Phenyl acyl acids attenuate the unfolded protein response in tunicamycin-treated neuroblastoma cells.

Understanding how neural cells handle proteostasis stress in the endoplasmic reticulum (ER) is important to decipher the mechanisms that underlie the cell death associated with neurodegenerative diseases and to design appropriate therapeutic tools. Here we have compared the sensitivity of a human neuroblastoma cell line (SH-SY5H) to the ER stress caused by an inhibitor of protein glycosylation with that observed in human embryonic kidney (HEK-293T) cells. In response to stress, SH-SY5H cells increase the expression of mRNA encoding downstream effectors of ER stress sensors and transcription factors related to the unfolded protein response (the spliced X-box binding protein 1, CCAAT-enhancer-binding protein homologous protein, endoplasmic reticulum-localized DnaJ homologue 4 and asparagine synthetase). Tunicamycin-induced death of SH-SY5H cells was prevented by terminal aromatic substituted butyric or valeric acids, in association with a decrease in the mRNA expression of stress-related factors, and in the accumulation of the ATF4 protein. Interestingly, this decrease in ATF4 protein occurs without modifying the phosphorylation of the translation initiation factor eIF2α. Together, these results show that when short chain phenyl acyl acids alleviate ER stress in SH-SY5H cells their survival is enhanced

Maternal imprinting on cognition markers of wild type and transgenic Alzheimer's disease model mice.

The risk of suffering from Alzheimer's disease (AD) is higher in individuals from AD-affected mothers. The purpose of this investigation was to study whether maternal transmission might produce AD-related alterations in progenies of mice that do not have any genotypic alteration. We used cognitively-intact mothers harbouring in heterozygosity the transgene for overexpressing the Swedish double mutant version of the human amyloid precursor protein (hAβPPswe). The phenotype of the offspring with or without the transgene resulting from crossing young Tg2576 females with wild-type males were compared with those of the offspring resulting from crossing wild-type females with Tg2576 males. The hAβPPswe-bearing offspring from Tg2576 mothers showed an aggravated AD-like phenotype. Remarkably, cognitive, immunohistochemical and some biochemical features displayed by Tg2576 heterozygous mice were also found in wild-type animals generated from Tg2576 females. This suggests the existence of a maternal imprinting in the wild-type offspring that confers a greater facility to launch an AD-like neurodegenerative cascade. Such progeny, lacking any mutant amyloid precursor protein, constitutes a novel model to study maternal transmission of AD and, even more important, to discover early risk markers that predispose to the development of AD

Limited unfolded protein response and inflammation in neuroserpinopathy

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare disease characterized by the deposition of multiple intracytoplasmic neuronal inclusions that contain mutated neuroserpin. Tg-Syracuse (Tg-Syr) mice express Ser49Pro mutated neuroserpin and develop clinical and neuropathological features of human FENIB. We used 8-, 34-, 45- and 80-week-old Tg-Syr mice to characterize neuroinflammation and the unfolded protein response (UPR) in a neurodegenerative disease in which abnormal protein aggregates accumulate within the endoplasmic reticulum (ER). There were scattered neuroserpin inclusions in Tg-Syr mice at 8 weeks of age; the numbers of neurons involved and the amount of neuroserpin per neuron increased with age throughout the CNS to 80 weeks of age; no similar inclusions were found in wild type (Tg-WT) mice at any age. Increases in numbers of astrocytes and microglia occurred at advanced disease stages. Among 22 markers in 80-week-old Tg-Syr mice, only II1b and II10rb mRNAs in the somatosensory cortex and CxCl10 and Il10rb mRNAs in the olfactory bulb were upregulated when compared with Tg-WT mice indicating a limited relationship between neuroserpin inclusions and inflammatory responses. The changes were accompanied by a transient increase in expression of Xbp1 spliced at 45 weeks and increased ERdJ4 mRNAs at 80 weeks. The sequestration of UPR activators GRP78 and GRP94 in neuroserpin inclusions might explain the limited UPR responses despite the accumulation of neuroserpin in the ER in this FENIB mouse model

Early-Onset Molecular Derangements in the Olfactory Bulb of Tg2576 Mice: Novel Insights Into the Stress-Responsive Olfactory Kinase Dynamics in Alzheimer’s Disease

The olfactory bulb (OB) is the first processing station in the olfactory pathway. Despite smell impairment, which is considered an early event in Alzheimer's disease (AD), little is known about the initial molecular disturbances that accompany the AD development at olfactory level. We have interrogated the time-dependent OB molecular landscape in Tg2576 AD mice prior to the appearance of neuropathological amyloid plaques (2-, and 6-month-old), using combinatorial omics analysis. The metabolic modulation induced by overproduction of human mutated amyloid precursor protein (APP) clearly differs between both time points. Besides the progressive perturbation of the APP interactome, functional network analysis unveiled an inverse regulation of downstream extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) routes in 2-month-old Tg2576 mice with respect to wild-type (WT) mice. In contrast, Akt and MAPK kinase 4 (SEK1)/ stress-activated protein kinase (SAPK) axis were parallel activated in the OB of 6-months-old-Tg2576 mice. Furthermore, a survival kinome profiling performed during the aging process (2-, 6-, and 18-month-old) revealed that olfactory APP overexpression leads to changes in the activation dynamics of protein kinase A (PKA), and SEK1/MKK4-SAPK/JNK between 6 and 18 months of age, when memory deficits appear and AD pathology is well established in transgenic mice. Interestingly, both olfactory pathways were differentially activated in a stage-dependent manner in human sporadic AD subjects with different neuropathological grading. Taken together, our data reflect the early impact of mutated APP on the OB molecular homeostasis, highlighting the progressive modulation of specific signaling pathways during the olfactory amyloidogenic pathology

The Spanish version of the reflective functioning questionnaire: Validity data in the general population and individuals with personality disorders.

