The Effect of Child Trauma on the Relation between Psychological Well-Being and Depressive Symptoms in Chilean University Students.

(1) Background: There is consistent evidence of the impact of early adverse experiences on mental health in adulthood, especially as a risk factor for depression. However, their influence on positive aspects of mental health such as well-being has been less extensively studied. Therefore, this study aims to investigate the effect of traumatic childhood experiences on the relationship between depression and psychological well-being in a sample of university students. (2) Methods: The Childhood Trauma Questionnaire-Short Form (CTQ-SF), the Beck Depression Inventory (BDI-IA), and Ryff's psychological well-being scale were administered to 700 Chilean university students. Several regression models were used to analyze the interaction between variables, with multivariate SEM being applied to hierarchize the relationships found. (3) Results: Emotional Neglect and Abuse stand out as the types of maltreatment with the greatest impact on mental health, associated first with a decrease in the self-acceptance dimension of psychological well-being and then with depressive symptomatology in adulthood. (4) Conclusions: Results provide evidence that early trauma has an important impact on mental health, increasing the risk of depression, however, its impact is greater on positive aspects of health, such as self-acceptance, a fundamental element in the construction of psychological well-being.

Fatores de risco para embolia pulmonar em pacientes com COVID-19 anticoagulados na unidade de terapia intensiva submetidos à angiografia por tomografia computadorizada / Pulmonary embolism risk factors for intensive care unit anticoagulated COVID-19 patients undergoing computed tomography angiography

RESUMO Objetivo: Avaliar a incidência de embolia pulmonar, seu relacionamento com os níveis de dímero D e outros possíveis fatores associados, além dos efeitos adversos da anticoagulação e meios de contraste. Métodos: Conduziu-se um estudo de coorte retrospectiva em um hospital público chileno. Foram incluídos os pacientes com idade acima de 18 anos com COVID-19, mecanicamente ventilados na unidade de terapia intensiva, admitidos entre março e junho de 2020. Todos os pacientes receberam tromboprofilaxia com heparina, que foi aumentada até uma dose de anticoagulação com níveis de dímero D acima de 3µg/mL. Resultados: Foram acompanhados 127 pacientes, dos quais 73 foram submetidos à angiografia por tomografia computadorizada (média de idade de 54 ± 12 anos; 49 homens). Sessenta e dois dos 73 pacientes (84,9%) receberam anticoagulação total antes da angiografia por tomografia computadorizada. Além disso, 18 dos 73 pacientes tiveram embolia pulmonar (24,7%). Na comparação entre pacientes com e sem embolia pulmonar, não se observaram diferenças significantes em termos de idade, sexo, obesidade, tabagismo, escores de Wells e Genebra revisado, dímero D ou mortalidade. O uso de anticoagulantes foi similar em ambos os grupos. O número de dias desde o início da anticoagulação até a angiografia por tomografia computadorizada foi significantemente menor no grupo com embolia pulmonar (p = 0,002). Três pacientes tiveram lesão renal aguda após o contraste (4,1%), e um paciente teve sangramento importante. Conclusão: Apesar da anticoagulação, um em cada quatro pacientes com COVID-19 submetidos à ventilação mecânica e avaliados com angiografia por tomografia computadorizada apresentou embolia pulmonar. Com uma maior demora para realização da angiografia por tomografia computadorizada após início de anticoagulação empírica, identificou-se um número significantemente menor de embolias

Abstract Objective: To assess pulmonary embolism incidence, its relationship with D-dimer levels and other possible associated factors in addition to anticoagulation and contrast medium adverse effects. Methods: A retrospective observational cohort study at a Chilean public hospital was performed. Intensive care unit mechanically ventilated COVID-19 patients older than 18 years old between March and June 2020 were included. All patients received heparin thromboprophylaxis, which was increased to the anticoagulation dose with D-dimer greater than 3µg/mL. Results: A total of 127 patients were followed up, of whom 73 underwent pulmonary computed tomography angiography (mean age, 54 ± 12 years; 49 men). Sixty-two of the 73 patients (84.9%) received full anticoagulation before computed tomography angiography. In addition, 18 of the 73 patients had pulmonary embolism (24.7%). When comparing patients with and without pulmonary embolism, no significant differences were observed in age, sex, obesity, smoking, Wells and revised Geneva scores, D-dimer or mortality. Anticoagulant use was similar in both groups. Days from the start of anticoagulation until computed tomography angiography were significantly lower in the pulmonary embolism group (p = 0.002). Three patients presented post contrast-acute kidney injury (4.1%), and one patient had major bleeding. Conclusion: Despite anticoagulation, one in four COVID-19 patients connected to mechanical ventilation and evaluated with pulmonary computed tomography angiography had pulmonary embolism. With a longer the delay in performing computed tomography angiography once empirical anticoagulation was started, significantly less pulmonary embolism was identified.

