimal residual disease status by sequencing, multiparameter flow cytometry, or quantitative polymerase chain reaction analysis was determined by survival analysis. The sequencing method achieved a sensitivity of 10-4 for single nucleotide variants and 10-5 for insertions/deletions and could be used in acute myeloid leukemia patients who carry any mutation (86% in our diagnostic data set). Sequencing-determined minimal residual disease positive status was associated with lower disease-free survival (hazard ratio 3.4, P=0.005) and lower overall survival (hazard ratio 4.2, P<0.001). Multivariate analysis showed that minimal residual disease positive status determined by sequencing was an independent factor associated with risk of death (hazard ratio 4.54, P=0.005) and the only independent factor conferring risk of relapse (hazard ratio 3.76, P=0.012). This sequencing-based method simplifies and standardizes minimal residual disease evaluation, with high applicability in acute myeloid leukemia. It is also an improvement upon flow cytometry- and quantitative polymerase chain reaction-based prediction of outcomes of patients with acute myeloid leukemia and could be incorporated in clinical settings and clinical trials.This study was supported by the Subdirección General de Investigación Sanitaria (Instituto de Salud Carlos III, Spain) grants PI13/02387 and PI16/01530, and the CRIS against Cancer foundation grant 2014/0120. ML holds a postdoctoral fellowship of the Spanish Ministry of Economy and Competitiveness (FPDI-2013- 16409). PRP holds a postdoctoral fellowship of the Spanish Instituto de Salud Carlos III: Contrato Predoctoral de Formación en Investigación en Salud i-PFIS (IFI 14/00008).S