Proteomic identification and functional characterization of prohibitin 1 and 2 in T cell activation, expansion, survival and disease

Several immune pathologies are the result of aberrant regulation of T lymphocytes. Pronounced T cell proliferation can result in autoimmunity or hematologic malignancy, whereas loss of T cell activity can manifest as immunodeficiency. Thus, there is a critical need to characterize the signal transduction pathways that mediate T cell activation so that novel and rational strategies to detect and effectively control T cell mediated disease can be achieved. ^ The first objective of this dissertation was to identify and characterize novel T cell regulatory proteins that are differentially expressed upon antigen induced activation. Using a functional proteomics approach, two members of the prohibitin (Phb) family of proteins, Phb1 and Phb2, were determined to be upregulated upon activation of primary human T cells. Furthermore, their regulated expression was dependent upon CD3 and CD28 signaling pathways which synergistically increased their expression. In contrast to previous reports of Phb nuclear localization, both proteins were determined to localize to the mitochondrial inner membrane of human T cells. Additionally, novel Phb phosphorylation sites were identified and characterized using mass spectrometry, phosphospecific antibodies and site directed mutagenesis. ^ Prohibitins have been proposed to play important roles in cancer development however the mechanism of action has not been elucidated. The second objective of this dissertation was to define the functional role of Phbs in T cell activity, survival and disease. Compared to levels in normal human T cells, Phb expression was higher in the human tumor T cell line Kit225 and subcellularly localized to the mitochondrion. Ablation of Phb expression by siRNA treatment of Kit225 cells resulted in disruption of mitochondrial membrane potential and significantly enhanced their sensitivity to cell death, suggesting they serve a protective function in T cells. Furthermore, Q-RT-PCR analysis of human oncology cDNA expression libraries indicated the Phbs may represent hematological cancer biomarkers. Indeed, Phb1 and Phb2 protein levels were 6-10 fold higher in peripheral blood mononuclear cells isolated from malignant lymphoma and multiple myeloma patients compared to healthy individuals. ^ Taken together, Phb1 and Phb2 are novel phosphoproteins upregulated during T cell activation and transformation to function in the maintenance of mitochondrial integrity and perhaps energy metabolism, thus representing previously unrecognized intracellular biomarkers and therapeutic targets for regulating T cell activation and hematologic malignancies. ^

The application of cognitive orientation to daily occupational performance (CO-OP) with children 5-7 years with developmental coordination disorder

There has been an increase in the use of cognitive frameworks in occupational therapy with children with developmental coordination disorder (DCD). Investigations into the utility of one such cognitive approach, namely Cognitive Orientation to (daily) Occupational Performance (CO-OP), with children with DCD have shown the intervention to be effective with children over 7 years. However, there has been limited research into its utility with younger children. This paper presents two case studies to demonstrate the use of CO-OP with children aged 5-7 years. Two boys with DCD engaged in 10 sessions of CO-OP. These younger children were found to be able to use the global framework (Goal, Plan, Do, Check) to improve their task performance, to develop plans using domain-specific strategies and to engage in checking strategies. Issues relating to attention, motivation and goal setting are discussed in the context of the two case studies.

Cognitive structures, strategies and instruction

This thesis is organised into three parts. In Part 1 relevant literature is reviewed and three critical components in the development of a cognitive approach to instruction are identified. These three components are considered to be the structure of the subject-matter, the learner's cognitive structures, and the learner's cognitive strategies which act as control and transfer devices between the instructional materials and the learner's cognitive structures. Six experiments are described in Part 2 which is divided into two methodologically distinct units. The three experiments of Unit 1 examined how learning from materials constructed from concept name by concept attribute matrices is influenced by learner or experimenter controlled sequence and organisation. The results suggested that the relationships between input organisation, output organisation and recall are complex and highlighted the importance of investigating organisational strategies at both acquisition and recall. The role of subjects previously acquired knowledge and skills in relation to the instructional material was considered to be an important factor. The three experiments of Unit 2 utilised a "diagramming relationships methodology" which was devised as one means of investigating the processes by which new information is assimilated into an individual's cognitive structure. The methodology was found to be useful in identifying cognitive strategies related to successful task performance. The results suggested that errors could be minimised and comprehension improved on the diagramming relationships task by instructing subjects in ways which induced successful processing operations. Part 3 of this thesis highlights salient issues raised by the experimental work within the framework outlined in Part 1 and discusses potential implications for future theoretical developments and research.