Pulmonary embolism risk factors for intensive care unit anticoagulated COVID-19 patients undergoing computed tomography angiography. / Fatores de risco para embolia pulmonar em pacientes com COVID-19 anticoagulados na unidade de terapia intensiva submetidos à angiografia por tomografia computadorizada.

OBJECTIVE: To assess pulmonary embolism incidence, its relationship with D-dimer levels and other possible associated factors in addition to anticoagulation and contrast medium adverse effects. METHODS: A retrospective observational cohort study at a Chilean public hospital was performed. Intensive care unit mechanically ventilated COVID-19 patients older than 18 years old between March and June 2020 were included. All patients received heparin thromboprophylaxis, which was increased to the anticoagulation dose with D-dimer greater than 3µg/mL. RESULTS: A total of 127 patients were followed up, of whom 73 underwent pulmonary computed tomography angiography (mean age, 54 ± 12 years; 49 men). Sixty-two of the 73 patients (84.9%) received full anticoagulation before computed tomography angiography. In addition, 18 of the 73 patients had pulmonary embolism (24.7%). When comparing patients with and without pulmonary embolism, no significant differences were observed in age, sex, obesity, smoking, Wells and revised Geneva scores, D-dimer or mortality. Anticoagulant use was similar in both groups. Days from the start of anticoagulation until computed tomography angiography were significantly lower in the pulmonary embolism group (p = 0.002). Three patients presented post contrast-acute kidney injury (4.1%), and one patient had major bleeding. CONCLUSION: Despite anticoagulation, one in four COVID-19 patients connected to mechanical ventilation and evaluated with pulmonary computed tomography angiography had pulmonary embolism. With a longer the delay in performing computed tomography angiography once empirical anticoagulation was started, significantly less pulmonary embolism was identified.

OBJETIVO: Avaliar a incidência de embolia pulmonar, seu relacionamento com os níveis de dímero D e outros possíveis fatores associados, além dos efeitos adversos da anticoagulação e meios de contraste. MÉTODOS: Conduziu-se um estudo de coorte retrospectiva em um hospital público chileno. Foram incluídos os pacientes com idade acima de 18 anos com COVID-19, mecanicamente ventilados na unidade de terapia intensiva, admitidos entre março e junho de 2020. Todos os pacientes receberam tromboprofilaxia com heparina, que foi aumentada até uma dose de anticoagulação com níveis de dímero D acima de 3µg/mL. RESULTADOS: Foram acompanhados 127 pacientes, dos quais 73 foram submetidos à angiografia por tomografia computadorizada (média de idade de 54 ± 12 anos; 49 homens). Sessenta e dois dos 73 pacientes (84,9%) receberam anticoagulação total antes da angiografia por tomografia computadorizada. Além disso, 18 dos 73 pacientes tiveram embolia pulmonar (24,7%). Na comparação entre pacientes com e sem embolia pulmonar, não se observaram diferenças significantes em termos de idade, sexo, obesidade, tabagismo, escores de Wells e Genebra revisado, dímero D ou mortalidade. O uso de anticoagulantes foi similar em ambos os grupos. O número de dias desde o início da anticoagulação até a angiografia por tomografia computadorizada foi significantemente menor no grupo com embolia pulmonar (p = 0,002). Três pacientes tiveram lesão renal aguda após o contraste (4,1%), e um paciente teve sangramento importante. CONCLUSÃO: Apesar da anticoagulação, um em cada quatro pacientes com COVID-19 submetidos à ventilação mecânica e avaliados com angiografia por tomografia computadorizada apresentou embolia pulmonar. Com uma maior demora para realização da angiografia por tomografia computadorizada após início de anticoagulação empírica, identificou-se um número significantemente menor de embolias.

