A Fuzzy Model for Performance Appraisal and Promotion Ranking System: A Case Study of Nigerian Air Force

Transparency in the performance appraisal and ranking of service personnel applying for promotion in any organisation is important for efficient human resource management. In this paper, an approach for the promotion screening and ranking of officers in Nigerian Air Force due for a particular rank is discussed. The approach uses fuzzy logic concepts to classify the officers for ranking decisions fairly through the various performance appraisal processes. The research established a new ranking procedure which makes it possible to rank and order the performance of the officers by aggregating the scores from each evaluator. The result from the system is to be used to appraise and promote eligible and qualified officer

In sillico μελέτες αναστολέων της μεταλλαγμένης ογκοπρωτεΐνης BRAFV600E

Το σηματοδοτικό μονοπάτι MAPK το οποίο επηρεάζει τον κυτταρικό πολλαπλασιασμό, την απόπτωση, την διαφοροποίηση και την επιβίωση έχει προκαλέσει το ενδιαφέρον στον τομέα της έρευνας κατά του καρκίνου αφού μεταλλάξεις σε κομβικές πρωτεΐνες του διαταράσσουν την κανονική λειτουργία του με αποτέλεσμα τη δημιουργία νεοπλασιών. Η BRAF είναι μία πρωτεϊνική κινάση σερίνης θρεονίνης και ανήκει στην οικογένεια των RAF πρωτεϊνών που αποτελούν ρυθμιστές στο μονοπάτιMAPK. Μεταλλάξεις που οδηγούν σε συνεχή ενεργοποίηση του BRAF εντοπίζονται σε διαφόρους τύπους καρκίνου όπως το μελάνωμα (50%), ο καρκίνος του θυρεοειδούς (35-70%), ο καρκίνος του παχέoς εντέρου (5-20%), ο καρκίνος του ήπατος (~14%) και ο καρκίνος των ωοθηκών (~30%). Η μετάλλαξη BRAFV600E είναι η πιο συχνή μετάλλαξη οδηγώντας σε υπερενεργοποίηση του μονοπατιού και σε καρκινογένεση. Το Vemurafenib (Zelboraf) και το Dabrafenib (Tafinlar) αποτελούν τα δύο εγκεκριμένα φάρμακα, εκλεκτικοί αναστολείς της BRAFV600E που χορηγούνται για τη θεραπεία μεταστατικού ή μη χειρουργήσιμου μελανώματος που φέρει τη συγκεκριμένη μετάλλαξη. Η αποτελεσματικότητά τους όμως είναι περιορισμένη λόγω εμφάνισης αντίστασης αλλά και της επαγωγής νέων καρκίνων μέσω της παράδοξης ενεργοποίησης του MAPK μονοπατιού σε wt-BRAF κύτταρα που φέρουν ογκογενή μετάλλαξη σε πρωτεΐνες που προηγούνται της BRAF στο μονοπάτι (RAS, υποδοχείς κινάσες τυροσίνης). Αν και η χρήση συνδυαστικών θεραπειών έχει δώσει ορισμένα καλά αποτελέσματα, πρόσφατα αναπτύχθηκε μια νέα γενιά εκλεκτικών αναστολέων της BRAFV600E (PLX7904 και PLX8394) που φαίνεται να διαφεύγουν της παράδοξης ενεργοποίησης του MAPK (paradox breakers). Επιπλέον, οι αναστολείς αυτοί παρουσιάζουν αποτελεσματικότητα έναντι αρκετών μηχανισμών που εμφανίζουν ανθεκτικότητα και επί του παρόντος είναι σε στάδιο κλινικών μελετών. Στην συγκεκριμένη διπλωματική εργασία διενεργήθηκε εικονική σάρωση με την χρήση φαρμακοφόρων μοντέλων και τεχνικές μοριακής πρόσδεσης (molecular docking) στοχεύοντας στην εύρεση νέων αναστολέων της BRAFV600E με βελτιωμένο βιολογικό προφίλ. Η δημιουργία των φαρμακοφόρων μοντέλων στόχευσε στην διατήρηση των ισχυρότερων στοιχείων (features) των φαρμακοφόρων μοντέλων που δημιουργήθηκαν με βάση τo φάρμακο Dabrafenib και το paradox breaker plx7904. Τα φαρμακοφόρα μοντέλα επικυρώθηκαν μέσω μιας βιβλιοθήκη ενεργών και ανενεργών μορίων από την βάση δεδομένων ChEMBL και στη συνέχεια εφαρμόστηκαν στην εικονική σάρωση της βιβλιοθήκη μορίων ZINC (~12 εκατ. μόρια). Οι ενώσεις που επιλέχθηκαν με βάση τη βέλτιστη προσαρμογή τους στα φαρμακοφόρα μοντέλα ελέχθησαν ως προς την insilico πρόσδεσή τους στο ενεργό κέντρο της BRAFV600E με χρήση μιας σειράς αλγορίθμων μοριακής πρόσδεσης (Glide HTVS και SP και πρωτόκολλο