The Oropharyngeal Dysphagia Screening Test for Patients and Professionals: Validation in Cognitive Impairment and in Severe Mental Illness.

Dysphagia is a symptom that appears with high prevalence in persons diagnosed with dementia, intellectual disability, or severe mental illness. Risk of aspiration pneumonia or even death is very high in these populations. However, screening for dysphagia risk in these patients is complicated by the fact that most of them suffer from cognitive impairments and behavioral manifestations that hinder the assessment process using the existing screening tests. The aim of this study was to validate the Oropharyngeal Dysphagia Screening Test for Patients and Professionals, in patients with cognitive impairment (dementia/intellectual disability) or with severe mental illness (schizophrenia and other psychotic disorders, bipolar disorder, or major depressive disorder). For this purpose, 148 institutionalized patients were evaluated by professionals responsible for their food intake. The Oropharyngeal Dysphagia Screening Test for Patients and Professionals was used to assess its validity in screening for oropharyngeal dysphagia in patients with cognitive impairments and in patients with severe mental illness. Also, the Eating Assessment Tool-10 and the Swallowing Disturbance Questionnaire were used for convergent reliability procedures. Four comparison groups were established: patients with cognitive impairment with and without oropharyngeal dysphagia, and patients with severe mental illness with and without oropharyngeal dysphagia. Results from the Oropharyngeal Dysphagia Screening Test for Patients and Professionals adequately distinguished between groups with and without dysphagia, in addition to presenting adequate levels of convergent validity and reliability. These results were obtained from other-reports (professionals responsible for patients' food intake), using a simple, quickly applied test that does not require the use of food in patients with an altered cognitive state or with severe mental illness. With this study we expand the validity of the Oropharyngeal Dysphagia Screening Test for Patients and Professionals in populations with severe cognitive deficits and mental illness in which there is a great deficiency of oropharyngeal dysphagia screening instruments.

Impulsive and compulsive reading comprehension in the prison population.

BACKGROUND: Developmental dyslexia is characterized by reading and writing deficits that persist into adulthood. Dyslexia is strongly associated with academic underachievement, as well as impulsive, compulsive, and criminal behaviors. The aims of this study were to investigate impulsive or compulsive reading comprehension, analyzing the differences in reading errors between two distinct groups -one with Antisocial Personality Disorder (ASPD) and another with Obsessive-Compulsive Personality Disorder (OCPD) and examine their correlation with criminal behavior within a prison population. METHODS: We gathered data from 194 participants: 81 with ASPD and 113 with OCPD from a prison center. Participants took part in interviews to gather data on demographic, criminal, and behavioral data. Additionally, the participants underwent various assessments, including the International Examination for Personality Disorders; Symptom Inventory, and Battery for the Assessment of Reading Processes in Secondary and High School - Revised. RESULTS: Our analysis revealed differences in reading skills between the ASPD and OCPD groups. Specifically, the OCPD group showed poorer performance on lexical selection, semantic categorization, grammar structures, grammatical judgements, and expository comprehension when compared with the ASPD group. Conversely, the OCPD group obtained higher scores on narrative comprehension relative to the ASPD group. CONCLUSIONS: The OCPD group showed slow lexical-phonological coding and phonological activation.

Development of visual attention control in early childhood: Associations with temperament and home environment.

Endogenous visual attention orienting is early available from infancy. It shows a steady development during the preschool period towards monitoring and managing executive attention to optimize the interplay between environmental contingencies and internal goals. The current study aims at understanding this transition from basic forms of endogenous control of visual orienting towards the engagement of executive attention, as well as their association with individual differences in temperament and home environment. A total of 150 children between 2 and 4 years of age were evaluated in a Visual Sequence Learning task, measuring visual anticipations in easy (context-free) and complex (context-dependent) stimuli transitions. Results showed age to be a predictor of a reduction in exogenous attention, as well as increased abilities to attempt to anticipate and to correctly anticipate in complex transitions. Home chaos predicted more complex correct anticipations, suggesting that the exposure to more unpredictable environments could benefit learning in context-dependent settings. Finally, temperamental surgency was found to be positively related to sustained attention in the task. Results are informative of age differences in visual attention control during toddlerhood and early childhood, and their association with temperament and home environment.

Writing Abilities in Compulsive Prisoners.