GERO Cohort Protocol, Chile, 2017-2022: Community-based Cohort of Functional Decline in Subjective Cognitive Complaint elderly.

BACKGROUND: With the global population aging and life expectancy increasing, dementia has turned a priority in the health care system. In Chile, dementia is one of the most important causes of disability in the elderly and the most rapidly growing cause of death in the last 20 years. Cognitive complaint is considered a predictor for cognitive and functional decline, incident mild cognitive impairment, and incident dementia. The GERO cohort is the Chilean core clinical project of the Geroscience Center for Brain Health and Metabolism (GERO). The objective of the GERO cohort is to analyze the rate of functional decline and progression to clinical dementia and their associated risk factors in a community-dwelling elderly with subjective cognitive complaint, through a population-based study. We also aim to undertake clinical research on brain ageing and dementia disorders, to create data and biobanks with the appropriate infrastructure to conduct other studies and facilitate to the national and international scientific community access to the data and samples for research. METHODS: The GERO cohort aims the recruitment of 300 elderly subjects (> 70 years) from Santiago (Chile), following them up for at least 3 years. Eligible people are adults not diagnosed with dementia with subjective cognitive complaint, which are reported either by the participant, a proxy or both. Participants are identified through a household census. The protocol for evaluation is based on a multidimensional approach including socio-demographic, biomedical, psychosocial, neuropsychological, neuropsychiatric and motor assessments. Neuroimaging, blood and stool samples are also obtained. This multidimensional evaluation is carried out in a baseline and 2 follow-ups assessments, at 18 and 36 months. In addition, in months 6, 12, 24, and 30, a telephone interview is performed in order to keep contact with the participants and to assess general well-being. DISCUSSION: Our work will allow us to determine multidimensional risks factors associated with functional decline and conversion to dementia in elderly with subjective cognitive complain. The aim of our GERO group is to establish the capacity to foster cutting edge and multidisciplinary research on aging in Chile including basic and clinical research. TRIAL REGISTRATION: NCT04265482 in ClinicalTrials.gov. Registration Date: February 11, 2020. Retrospectively Registered.

Parto prematuro en pacientes COVID-19 en Hospital San Juan de Dios / Premature delivery in COVID-19 patients at San Juan de Dios Hospital

INTRODUCCIÓN Y OBJETIVO: La pandemia por SARS-CoV-2 afecta a las embarazadas con diferentes manifestaciones clínicas; una de ellas es el parto prematuro. El objetivo del presente estudio es caracterizar a las embarazadas con COVID-19 que tuvieron su parto y determinar la razón de aumento de parto prematuro en este grupo en comparación con aquellas que no presentaban la enfermedad. MÉTODOS: Estudio observacional de cohorte retrospectivo donde se incluyeron pacientes embarazadas entre abril y junio del año 2020 en la Maternidad del Hospital San Juan de Dios. Se seleccionaron aquellas que tuvieron su parto y se evaluaron los datos demográficos y médicos, antecedentes obstétricos, información respecto al parto, antecedentes del recién nacido y características de la enfermedad por COVID-19. RESULTADOS: Entre las pacientes COVID-19 un 16.9% tuvo parto prematuro, alcanzando un OR de 1,79 (0,76-3,84 IC 95%) respecto a aquellas sin la enfermedad que, aunque no significativo, evidencia tendencia. Entre las que cursaron con COVID-19 severo todas tuvieron parto prematuro, con un OR significativo (>= 7.84 IC 95%) en comparación con aquellas con cuadro leve o negativas a COVID-19. Un 10.1% de los recién nacidos de madres COVID-19 requirió reanimación neonatal, mientras que en las negativas fue de un 5.5%. CONCLUSIONES: Entre las pacientes COVID-19 se observo una tendencia a aumento del riesgo de parto prematuro respecto a aquellas sin la enfermedad, siendo significativo el aumento del riesgo en aquellas que cursaban con síntomas y aún más significativo si presentaban enfermedad severa.