Social-cognitive antecedents of ambidextrous orientation in family-owned startups: The role of family ties, achievement motivation, and internal locus of control

Regulatory Focus Theory predicts that the motivation to self-regulate goal-directed thought and behavior depends on two distinct regulation strategies: a promotion focus based on attaining gains and a prevention focus based on avoiding losses. This study took a social-cognitive approach predicting that regulatory focus has an impact on how family startups (several family related founders) explore "new ideas", exploit "old certainties" and achieve the balance of both (ambidexterity), compared to lone founder startups (only one founder present). It was proposed that the social context of family ties among founders leads them to a prevention focus concerned with avoiding the loss of the socio-emotional benefits of those ties. In order to avoid such a loss, family founders were expected to increase their risk perceptions and thus, explore less than lone founders, who lack such socio-emotional ties. It was also proposed that two commonly used psychological traits in entrepreneurship research —achievement motivation and internal locus of control, predispose entrepreneurs to a promotion focus. Founders with a promotion focus, in turn, were hypothesized to lead startups to more risk-seeking behaviors and to more explorative orientation. The previous argument was used as a springboard to derive hypotheses about ambidexterity (the ability to exploit and explore simultaneously) and survival hazards. Using Regulatory Focus Theory, exploitative orientation, conceptualized as the motivational strength to continue on previous paths of action, was hypothesized to be not significantly different from that of lone founder startups. Taking previous arguments together, lone founder startups were hypothesized to be more ambidextrous than family startups. Finally, ambidexterity and internal locus of control were hypothesized to reduce survival hazards in family startups. The findings suggested that family startups explore less than lone founder startups even after controlling for group effects. Interesting but contradictory findings revealed that internal locus of control have both a positive direct effect and a positive interaction that increases the explorative and ambidextrous orientation gap of family startups over lone founder startups. As expected, ambidexterity and internal locus of control reduced survival hazards on family startups. Implications for practitioners were derived based on a sample of 470 nascent entrepreneurs.

Acceptance of relapse fears in breast cancer patients: effects of an act-based abridged intervention

Objective: Relapse fear is a common psychological scar in cancer survivors. The aim of this study is to assess the effects of an abridged version of Acceptance and Commitment Therapy (ACT) in breast cancer patients.Method: An open trial was developed with 12 non-metastatic breast cancer patients assigned to 2 conditions, ACT and waiting list. Interventions were applied in just one session and focused on the acceptance of relapse fears through a ‘defusion’ exercise. Interference and intensity of fear measured through subjective scales were collected after each intervention and again 3 months later. Distress, hypochondria and ‘anxious preocupation’ were also evaluated through standardized questionnaires.Results: The analysis revealed that ‘defusion’ contributed to decrease the interference of the fear of recurrence, and these changes were maintained three months after intervention in most subjects. 87% of participants showed clinically significant decreases in interference at follow-up sessions whereas no patient in the waiting list showed such changes. Statistical analysis revealed that the changes in interference were significant when comparing pre, post and follow-up treatment, and also when comparing ACT and waiting list groups. Changes in intensity of fear, distress, anxious preoccupation and hypochondria were also observed.Conclusions: Exposure through ‘defusion’ techniques might be considered a useful option for treatment of persistent fears in cancer patients. This study provides evidence for therapies focusing on psychological acceptance in cancer patients through short, simple and feasible therapeutic methods.

The perception of the African-American community through the eyes of the Hispanic media in the U.S.: a critical discourse analysis of the reporting of the death of Michael Brown

In this paper, 36 English and 38 Spanish news articles were selected from English and Spanish newspapers and magazines published in the U.S.A. from August 2014 to November 2014. All articles discuss the death of Michael Brown, the ensuing protests and police investigations. A discourse analysis shows that there are few differences between reporting by the mainstream and the Hispanic media. Like the mainstream media, the Hispanic media adopts a neutral point of view with regard to the African-American minority. However, it presents a negative opinion with regard to the police. It appears that the Hispanic media does not explicitly side with the African-American community, but rather agrees more with the mainstream media’s opinion and is substantially influenced by it.