Research has found links between academic failure and criminal offending and suggest that many incarcerated young people have experienced significant behavioral and learning problems in school, which could result in criminal outcomes and poor academic performance. The objective of this study was to analyse writing disorders in impulsive and compulsive prisoners. The sample was composed of 194 male prisoners, of which 81 had been diagnosed with Antisocial Personality Disorder and 113 with Obsessive Compulsive Personality Disorder. Male participants were recruited at the Granada Prison Center. They completed the Demographic, Crime, and Institutional Behavior Interview; the International Personality Disorder Examination (IPDE); The Symptom Checklist (SCL-90-R) and Assessment Battery of Writing Processes (PROESC in its Spanish acronym). We found that prisoners with writing disorders generally have difficulties in the skills necessary to write properly due to impulsive and compulsive behavior.

Las repercusiones de la Dislexia en la Autoestima, en el Comportamiento Socioemocional y en la Ansiedad en Escolares / Dyslexia impact on self-esteem, socioemotional behavior, and anxiety during the schooling period

Más allá de las repercusiones neurobiológicas, cognitivas y académicas que acarrea la dislexia, se conocen poco las consecuencias en otras dimensiones del desarrollo humano, como las emocionales y de comportamiento socioemocional. Niños y adolescentes con dislexia (n = 41) fueron comparados con compañeros de su misma clase sin dificultades (n = 25), mediante pruebas estandarizadas que evaluaban la autoestima, la ansiedad y los problemas de comportamiento socioemocional. Los resultados, derivados del análisis estadístico con t de Student, mostraron que los alumnos con dislexia manifestaban un nivel menor de autoestima y mayor en problemas de comportamiento que sus iguales sin dificultades. Si bien presentaron más ansiedad en general, las diferencias resultaron significativas únicamente en ansiedad social y de separación. Por su repercusión a nivel escolar urge considerar las medidas para remediar las secuelas asociadas a las dificultades de aprendizaje, trabajando directamente las dimensiones emocionales afectadas y reduciendo las dificultades académicas de estos escolares, así como reflexionando sobre las metodologías didácticas en el grupo clase

Most research about dyslexia and comorbid learning difficulties has focused on neurobiological, cognitive, and academic effects. However, less is known about the dyslexia impact on other aspects of human development, as socioemotional or affective dimensions (i.e., self-esteem, anxiety, or socioemotional behavior). These dimensions were tested in students with dyslexia (n = 41), compared to students without learning difficulties (n = 25). Standardized measures of self-esteem, anxiety, and socioemotional behavior were used. Results of the analysis with Student's t indicated higher scores in the control group than in students with dyslexia in both self-esteem and socioemotional behavior. Results regarding anxiety showed that students with dyslexia would present more anxiety, particularly in social anxiety and separation anxiety. This study highlights the need for intervention measures to be applied at school, working in parallel learning difficulties with affective and socioemotional dimensions in students with dyslexia

Common and Differential Traits of the Membrane Lipidome of Colon Cancer Cell Lines and their Secreted Vesicles: Impact on Studies Using Cell Lines.

Colorectal cancer (CRC) is the fourth leading cause of cancer death in the world. Despite the screening programs, its incidence in the population below the 50s is increasing. Therefore, new stratification protocols based on multiparametric approaches are highly needed. In this scenario, the lipidome is emerging as a powerful tool to classify tumors, including CRC, wherein it has proven to be highly sensitive to cell malignization. Hence, the possibility to describe the lipidome at the level of lipid species has renewed the interest to investigate the role of specific lipid species in pathologic mechanisms, being commercial cell lines, a model still heavily used for this purpose. Herein, we characterize the membrane lipidome of five commercial colon cell lines and their extracellular vesicles (EVs). The results demonstrate that both cell and EVs lipidome was able to segregate cells according to their malignancy. Furthermore, all CRC lines shared a specific and strikingly homogenous impact on ether lipid species. Finally, this study also cautions about the need of being aware of the singularities of each cell line at the level of lipid species. Altogether, this study firmly lays the groundwork of using the lipidome as a solid source of tumor biomarkers.

Wisconsin Card Sorting Test-Learning Potential: Usefulness for Assessing Children with Autism Spectrum Disorder.