IFD) ενώ στα φίλτρα που εφαρμόστηκαν συμπεριελήφθηκαι η μελέτη των ADME ιδιοτήτων τους. Η διαδικασία προέκρινε μια τελική ομάδα ενώσεων με δυνατότητα ανάπτυξης ισχυρών αλληλεπιδράσεων με τα κρίσιμα αμινοξέα του ενεργού κέντρου της πρωτεΐνης και ικανοποιητικές ADME ιδιότητες. Η προμήθεια των ενώσεων θα επιτρέψει την in vitro αξιολόγηση της ανασταλτικής τους δράσης και εκλεκτικότητας έναντι της BRAFV600E ενώ τα πλέον υποσχόμενα μόρια θα δοκιμαστούν σε κυτταρικές σειρές για την αποτελεσματικότητά τους.The mitogen-activated protein kinase (MAPK) signaling pathway which affects cell proliferation, apoptosis, migration and differentiation has attracted the attention of anticancer research since abnormal activation of the pathway components is often identified in human cancers. BRAF belongs to the RAF family of serine/threonine protein kinases which are key regulators of the MAPK cascade. Activating BRAF mutations are harbored in certain cancers as in melanoma (50%), thyroid cancer (35-70%), colorectal cancer (5-20%), liver cancer (~14%) and ovarian cancer (~30%). BRAF-V600E is the most frequent mutation leading to multiple and uncontrolled amplification of downstream signal with tumorigenesis as a result. Two selective BRAFV600E inhibitors, Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar), have been already approved for the treatment of unresectable and metastatic BRAF mutated melanoma. However, their efficacy is limited due to intrinsic resistance or the development of acquired resistance. Besides, in the context of wild-type BRAF cells bearing upstream activation (RAS, receptor tyrosine kinase), treatment with BRAF-V600E inhibitors leads to the paradoxical enhancement of MAPK signaling, resulting in enhancement of wt-tumour growth and adverse effects. For that reason combined treatments are being tested with very good clinical outcomes. A new generation of BRAF V600E inhibitors (PLX7904 and PLX8394), being capable of overcoming the MAPK paradoxical activation, has been discovered recently and are currently in clinical investigations. In this thesis, we have conducted a virtual screening approach ,utilizing structure based pharmacophore modeling and in silico docking, towards the identification of novel, selective BRAFV600E inhibitors which potentially could be less prone to resistance and avoid the paradox enhancement of MAPK pathway in wt-BRAF cells. Pharmacophore model generation was based on the top-ranked features extracted from the respective models originated from the crystal complexes of BRAFV600E with the paradox breaker PLX7904 (pdb: 4xv1) and Dabrafenib (pdb: 4xv2). We validated our models by utilizing a library of actives and inactives recovered by ChEMBL database. ZINC database (12M compounds) was queried against the generated pharmacophore models and the selected compounds based on the pharmacophore fit score we refiltered according to a defined set of physicochemical properties. . The filtered compounds were evaluated for their in silico binding at the BRAFV600E active site using Glide HTVS and SP and Induced Fit Docking protocol.The best ranked molecules were further analysed for their drug-likeness properties. The process qualified a final dataset of molecules capable of developing strong interactions with the crucial amino acids of the binding site,and predicted to bear a satisfactory ADME profile. Our future plans include the purchase of the qualified molecules and the in vitro assessment of their inhibitory activity and selectivity against BRAFV600E

Representação da informação incerta por meio de ontologias: um framework para smart homes