Multilingualism and conceptual modelling

One of the leading motivations behind the multilingual semantic web is to make resources accessible digitally in an online global multilingual context. Consequently, it is fundamental for knowledge bases to find a way to manage multilingualism and thus be equipped with those procedures for its conceptual modelling. In this context, the goal of this paper is to discuss how common-sense knowledge and cultural knowledge are modelled in a multilingual framework. More particularly, multilingualism and conceptual modelling are dealt with from the perspective of FunGramKB, a lexico-conceptual knowledge base for natural language understanding. This project argues for a clear division between the lexical and the conceptual dimensions of knowledge. Moreover, the conceptual layer is organized into three modules, which result from a strong commitment towards capturing semantic knowledge (Ontology), procedural knowledge (Cognicon) and episodic knowledge (Onomasticon). Cultural mismatches are discussed and formally represented at the three conceptual levels of FunGramKB.

A cognitive study of polysemy in Chinese 手 shǒu and Spanish mano ‘hand’

When studying polysemy in Chinese and Spanish, a cognitive approach shows what is common in the polysemous patterns of both languages, so that we can make generalizations applicable to other languages and other semantic phenomena of language. The paper’s hypothesis is that there are universal mechanisms of semantic extension that can be highlighted and can be used in teaching and learning languages.

Social-cognitive Antecedents of Ambidextrous Orientation in Family-owned Startups: The Role of Family Ties, Achievement Motivation, and Internal Locus of Control

Regulatory Focus Theory predicts that the motivation to self-regulate goal-directed thought and behavior depends on two distinct regulation strategies: a promotion focus based on attaining gains and a prevention focus based on avoiding losses. This study took a social-cognitive approach predicting that regulatory focus has an impact on how family startups (several family related founders) explore “new ideas”, exploit “old certainties” and achieve the balance of both (ambidexterity), compared to lone founder startups (only one founder present). It was proposed that the social context of family ties among founders leads them to a prevention focus concerned with avoiding the loss of the socio-emotional benefits of those ties. In order to avoid such a loss, family founders were expected to increase their risk perceptions and thus, explore less than lone founders, who lack such socio-emotional ties. It was also proposed that two commonly used psychological traits in entrepreneurship research --achievement motivation and internal locus of control, predispose entrepreneurs to a promotion focus. Founders with a promotion focus, in turn, were hypothesized to lead startups to more risk-seeking behaviors and to more explorative orientation. The previous argument was used as a springboard to derive hypotheses about ambidexterity (the ability to exploit and explore simultaneously) and survival hazards. Using Regulatory Focus Theory, exploitative orientation, conceptualized as the motivational strength to continue on previous paths of action, was hypothesized to be not significantly different from that of lone founder startups. Taking previous arguments together, lone founder startups were hypothesized to be more ambidextrous than family startups. Finally, ambidexterity and internal locus of control were hypothesized to reduce survival hazards in family startups. The findings suggested that family startups explore less than lone founder startups even after controlling for group effects. Interesting but contradictory findings revealed that internal locus of control have both a positive direct effect and a positive interaction that increases the explorative and ambidextrous orientation gap of family startups over lone founder startups. As expected, ambidexterity and internal locus of control reduced survival hazards on family startups. Implications for practitioners were derived based on a sample of 470 nascent entrepreneurs.

Differential expression of genes in salivary glands of male Rhipicephalus (Boophilus)microplus in response to infection with Anaplasma marginale