This study analyzes the Wisconsin Card Sorting Test-Learning Potential (WCST-LP) in children with Autism Spectrum Disorder (ASD) versus children with typical development (TD). Its main aim was to assess: the test's construct validity; the effect of IQ on its pretest and LP scores; and whether the WCST-LP held any relationship to cognitive/EF and social abilities. Participants were 105 children (43 with ASD/62 with TD). Results showed evidence of construct validity in an ASD population (improvements from pretest to posttest), that full IQ influenced pretest performance but did not affect LP, and that a relationship between LP and verbal and social abilities existed only in children with ASD. Conclusions indicate the appropriateness of the WCST-LP in ASD prognosis assessment.

Design and Validation of the Oropharyngeal Dysphagia Screening Test for Patients and Professionals: A Preliminary Study.

Dysphagia is a very common symptom in people of advanced age and with neurological diseases, although it often remains undiagnosed. At present, there are few assessment tools adapted for the Spanish-speaking population; of the few existing, most of them follow a self-reporting format, which requires a well-preserved cognitive state in the patient in order to be tested. Therefore, the main aim of this study was to design and validate an instrument for screening dysphagia without food, which could have a quick application and did not compromise the patient's safety. A secondary aim was to study the test's ability to examine this symptom in people with cognitive disorders. The study was carried out with 206 participants divided into three groups: people with dysphagia and with preserved cognitive abilities, people with dysphagia and with altered cognitive abilities, and people without dysphagia and with preserved cognitive skills (control group). Participants were assessed with the designed Oropharyngeal Dysphagia Screening Test for Patients and Professionals and other dysphagia tests. The results revealed appropriate psychometric features: reliability and validity both for screening dysphagia directly with the patients or if the tester is the professional caregiver responsible for feeding (in cases of altered cognitive abilities). As conclusion, the Oropharyngeal Dysphagia Screening Test for Patients and Professionals is an instrument of easy use and of short duration that has shown adequate results of reliability and validity, thus being useful for the screening of dysphagia in Spanish-speaking populations.

Testing the visual impedance effect in children with and without reading difficulties using a new visual reasoning task.

This study examined reasoning skills in children, specifically transitive reasoning and the visual impedance effect, with a new visual/pictorial task. The visual impedance effect is the effect produced by the possible interference in the reasoning process of irrelevant details elicited from the premises of a reasoning task. The new task had no reading requirements, which made it suitable for testing reasoning in primary school children, especially children with reading difficulties (RD), such as dyslexia. The study aimed also to validate the possible use of the task for studying reasoning and detecting the visual impedance effect without the interference of reading skills and to investigate the association between transitive reasoning and reading abilities. A pilot study (N = 10) was used to test the suitability of the new task for primary school children. Afterwards, the task was tested on a larger sample of children of third to sixth Grade, with and without RD (N = 84). Results showed that the new task is able to detect the main reasoning effects as well as the visual impedance effect. The findings are discussed, with the new task considered appropriate for studying reasoning skills in child populations both with and without RD.

The triacylglycerol, hydroxytriolein, inhibits triple negative mammary breast cancer cell proliferation through a mechanism dependent on dihydroceramide and Akt.

The plasma membrane is an attractive target for new anticancer drugs, not least because regulating its lipid structure can control multiple signaling pathways involved in cancer cell proliferation, differentiation and survival. Accordingly, the novel anticancer drug hydroxytriolein (HTO) was designed to interact with and regulate the composition and structure of the membrane, which in turn controls the interaction of amphitropic signaling membrane proteins with the lipid bilayer. Changes in signaling provoked by HTO impair the growth of triple negative breast cancer (TNBC) cells, aggressive breast tumor cells that have a worse prognosis than other types of breast cancers and for which there is as yet no effective targeted therapy. HTO alters the lipid composition and structure of cancer cell membranes, inhibiting the growth of MDA-MB-231 and BT-549 TNBC cells in vitro. Depending on the cellular context, HTO could regulate two pathways involved in TNBC cell proliferation. On the one hand, HTO might stimulate ERK signaling and induce TNBC cell autophagy, while on the other, it could increase dihydroceramide and ceramide production, which would inhibit Akt independently of EGFR activation and provoke cell death. In vivo studies using a model of human TNBC show that HTO and its fatty acid constituent (2-hydroxyoleic acid) impair tumor growth, with no undesired side effects. For these reasons, HTO appears to be a promising anticancer molecule that targets the lipid bilayer (membrane-lipid therapy). By regulating membrane lipids, HTO controls important signaling pathways involved in cancer cell growth, the basis of its pharmacological efficacy and safety.