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Educação, Programa de Pós-Graduação em Ciência da Informação, Florianópolis, 2019.Nas smart homes e outros cenários da Internet das Coisas (IoT), muitas vezes, as informações coletadas estão sujeitas a interferências externas. Além disso, pode ser necessário representar situações nas quais não é possível se obter informações completas ou precisas sobre determinado fenômeno, gerando a necessidade de se lidar com a informação incerta. As ontologias apresentam um formato amplamente utilizado para a representação das informações coletadas nas smart homes. Sendo assim, atualmente existem várias abordagens não padronizadas na literatura baseadas em ontologias para a representação da informação incerta, ou ontologias incertas . Diante desse contexto, o objetivo deste trabalho é propor um framework para ser utilizado como ferramenta de referência no processo de seleção de ontologias incertas para cenários de smart homes. Para isso, foram identificadas ontologias incertas para smart homes por meio de uma Revisão Sistemática da Literatura (RSL) e foram realizadas pesquisas nos anais do International Workshop on Uncertainty Reasoning for the Semantic Web (URSW). O framework proposto é composto por dois artefatos gerados a partir de informações extraídas das ontologias incertas identificadas: a) questionário para auxiliar na identificação das necessidades de representação da informação incerta; e b) quadro de referência para ser consultado durante a seleção de uma ontologia incerta de acordo com as necessidades de representação da informação incerta. Ao todo, foram identificados 16 trabalhos que propõem ontologias incertas. Com base nestes trabalhos, elaborou-se o questionário com seis questões e diferentes opções de respostas que remetem as ontologias incertas. O quadro de referência foi elaborado contendo os 16 trabalhos identificados e as características das ontologias incertas propostas por cada trabalho. O framework foi aplicado em nove cenários de smart homes que utilizam ontologias, mas não representam a informação incerta, de modo a exemplificar o papel do framework como ferramenta de referência. Como resultado de sua aplicação, para cada cenário, exceto um, identificou-se uma ou mais opções de ontologias incertas. Isto indica que as ontologias incertas disponíveis cobrem grande parte das necessidades de representação atualmente, mas não completamente. Espera-se que o framework proposto possa ser utilizado como referência para facilitar o acesso e uso das ontologias incertas pelos profissionais interessados na construção de ontologias. Finalmente, espera-se gerar oportunidades para que sejam desenvolvidas aplicações que elevem a qualidade e capacidade dos cenários de smart homes tendo em vista principalmente as necessidades e bem-estar das pessoas.Abstract : In smart homes and other Internet of Things (IoT) scenarios, often information collected is subject to external interference. Moreover, it may be necessary to represent situations in which it is not possible to obtain complete or accurate information about a specific phenomenon, causing the need to deal with uncertain information. Ontologies provides a widespread format for representing information collected in smart homes. This way, nowadays there are many non-standard ontology-based approaches in literature focused in the task of uncertain information representation, or \"uncertain ontologies\". Given this context, the objective of this work is to propose a framework to be used as a reference tool in the process of selecting uncertain ontologies for smart home scenarios. For this purpose, uncertain ontologies for smart homes and other IoT scenarios are identified by means of a Systematic Review of Literature (RSL) and by research in proceedings from International Workshop on Uncertainty Reasoning for the Semantic Web (URSW). The proposed framework is composed by two artifacts generated from information extracted from identified uncertain ontologies: a) a survey to assist in identifying the needs for representing uncertain information; and b) a reference table which can be used for selection of uncertain ontologies according to the representation needs. Altogether, 16 uncertain ontologies proposals have been identified. Based on these proposals, the questionnaire was elaborated with six questions and different options of answers referring to uncertain ontologies. The reference table was built containing the 16 ontologies proposals and its specific features. The framework was applied in nine scenarios of smart homes which use ontologies, but do not represent the uncertain information, in order to exemplify the role of the framework as a reference tool. As a result of its application one or more uncertain ontologies options were identified for most of the work. This indicates that the available uncertain ontologies cover most of the representation needs currently, but not all. It is expected that the proposed framework will be used as a reference to ease the access and use of uncertain ontologies by professionals interested in the creation of ontologies. Finally, it is expected to generate opportunities to develop applications which raise the quality and capacity of smart home scenarios especially in view of the needs and well-being of people