INTRODUCTION AND OBJECTIVES: The SARS-CoV-2 pandemic has affected pregnant women with different clinical manifestations, one of them premature labor. The objective of this study is to characterize the pregnant patients with COVID-19 who had their delivery and to determine the risk of preterm delivery in this group compared to those who did not have the disease at the Maternity Department in San Juan de Dios Hospital, and determine what the rate of premature delivery is. METHODS: Retrospective observational cohort study where pregnant patients were included between April and June of 2020 at the Maternity Department in San Juan de Dios Hospital. Patients who had their delivery were selected and demographic and medical data, obstetric history, information regarding delivery, newborn history and characteristics of COVID-19 disease were evaluated. RESULTS: Among COVID-19 positives, a 16.9% had premature labor, reaching a nonsignificant OR 1.79 (0.76-3.84 95% CI) compared to those COVID-19 negative. Among those with severe COVID-19, all had preterm birth, with a significant OR (>=7.84 95% CI) compared to those with mild symptoms or COVID-19 negative. 10.1% of newborns of COVID-19 mothers required neonatal resuscitation, while, in the negative ones it was 5.5%. CONCLUSIONS: Among COVID-19 patients, a trend towards increased risk of preterm birth was observed compared to those without the disease, with the increased risk being significant in those with symptoms and even more significant if they had severe disease.

ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response.

RNA editing has emerged as a novel mechanism in cancer progression. The double stranded RNA-specific adenosine deaminase (ADAR) modifies the expression of an important proportion of genes involved in cell cycle control, DNA damage response (DDR) and transcriptional processing, suggesting an important role of ADAR in transcriptome regulation. Despite the phenotypic implications of ADAR deregulation in several cancer models, the role of ADAR on DDR and proliferation in breast cancer has not been fully addressed. Here, we show that ADAR expression correlates significantly with clinical outcomes and DDR, cell cycle and proliferation mRNAs of previously reported edited transcripts in breast cancer patients. ADAR's knock-down in a breast cancer cell line produces stability changes of mRNAs involved in DDR and DNA replication. Breast cancer cells with reduced levels of ADAR show a decreased viability and an increase in apoptosis, displaying a significant decrease of their DDR activation, compared to control cells. These results suggest that ADAR plays an important role in breast cancer progression through the regulation of mRNA stability and expression of those genes involved in proliferation and DDR impacting the viability of breast cancer cells.

[Depressive symptomatology and psychological well-being among Chilean university students]. / Sintomatologia depresiva y bienestar psicológico en estudiantes universitarios chilenos.

BACKGROUND: Quality of life and psychological well-being are readily hampered by depression. The changes that students face during college life impact their psychological health and well-being, including the emergence of mental health problems like depression Aim: To determine the relationship between depressive symptoms, sociodemographic parameters and psychological well-being in undergraduate university students. MATERIAL AND METHODS: Five hundred eighty university students of both sexes, from the Metropolitan and IX Regions of Chile answered the Beck Depression Inventory (BDI-IA) and the Ryff's psychological well-being scale. RESULTS: Twenty eight percent of respondents had clinically significant depressive symptoms, and these were more frequent in women. There was an inverse and statistically significant relationship between psychological well-being and depressive symptoms. This fact was especially marked in dimensions of autonomy, positive relationships with others and purpose in life. CONCLUSIONS: There is a high frequency of depressive symptoms among these students. We discuss whether psychological well-being and depressive symptomatology represent two extremes within a continuum or they are two independent dimensions that can account for differential causal mechanisms linked to mental health and illness.

Sintomatologia depresiva y bienestar psicológico en estudiantes universitarios chilenos / Depressive symptomatology and psychological well-being among Chilean university students

Background: Quality of life and psychological well-being are readily hampered by depression. The changes that students face during college life impact their psychological health and well-being, including the emergence of mental health problems like depression Aim: To determine the relationship between depressive symptoms, sociodemographic parameters and psychological well-being in undergraduate university students. Material and Methods: Five hundred eighty university students of both sexes, from the Metropolitan and IX Regions of Chile answered the Beck Depression Inventory (BDI-IA) and the Ryff's psychological well-being scale. Results: Twenty eight percent of respondents had clinically significant depressive symptoms, and these were more frequent in women. There was an inverse and statistically significant relationship between psychological well-being and depressive symptoms. This fact was especially marked in dimensions of autonomy, positive relationships with others and purpose in life. Conclusions: There is a high frequency of depressive symptoms among these students. We discuss whether psychological well-being and depressive symptomatology represent two extremes within a continuum or they are two independent dimensions that can account for differential causal mechanisms linked to mental health and illness.