Reasoning and Reading in Adults. A New Reasoning Task for Detecting the Visual Impendance Effect.

The visual impedance hypothesis states that at the time of reasoning, the reading context provokes visual images, which may add irrelevant details to an inference and thus could hamper reasoning. This study aims to create a new visual version of a reasoning task, similar to the traditional propositional task of relational syllogisms, but based on visuospatial components. Using such a task, it would be possible to investigate the deductive ability of relational inferences in tests without the need for reading. Two reasoning tasks were used and measures of working memory, visuospatial memory, intelligence, and reading comprehension were taken. The participants were 61 university students without reading difficulties. Results show that both versions of the reasoning task work similarly in finding the main reasoning effects expected. Findings support the visual impedance effect, that is, fewer correct responses in problems with imaginable contents than with neutral ones. They indicate that this new visual task could be used to explore reasoning skills without reading being involved, and this would be useful for testing reasoning in people both with and without reading difficulties.

Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: implications for therapy.

Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble glycogen, which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions. Because soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified WT and GBE1Y329S proteins with different types of model membranes (liposomes). Interestingly, both triheptanoin and some triacylglycerol mimetics (TGMs) we have designed (TGM0 and TGM5) markedly enhance GBE1Y329S activity, possibly enough for reversing APBD symptoms. We show that the GBE1Y329S mutation exposes a hydrophobic amino acid stretch, which can either stabilize and enhance or alternatively, reduce the enzyme activity via alteration of protein-membrane interactions. Additionally, we found that WT, but not Y329S, GBE1 activity is modulated by Ca2+ and phosphatidylserine, probably associated with GBE1-mediated regulation of energy consumption and storage. The thermal stabilization and increase in GBE1Y329S activity induced by TGM5 and its omega-3 oil structure suggest that this molecule has a considerable therapeutic potential for treating APBD.

Role of the C-terminal basic amino acids and the lipid anchor of the Gγ2 protein in membrane interactions and cell localization.

Heterotrimeric G proteins are peripheral membrane proteins that frequently localize to the plasma membrane where their presence in molar excess over G protein coupled receptors permits signal amplification. Their distribution is regulated by protein-lipid interactions, which has a clear influence on their activity. Gßγ dimer drives the interaction between G protein heterotrimers with cell membranes. We focused our study on the role of the C-terminal region of the Gγ2 protein in G protein interactions with cell membranes. The Gγ2 subunit is modified at cysteine (Cys) 68 by the addition of an isoprenyl lipid, which is followed by the proteolytic removal of the last three residues that leaves an isoprenylated and carboxyl methylated Cys-68 as the terminal amino acid. The role of Cys isoprenylation of the CAAX box has been defined for other proteins, yet the importance of proteolysis and carboxyl methylation of isoprenylated proteins is less clear. Here, we showed that not only geranylgeranylation but also proteolysis and carboxyl methylation are essential for the correct localization of Gγ2 in the plasma membrane. Moreover, we showed the importance of electrostatic interactions between the inner leaflet of the plasma membrane and the positively charged C-terminal domain of the Gγ2 subunit (amino acids Arg-62, Lys-64 and Lys-65) as a second signal to reach the plasma membrane. Indeed, single or multiple point mutations at Gγ2 C-terminal amino acids have a significant effect on Gγ2 protein-plasma membrane interactions and its localization to charged Ld (liquid disordered) membrane microdomains. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Identification of Biomarkers of Necrosis in Xenografts Using Imaging Mass Spectrometry.

Xenografts are commonly used to test the effect of new drugs on human cancer. However, because of their heterogeneity, analysis of the results is often controversial. Part of the problem originates in the existence of tumor cells at different metabolic stages: from metastatic to necrotic cells, as it happens in real tumors. Imaging mass spectrometry is an excellent solution for the analysis of the results as it yields detailed information not only on the composition of the tissue but also on the distribution of the biomolecules within the tissue. Here, we use imaging mass spectrometry to determine the distribution of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and their plasmanyl- and plasmenylether derivatives (PC-P/O and PE-P/O) in xenografts of five different tumor cell lines: A-549, NCI-H1975, BX-PC3, HT29, and U-87 MG. The results demonstrate that the necrotic areas showed a higher abundance of Na(+) adducts and of PC-P/O species, whereas a large abundance of PE-P/O species was found in all the xenografts. Thus, the PC/PC-ether and Na(+)/K(+) ratios may highlight the necrotic areas while an increase on the number of PE-ether species may be pointing to the existence of viable tumor tissues. Furthermore, the existence of important changes in the concentration of Na(+) and K(+) adducts between different tissues has to be taken into account while interpreting the imaging mass spectrometry results. Graphical Abstract ᅟ.