Introduction Mentalization or reflective functioning (RF) is the capacity to interpret oneself or the others in terms of internal mental states. Its failures have been linked to several mental disorders and interventions improving RF have a therapeutic effect. Mentalizing capacity of the parents influences the children’s attachment. The Reflective Functioning Questionnaire (RFQ-8) is a widely used tool for the assessment of RF. No instrument is available to assess general RF in Spanish-speaking samples. The aim of this study is to develop a Spanish version of the RFQ-8 and to evaluate its reliability and validity in the general population and in individuals with personality disorders. Methods 602 non-clinical and 41 personality disordered participants completed a Spanish translation of the RFQ and a battery of self-reported questionnaires assessing several RF related constructs (alexithymia, perspective taking, identity diffusion and mindfulness), psychopathology (general and specific) and interpersonal problems. Temporal stability was tested in a non-clinical sub-sample of 113 participants. Results Exploratory and confirmatory factor analyses suggested a one-factor structure in the Spanish version of the RFQ-8. RFQ-8 understood as a single scale was tested, with low scorings reflecting genuine mentalizing, and high scorings uncertainty. The questionnaire showed good internal consistence in both samples and moderate temporal stability in non-clinical sample. RFQ correlated significantly with identity diffusion, alexithymia, and general psychopathology in both samples; and with mindfulness, perspective taking, and interpersonal problems in clinical sample. Mean values of the scale were significantly higher in the clinical group. Discussion This study provides evidence that the Spanish version of the RFQ-8, understood as a single scale, has an adequate reliability and validity assessing failures in reflective functioning (i.e., hypomentalization) in general population and personality disorders.The study received a Health Strategic Action fund from the Carlos III Health Institute of the Spanish Ministry of Science and Innovation. ID PI16/02058. https://www.isciii.es/QueHacemos/Financiacion/solicitudes/Paginas/default.aspx No researcher have received money from the fund. This kind of public funds are managed by public institutes (in this case BIOEF) that ensure this money is only used for some of the material resources necessary to carry out the investigation. https://www.bioef.org/es/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia

For PETHEMA Programa para el Estudio de la Terapéutica en Hemopatías Malignas Cooperative Study Group.The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (≥0.1%; ≥0.01-0.1%; and <0.01), with a 5-year RFS of 38%, 50% and 71%, respectively (p = 0.002). Cytogenetics is the most relevant prognosis factor in AML, however intermediate risk cytogenetics represent a grey zone that require other biomarkers for risk stratification, and we show that MRD evaluation discriminate three prognostic subgroups (p = 0.03). Also, MRD assessments yielded relevant information on favourable and adverse cytogenetics, since patients with favourable cytogenetics and high MRD levels have poor prognosis and patients with adverse cytogenetics but undetectable MRD overcomes the adverse prognosis. Interestingly, in patients with intermediate or high MRD levels, intensification with transplant improved the outcome as compared with chemotherapy, while the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis revealed age, MRD and cytogenetics as independent variables. Moreover, a scoring system, easy in clinical practice, was generated based on MRD level and cytogenetics.This work was supported in part by Spanish grants from Fondo de Investigación Sanitaria-ISCIII (FIS 00/0023-03, PI12/02321), DGCYT (SAF 94- 0308, SAF2001-1687), Conserjería de Educación de Castilla y León (HUS416A12), and Red Temática de Investigación Cooperativa en Cáncer (RTICC-ISCIII) (RD12/0036/0069).Peer Reviewe

The Spanish version of the reflective functioning questionnaire: Validity data in the general population and individuals with personality disorders

INTRODUCTION: Mentalization or reflective functioning (RF) is the capacity to interpret oneself or the others in terms of internal mental states. Its failures have been linked to several mental disorders and interventions improving RF have a therapeutic effect. Mentalizing capacity of the parents influences the children's attachment. The Reflective Functioning Questionnaire (RFQ-8) is a widely used tool for the assessment of RF. No instrument is available to assess general RF in Spanish-speaking samples. The aim of this study is to develop a Spanish version of the RFQ-8 and to evaluate its reliability and validity in the general population and in individuals with personality disorders. METHODS: 602 non-clinical and 41 personality disordered participants completed a Spanish translation of the RFQ and a battery of self-reported questionnaires assessing several RF related constructs (alexithymia, perspective taking, identity diffusion and mindfulness), psychopathology (general and specific) and interpersonal problems. Temporal stability was tested in a non-clinical sub-sample of 113 participants. RESULTS: Exploratory and confirmatory factor analyses suggested a one-factor structure in the Spanish version of the RFQ-8. RFQ-8 understood as a single scale was tested, with low scorings reflecting genuine mentalizing, and high scorings uncertainty. The questionnaire showed good internal consistence in both samples and moderate temporal stability in non-clinical sample. RFQ correlated significantly with identity diffusion, alexithymia, and general psychopathology in both samples; and with mindfulness, perspective taking, and interpersonal problems in clinical sample. Mean values of the scale were significantly higher in the clinical group. DISCUSSION: This study provides evidence that the Spanish version of the RFQ-8, understood as a single scale, has an adequate reliability and validity assessing failures in reflective functioning (i.e., hypomentalization) in general population and personality disorders