Psychotherapy and Genetic Neuroscience: An Emerging Dialog.

Recent research in psychiatric genetics has led to a move away from simple diathesis-stress models to more complex models of psychopathology incorporating a focus on gene-environment interactions and epigenetics. Our increased understanding of the way biology encodes the impact of life events on organisms has also generated more sophisticated theoretical models concerning the molecular processes at the interface between "nature" and "nurture." There is also increasing consensus that psychotherapy entails a specific type of learning in the context of an emotional relationship (i.e., the therapeutic relationship) that may also lead to epigenetic modifications across different therapeutic treatment modalities. This paper provides a systematic review of this emerging body of research. It is concluded that, although the evidence is still limited at this stage, extant research does indeed suggest that psychotherapy may be associated with epigenetic changes. Furthermore, it is argued that epigenetic studies may play a key role in the identification of biomarkers implicated in vulnerability for psychopathology, and thus may improve diagnosis and open up future research opportunities regarding the mechanism of action of psychotropic drugs as well as psychotherapy. We review evidence suggesting there may be important individual differences in susceptibility to environmental input, including psychotherapy. In addition, given that there is increasing evidence for the transgenerational transmission of epigenetic modifications in animals and humans exposed to trauma and adversity, epigenetic changes produced by psychotherapy may also potentially be passed on to the next generation, which opens up new perspective for prevention science. We conclude this paper stressing the limitations of current research and by proposing a set of recommendations for future research in this area.

Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.

BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C-1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.

Genetic Diversity and Virulence Determinants of Escherichia coli Strains Isolated from Patients with Crohn's Disease in Spain and Chile.

Adherent-invasive Escherichia coli (AIEC) strains are genetically variable and virulence factors for AIEC are non-specific. FimH is the most studied pathogenicity-related protein, and there have been few studies on other proteins, such as Serine Protease Autotransporters of Enterobacteriacea (SPATEs). The goal of this study is to characterize E. coli strains isolated from patients with Crohn's disease (CD) in Chile and Spain, and identify genetic differences between strains associated with virulence markers and clonality. We characterized virulence factors and genetic variability by pulse field electrophoresis (PFGE) in 50 E. coli strains isolated from Chilean and Spanish patients with CD, and also determined which of these strains presented an AIEC phenotype. Twenty-six E. coli strains from control patients were also included. PFGE patterns were heterogeneous and we also observed a highly diverse profile of virulence genes among all E. coli strains obtained from patients with CD, including those strains defined as AIEC. Two iron transporter genes chuA, and irp2, were detected in various combinations in 68-84% of CD strains. We found that the most significant individual E. coli genetic marker associated with CD E. coli strains was chuA. In addition, patho-adaptative fimH mutations were absent in some of the highly adherent and invasive strains. The fimH adhesin, the iron transporter irp2, and Class-2 SPATEs did not show a significant association with CD strains. The V27A fimH mutation was detected in the most CD strains. This study highlights the genetic variability of E. coli CD strains from two distinct geographic origins, most of them affiliated with the B2 or D E. coli phylogroups and also reveals that nearly 40% of Chilean and Spanish CD patients are colonized with E.coli with a characteristic AIEC phenotype.

Aging and Health Policies in Chile: New Agendas for Research.

Abstract-Population aging is among the most important global transformations. Compared to European and North American countries, Chile is among the countries with the fastest growth of life expectancy at birth during recent decades. The aging of Chile's population is related to the improvement of living conditions, but also entails risks that tend to be associated with a rapid economic growth accompanied by large income inequalities and a chronic deficit of basic social benefits. The rapid demographic transition towards an aged population has unfolded in a context of poor development of public policies to tackle the opportunities and needs associated with an aging society. This article provides a brief overview of current Chilean public policy on aging, with a focus on healthy aging as defined by World Health Organization. The discussion addresses core challenges to successfully achieve healthy aging in Chile.

Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration.

Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC) cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC) cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC) cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration.

Modeling acclimatization by hybrid systems: condition changes alter biological system behavior models.