Background: Bovine anaplasmosis, caused by the rickettsial tick-borne pathogen Anaplasma marginale (Rickettsiales: Anaplasmataceae), is vectored by Rhipicephalus (Boophilus) microplus in many tropical and subtropical regions of the world. A. marginale undergoes a complex developmental cycle in ticks which results in infection of salivary glands from where the pathogen is transmitted to cattle. In previous studies, we reported modification of gene expression in Dermacentor variabilis and cultured Ixodes scapularis tick cells in response to infection with A. marginale. In these studies, we extended these findings by use of a functional genomics approach to identify genes differentially expressed in R. microplus male salivary glands in response to A. marginale infection. Additionally, a R. microplus-derived cell line, BME26, was used for the first time to also study tick cell gene expression in response to A. marginale infection. Results: Suppression subtractive hybridization libraries were constructed from infected and uninfected ticks and used to identify genes differentially expressed in male R. microplus salivary glands infected with A. marginale. A total of 279 ESTs were identified as candidate differentially expressed genes. Of these, five genes encoding for putative histamine-binding protein (22Hbp), von Willebrand factor (94Will), flagelliform silk protein (100Silk), Kunitz-like protease inhibitor precursor (108Kunz) and proline-rich protein BstNI subfamily 3 precursor (7BstNI3) were confirmed by real-time RT-PCR to be down-regulated in tick salivary glands infected with A. marginale. The impact of selected tick genes on A. marginale infections in tick salivary glands and BME26 cells was characterized by RNA interference. Silencing of the gene encoding for putative flagelliform silk protein (100Silk) resulted in reduced A. marginale infection in both tick salivary glands and cultured BME26 cells, while silencing of the gene encoding for subolesin (4D8) significantly reduced infection only in cultured BME26 cells. The knockdown of the gene encoding for putative metallothionein (93 Meth), significantly up-regulated in infected cultured BME26 cells, resulted in higher A. marginale infection levels in tick cells. Conclusions: Characterization of differential gene expression in salivary glands of R. microplus in response to A. marginale infection expands our understanding of the molecular mechanisms at the tick-pathogen interface. Functional studies suggested that differentially expressed genes encoding for subolesin, putative von Willebrand factor and flagelliform silk protein could play a role in A. marginale infection and multiplication in ticks. These tick genes found to be functionally relevant for tick-pathogen interactions will likely be candidates for development of vaccines designed for control of both ticks and tick-borne pathogens.

Neoinstitutionalism and the appropriation of bourdieu's work: a critical assessment

Despite the still present hegemony of the structural-functionalist orthodoxy, the mid 1980's witnesses the insurgence of new philosophical approaches. This body of work had become a vital intellectual and ideological resource for those who wanted to confront the functionalist dominance in organization studies, such as structuration theory, labour process theory and neoinstitutionalist theory. The purpose of this paper is to review the incorporation of Bourdieu's work into neoinstitutionalism. I argue that this appropriation has resulted in a significant loss of theoretical strength. By giving place to the cognitivist metaphors of mental models, "scripts" and "schemas", instead of adopting the notion of habitus, neoinstitutionalism reinforces some of the ever-present dichotomies in social sciences, especially those of agency/structure and individual/society. While neoinstitutionalism was refining the cognitive approach in the 1990's, Bourdieu was moving towards psychoanalysis. Some indications for future research are provided in the concluding notes.

Percepción de riesgo, estrés y consumo de drogas. Estudio transcultural entre adolescentes de Barcelona y Bogotá

Este estudio explora las diferencias en los hábitos de consumo de sustancias psicoactivas, entre jóvenes de Barcelona y Bogotá. Evalúa la influencia de la percepción de riesgo sobre hábitos de consumo y estrategias de afrontamiento. Adicionalmente examina la influencia de la gravedad percibida de una situación estresante sobre estas últimas. Participaron 865 jóvenes de ambas ciudades, entre los 15 y los 18 años. Se utilizaron las variables de riesgo estudiadas por Benthin, Slovic y Severson (1993) para evaluar la percepción de riesgo. Los hábitos de consumo se evaluaron mediante la frecuencia, la intención de consumo, así como la edad de inicio. Se utilizó el CRI:Youth de Moos (1992) para determinar las estrategias de afrontamiento y la valoración del problema estresante. Se encontró que existen diferencias en la edad en que se inicia el consumo de alcohol y en la que se embriagan por primera vez según el género, la ciudad donde residen y la edad del adolescente. Los jóvenes de Barcelona tienen una propensión y un consumo real de marihuana y tabaco mayor que los jóvenes de Bogotá. Percibir placer o beneficios predice un incremento en la intención y la frecuencia de consumo de la mayoría de las sustancias. La facilidad para acceder a éstas sólo presenta una asociación con el uso frecuente del tabaco. Los datos sugieren que la gravedad percibida de estresores relativos a las drogas y la ciudad de residencia tienen un efecto sobre la utilización de las estrategias de evitación y aproximación cognitiva. Adicionalmente no se detectaron diferencias en función de las estrategias de afrontamiento empleadas según las variables de percepción de riesgo a excepción de la presión percibida, la cual aumenta el uso de la reevaluación del problema y la búsqueda de recompensas.

Does falls efficacy predict gait performance in high-functioning older people?