Optimized Protocol To Analyze Changes in the Lipidome of Xenografts after Treatment with 2-Hydroxyoleic Acid.

Xenografts are a popular model for the study of the action of new antitumor drugs. However, xenografts are highly heterogeneous structures, and therefore it is sometimes difficult to evaluate the effects of the compounds on tumor metabolism. In this context, imaging mass spectrometry (IMS) may yield the required information, due to its inherent characteristics of sensitivity and spatial resolution. To the best of our knowledge, there is still no clear analysis protocol to properly evaluate the changes between samples due to the treatment. Here we present a protocol for the evaluation of the effect of 2-hydroxyoleic acid (2-OHOA), an antitumor compound, on xenografts lipidome based on IMS. Direct treated/control comparison did not show conclusive results. As we will demonstrate, a more sophisticated protocol was required to evaluate these changes including the following: (1) identification of different areas in the xenograft, (2) classification of these areas (necrotic/viable) to compare similar types of tissues, (3) suppression of the effect of the variation of adduct formation between samples, and (4) normalization of the variables using the standard deviation to eliminate the excessive impact of the stronger peaks in the statistical analysis. In this way, the 36 lipid species that experienced the largest changes between treated and control were identified. Furthermore, incorporation of 2-hydroxyoleic acid to a sphinganine base was also confirmed by MS/MS. Comparison of the changes observed here with previous results obtained with different techniques demonstrates the validity of the protocol.

The Novel Anticancer Drug Hydroxytriolein Inhibits Lung Cancer Cell Proliferation via a Protein Kinase Cα- and Extracellular Signal-Regulated Kinase 1/2-Dependent Mechanism.

Membrane lipid therapy is a novel approach to rationally design or discover therapeutic molecules that target membrane lipids. This strategy has been used to design synthetic fatty acid analogs that are currently under study in clinical trials for the treatment of cancer. In this context, and with the aim of controlling tumor cell growth, we have designed and synthesized a hydroxylated analog of triolein, hydroxytriolein (HTO). Both triolein and HTO regulate the biophysical properties of model membranes, and they inhibit the growth of non-small-cell lung cancer (NSCLC) cell lines in vitro. The molecular mechanism underlying the antiproliferative effect of HTO involves regulation of the lipid membrane structure, protein kinase C-α and extracellular signal-regulated kinase activation, the production of reactive oxygen species, and autophagy. In vivo studies on a mouse model of NSCLC showed that HTO, but not triolein, impairs tumor growth, which could be associated with the relative resistance of HTO to enzymatic degradation. The data presented explain in part why olive oil (whose main component is the triacylglycerol triolein) is preventive but not therapeutic, and they demonstrate a potent effect of HTO against cancer. HTO shows a good safety profile, it can be administered orally, and it does not induce nontumor cell (fibroblast) death in vitro or side effects in mice, reflecting its specificity for cancer cells. For these reasons, HTO is a good candidate as a drug to combat cancer that acts by regulating lipid structure and function in the cancer cell membrane.

Dietary glycaemic index and glycaemic load in a rural elderly population (60-74 years of age) and their relationship with cardiovascular risk factors.