In order to describe the dynamic behavior of a complex biological system, it is useful to combine models integrating processes at different levels and with temporal dependencies. Such combinations are necessary for modeling acclimatization, a phenomenon where changes in environmental conditions can induce drastic changes in the behavior of a biological system. In this article we formalize the use of hybrid systems as a tool to model this kind of biological behavior. A modeling scheme called strong switches is proposed. It allows one to take into account both minor adjustments to the coefficients of a continuous model, and, more interestingly, large-scale changes to the structure of the model. We illustrate the proposed methodology with two applications: acclimatization in wine fermentation kinetics, and acclimatization of osteo-adipo differentiation system linking stimulus signals to bone mass.

Reusing and composing models of cell fate regulation of human bone precursor cells.

In order to treat osteoporosis and other bone mass disorders it is necessary to understand the regulatory processes that control the cell fate decisions responsible for going from bone precursor cells to bone tissue. Many processes interact to regulate cell division, differentiation and apoptosis. There are models for these basic processes, but not for their interactions. In this work we use the theory of switched systems, reuse and composition of validated models to describe the cell fate decisions leading to bone and fat formation. We describe the differentiation of osteo-adipo progenitor cells by composing its model with differentiation stimuli. We use the activation of the Wnt pathway as stimulus to osteoblast lineage, including regulation of cell division and apoptosis. This model is our first step to simulate physiological responses in silico to treatments for bone mass disorders.

Genome-wide identification of new Wnt/beta-catenin target genes in the human genome using CART method.

BACKGROUND: The importance of in silico predictions for understanding cellular processes is now widely accepted, and a variety of algorithms useful for studying different biological features have been designed. In particular, the prediction of cis regulatory modules in non-coding human genome regions represents a major challenge for understanding gene regulation in several diseases. Recently, studies of the Wnt signaling pathway revealed a connection with neurodegenerative diseases such as Alzheimer's. In this article, we construct a classification tool that uses the transcription factor binding site motifs composition of some gene promoters to identify new Wnt/beta-catenin pathway target genes potentially involved in brain diseases. RESULTS: In this study, we propose 89 new Wnt/beta-catenin pathway target genes predicted in silico by using a method based on multiple Classification and Regression Tree (CART) analysis. We used as decision variables the presence of transcription factor binding site motifs in the upstream region of each gene. This prediction was validated by RT-qPCR in a sample of 9 genes. As expected, LEF1, a member of the T-cell factor/lymphoid enhancer-binding factor family (TCF/LEF1), was relevant for the classification algorithm and, remarkably, other factors related directly or indirectly to the inflammatory response and amyloidogenic processes also appeared to be relevant for the classification. Among the 89 new Wnt/beta-catenin pathway targets, we found a group expressed in brain tissue that could be involved in diverse responses to neurodegenerative diseases, like Alzheimer's disease (AD). These genes represent new candidates to protect cells against amyloid beta toxicity, in agreement with the proposed neuroprotective role of the Wnt signaling pathway. CONCLUSIONS: Our multiple CART strategy proved to be an effective tool to identify new Wnt/beta-catenin pathway targets based on the study of their regulatory regions in the human genome. In particular, several of these genes represent a new group of transcriptional dependent targets of the canonical Wnt pathway. The functions of these genes indicate that they are involved in pathophysiology related to Alzheimer's disease or other brain disorders.

Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/beta-catenin signaling pathway.

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) plays a key role in the regulation of calcium-dependent gene expression. The expression of CaMKIV and the activation of CREB regulated genes are involved in memory and neuronal survival. We report here that: (a) a bioinformatic analysis of 15,476 promoters of the human genome predicted several Wnt target genes, being CaMKIV a very interesting candidate; (b) CaMKIV promoter contains TCF/LEF transcription motifs similar to those present in Wnt target genes; (c) biochemical studies indicate that lithium and the canonical ligand Wnt-3a induce CaMKIV mRNA and protein expression levels in rat hippocampal neurons as well as CaMKIV promoter activity; (d) treatment of hippocampal neurons with Wnt-3a increases the binding of beta-catenin to the CaMKIV promoter: (e) In vivo activation of the Wnt signaling improve spatial memory impairment and restores the expression of CaMKIV in a mice double transgenic model for Alzheimer's disease which shows decreased levels of the kinase. We conclude that CaMKIV is regulated by the Wnt signaling pathway and that its expression could play a role in the neuroprotective function of the Wnt signaling against the Alzheimer's amyloid peptide.