Introduction: Falls efficacy, defined as confidence in performing activities without falling, is a measure of fear of falling associated with gait impairment, falls and functional decline in frail older people. This relationship has not been well studied in high-functioning older people. Objective: To evaluate the relationship between falls efficacy and gait performance in a cohort of high-functioning older people. Methods: Subjects (N = 864) were a subsample of communitydwelling older people aged 65 to 70 years, enrolled in the "Lc65+" cohort, who completed gait assessment at baseline. Data were collected on demographics, functional, cognitive, affective, and health status. Falls efficacy was assessed using the Falls Efficacy Scale- International (FES-I) that measures confidence in performing 16 activities of daily life (ADL) without falling (score from 16 to 64, higher score indicates lower confidence). Gait parameters were measured over a 20 m walk at preferred gait speed using Physilog, an ambulatory gait monitoring system. Results: Participants (mean age 68.0 ± 1.4 years, 55.0% women) had excellent physical (92.2% independent in basic ADL, mean gait speed 1.13 ± 0.16 m/sec) and cognitive (98.0% with MMSE 024) performance. Nevertheless, 22.1% reported depressive symptoms and 16.1% one or more fall in the previous year. Mean FES-I score was 18.8 ± 4.1. Falls efficacy was associated with gait speed (Spearman rho -0.23, P <.001) and gait variability (Spearman rho 0.10, P = .006), measured by the coefficient of variation of stride velocity. These associations remained in multivariate analysis for both gait speed (adj [beta] coeff: -0.008, 95%CI -0.005 to -0.010, P <.001) and gait variability (adj [beta] coeff 0.024, 95%CI 0.003 to 0.045, P = .023) independent of gender, falls, functional, affective, cognitive, and frailty (Fried's criteria) status. On average, compared to subjects with poor confidence in performing one ADL without falling, those with full confidence had a 0.02 m/sec (2%) faster gait speed and a 2% decrease in gait variability. Conclusion: Even in high-functioning older people, poor falls efficacy is associated with reduced gait speed and stability, independent of health, functional, and frailty status. The direction of this relationship needs to be investigated prospectively to determine causality and design interventions to improve gait performance, reduce fall risk, and prevent functional decline.

Validation of an adapted falls efficacy scale in older rehabilitation patients.

OBJECTIVE: To determine the psychometric properties of an adapted version of the Falls Efficacy Scale (FES) in older rehabilitation patients. DESIGN: Cross-sectional survey. SETTING: Postacute rehabilitation facility in Switzerland. PARTICIPANTS: Seventy elderly persons aged 65 years and older receiving postacute, inpatient rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FES questions asked about subject's confidence (range, 0 [none]-10 [full]) in performing 12 activities of daily living (ADLs) without falling. Construct validity was assessed using correlation with measures of physical (basic ADLs [BADLs]), cognitive (Mini-Mental State Examination [MMSE]), affective (15-item Geriatric Depression Scale [GDS]), and mobility (Performance Oriented Mobility Assessment [POMA]) performance. Predictive validity was assessed using the length of rehabilitation stay as the outcome. To determine test-retest reliability, FES administration was repeated in a random subsample (n=20) within 72 hours. RESULTS: FES scores ranged from 10 to 120 (mean, 88.7+/-26.5). Internal consistency was optimal (Cronbach alpha=.90), and item-to-total correlations were all significant, ranging from .56 (toilet use) to .82 (reaching into closets). Test-retest reliability was high (intraclass correlation coefficient, .97; 95% confidence interval, .95-.99; P<.001). Subjects reporting a fall in the previous year had lower FES scores than nonfallers (85.0+/-25.2 vs 94.4+/-27.9, P=.054). The FES correlated with POMA (Spearman rho=.40, P<.001), MMSE (rho=.37, P=.001), BADL (rho=.43, P<.001), and GDS (rho=-.53, P<.001) scores. These relationships remained significant in multivariable analysis for BADLs and GDS, confirming FES construct validity. There was a significant inverse relationship between FES score and the length of rehabilitation stay, independent of sociodemographic, functional, cognitive, and fall status. CONCLUSIONS: This adapted FES is reliable and valid in older patients undergoing postacute rehabilitation. The independent association between poor falls efficacy and increased length of stay has not been previously described and needs further investigations.

Estat de la qüestió de l'estudi de l'aspecte lèxic : una proposta cognitiva de classficació d'esdeveniments

Peer-reviewed