PURPOSE: To examine the association between dietary glycaemic index (GI) and dietary glycaemic load (GL) with cardiovascular disease (CVD) risk factors in a rural elderly population. METHODS: A cross-sectional study was conducted in 343 subjects (60-74 years) residing in a Spanish rural area (Priego de Córdoba). Subjects were selected using stratified random sampling. Food intake was assessed using a validated food frequency questionnaire (FFQ). We assigned GI values to each item of the FFQ to estimate dietary GI and GL. Multivariate linear regression models were fitted to assess the association between GI/GL with CVD risk factors (blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, body mass index, waist circumference and blood pressure). The potential modifying effect of sex, smoking status, diabetes and medication has been explored. RESULTS: A statistically significant inverse association between dietary GI and blood glucose was found in the multivariate model (p = 0.029): for every 10 unit increment of GI, serum glucose levels decreased by 0.2 units. However, statistical significance was lost after controlling for diabetes or hypoglycaemic medication. In the crude model, dietary GL was associated with triglycerides (ß for every 10 GL units increase = 0.70, p = 0.005), but statistical significance was lost in the multivariate model (p = 0.508). No associations were found between dietary GI/GL and the rest of the variables studied. CONCLUSIONS: Neither dietary GI nor GL were associated with CVD risk factors in the study population of Priego de Córdoba. Results obtained suggest the necessity to consider the diagnosis of diabetes in these studies.

Analysis of the lipidome of xenografts using MALDI-IMS and UHPLC-ESI-QTOF.

Human tumor xenografts in immunodeficient mice are a very popular model to study the development of cancer and to test new drug candidates. Among the parameters analyzed are the variations in the lipid composition, as they are good indicators of changes in the cellular metabolism. Here, we present a study on the distribution of lipids in xenografts of NCI-H1975 human lung cancer cells, using MALDI imaging mass spectrometry and UHPLC-ESI-QTOF. The identification of lipids directly from the tissue by MALDI was aided by the comparison with identification using ESI ionization in lipid extracts from the same xenografts. Lipids belonging to PCs, PIs, SMs, DAG, TAG, PS, PA, and PG classes were identified and their distribution over the xenograft was determined. Three areas were identified in the xenograft, corresponding to cells in different metabolic stages and to a layer of adipose tissue that covers the xenograft.

Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets.

The complex dual mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent anti-tumor compound used in membrane lipid therapy (MLT), has yet to be fully elucidated. It has been demonstrated that 2OHOA increases the sphingomyelin (SM) cell content via SM synthase (SGMS) activation. Its presence in membranes provokes changes in the membrane lipid structure that induce the translocation of PKC to the membrane and the subsequent overexpression of CDK inhibitor proteins (e.g., p21(Cip1)). In addition, 2OHOA also induces the translocation of Ras to the cytoplasm, provoking the silencing of MAPK and its related pathways. These two differential modes of action are triggered by the interactions of 2OHOA with either lipids or proteins. To investigate the molecular basis of the different interactions of 2OHOA with membrane lipids and proteins, we synthesized the R and S enantiomers of this compound. A molecular dynamics study indicated that both enantiomers interact similarly with lipid bilayers, which was further confirmed by X-ray diffraction studies. By contrast, only the S enantiomer was able to activate SMS in human glioma U118 cells. Moreover, the anti-tumor efficacy of the S enantiomer was greater than that of the R enantiomer, as the former can act through both MLT mechanisms. The present study provides additional information on this novel therapeutic approach and on the magnitude of the therapeutic effects of type-1 and type-2 MLT approaches. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

Two isoforms of Sister-Of-Mammalian Grainyhead have opposing functions in endothelial cells and in vivo.

OBJECTIVE: Sister-of-Mammalian Grainyhead (SOM) is a member of the Grainyhead family of transcription factors. In humans, 3 isoforms are derived from differential first exon usage and alternative splicing and differ only in their N terminal domain. SOM2, the only variant also present in mouse, induces endothelial cell migration and protects against apoptosis. The functions of the human specific isoforms SOM1 and SOM3 have not yet been investigated. Therefore we wanted to elucidate their functions in endothelial cells. APPROACH AND RESULTS: Overexpression of SOM1 in primary human endothelial cells induced migration, phosphorylation of Akt1 and endothelial nitric oxide synthase, and protected against apoptosis, whereas SOM3 had opposite effects; isoform-specific knockdowns confirmed the disparate effects on apoptosis. After reporter assays demonstrated that both are active transcription factors, microarray analyses revealed that they induce different target genes, which could explain the different cellular effects. Overexpression of SOM3 in zebrafish embryos resulted in increased lethality and severe deformations, whereas SOM1 had no deleterious effect. CONCLUSIONS: Our data demonstrate that the splice variant-derived isoforms SOM1 and SOM3 induce opposing effects in primary human endothelial cells and in a whole animal model, most likely through the induction of different target genes.