Log-Linear Model Based Behavior Selection Method for Artificial Fish Swarm Algorithm

Artificial fish swarm algorithm (AFSA) is a population based optimization technique inspired by social behavior of fishes. In past several years, AFSA has been successfully applied in many research and application areas. The behavior of fishes has a crucial impact on the performance of AFSA, such as global exploration ability and convergence speed. How to construct and select behaviors of fishes are an important task. To solve these problems, an improved artificial fish swarm algorithm based on log-linear model is proposed and implemented in this paper. There are three main works. Firstly, we proposed a new behavior selection algorithm based on log-linear model which can enhance decision making ability of behavior selection. Secondly, adaptive movement behavior based on adaptive weight is presented, which can dynamically adjust according to the diversity of fishes. Finally, some new behaviors are defined and introduced into artificial fish swarm algorithm at the first time to improve global optimization capability. The experiments on high dimensional function optimization showed that the improved algorithm has more powerful global exploration ability and reasonable convergence speed compared with the standard artificial fish swarm algorithm

Post-transcriptional mechanisms that regulate cancer stem cell maintenance

Within a tumor, a subpopulation of cells, namely the cancer stem cells (CSCs), can self-renew, generate more differentiated progeny, and replicate the tumor of origin in vivo, thereby sustaining and promoting tumor growth. Importantly, these cells are often quiescent and resistant to treatment, so that efforts should be put into finding novel ways to target CSCs to improve patient survival. While genetic mutations participate in creating a CSC phenotype, epigenetic mecha- nisms play an equally important role in transformation. Among these, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) modulate the expression of a large network of genes. Let-7 miRNAs induce differentiation, but are often repressed in cancer. Here, we attempted to enhance miRNA maturation and restore their function in glioblastoma (GBM), a highly aggressive primary brain malignancy with an exceedingly poor prognosis, using the small molecule enoxacin, which has been shown to stimulate miRNA maturation in other settings. We injected primary patient-derived GBM cells in mice and treated them with enoxacin and temozolomide (an alkylating agent used in GBM treatment), alone or in combination. Enoxacin did not impair tumor formation, suggesting that miRNA maturation cannot be further stimulated in GBM. Subsequently, we looked at lncRNAs expressed in GBM that may be involved in CSC maintenance and focused on H19. Expression of H19 correlated with poor patient outcome, and H19 binds IMP2, an RNA-binding protein (RBP) essential for CSC maintenance in GBM. Although we could not reach clear conclusions as to its role in GBM due to technical issues, we believe that H19 may be involved in GBM tumorigenesis, and its function requires further investigation. In addition to non-coding RNAs, RBPs are essential regulators of gene expression, as they are involved in every step of mRNA life. Among RBPs involved in cancer, LIN28B, an oncofetal RBP that inhibits let-7 maturation, is necessary for CSC survival in a subset of highly aggressive Ewing sarcomas (EwS). EwS is the second most common primary bone cancer in children and adolescents, and harbors the t(11;22) translocation leading to the chimeric transcription factor EWS-FLI1. Of note, LIN28B stabillizes EWS-FLI1 transcripts, and mediates CSC maintenance. We explored the biological relevance of IMPs for EwS CSCs. IMPs are RBPs known to inhibit the let-7 pathway. However, silencing IMP paralogs failed to affect CSC tumorigenicity. Therefore, our results further support the role of LIN28B for CSC maintenance. Because LIN28B affects translation of targets, we will further investigate the role of LIN28B in EwS by comparing whole -- RNA and proteomic data of LIN28B+ EwS. In doing so, we will identify pathways regulated by LIN28B independently of let-7 and EWS-FLI1, that increase the aggressiveness of a subset of EwS. Moreover, these pathways may be applicable to other LIN28B+ childhood cancers driven by a fusion protein. Dans une tumeur, les cellules souches cancéreuses (CSC) sont capables de se renouveler, générer des cellules plus différenciées, et répliquer la tumeur d’origine in vivo. Ces cellules sont notamment souvent quiescentes et résistantes aux traitements, faisant d’une priorité l’identification de nouvelles méthodes pour cibler les CSC afin d’augmenter la survie du patient. Alors que les mutations génétiques favorisent l’acquisition d’un phénotype de CSC, les mécanismes épigénétiques jouent un rôle tout aussi prépondérant dans la transformation tumorale. Parmi eux, les microARN (miRNA) et longs ARN non-codants (long non-coding RNAs, lncRNA) peuvent influencer l’expression d’un vaste réseau de gènes. Les miRNA let-7 sont exprimés dans les cellules différenciées mais sont souvent réprimés dans les cancers. Ici, nous avons tenté d’accroître leur expression et rétablir leurs fonctions dans le glioblastome (GBM), une tumeur primaire cérébrale hautement aggressive, en utilisant la molécule d’enoxacine qui stimule la maturation de miRNA. Nous avons injecté des organoïdes de GBM dérivés de tumeurs de patients dans des souris que nous avons traitées avec l’enoxacine et/ou du temozolomide (l’agent de chimiothérapie couramment utilisé pour le traitement des GBM), seuls ou en combinaison. L’enoxacine n’a pas diminué la formation de tumeurs, suggérant que la maturation de miRNA ne peut pas être stimulée dans les GBM. Nous avons donc cherché les lncRNA exprimés dans les GBM qui pourraient être impliqués dans le maintien des CSC. Nous avons identifié H19, dont l’expression corrèle avec un mauvais pronostic. H19 peut se lier à IMP2, une protéine liant les ARN (RNA-binding proteins, RBP) essentielle au maintien des CSC dans les GBM. Bien que nous n’ayons pas pu atteindre de conclusions en raison de difficultés techniques, il semble que H19 soit impliqué dans la tumorigénèse des GBM, et sa fonction dans ce contexte mérite d’être explorée. Les RBP sont des régulateurs essentiels de l’expression génique, car impliqués dans chaque étape de la vie de l’ARN messager. LIN28B, une RBP oncofoetale capable d’inhiber la maturation des miRNA let-7, est requise pour la survie des CSC dans une partie des sarcomes d’Ewing (SE), le deuxième cancer primaire de l’os le plus fréquent chez les enfants et adolescents, caractérisé par la translocation t(11;22), formant la protéine de fusion EWS-FLI1. Nous avons étudié le rôle de la famille de RBP IMP, comprenant trois paralogues partiellement redondants et capables de réprimer la cascade de signalisation des let-7. Le knockdown de chacun des trois IMPs n’a pas réduit la tumorigenicité des CSC. Nos résultats renforcent donc la position de LIN28B pour le maintien des CSC. Sachant que LIN28B affecte la traduction d’ARN cibles, nous souhaitons investiguer son rôle dans le SE en comparant les données des ARN et du protéome totaux des SE LIN28B+. Ainsi, nous pourrons identifier des circuits régulés par LIN28B indépendamment des let-7 et d’EWS-FLI1 qui contribuent au phenotype agressif d’une partie des SE. De plus, ces circuits pourraient être impliqués dans d’autre cancers pédiatriques LIN28B+ présentant une protéine de fusion

Isolation, characterization, and expression analysis of [beta]-1, 3-glucanase genes from strawberry plants

Plant beta-1, 3-glucanases are pathogenesis-related proteins, which are implicated in plant defense responses against pathogen infection. As an initial step in understanding the roles of beta-1, 3-glucanases in the strawberry plant defense system, genome walking, and 3\u27 and 5\u27 RACE were performed to isolate beta-1, 3-glucanase genomic and cDNA clones. In addition, real time PCR was performed to determine the expression levels of two of the isolated beta-1, 3-glucanase genes in healthy and fungal infected plants. Two genomic clones, FaBG2-1 and FaBG2-2, and a cDNA clone, FaBG2-3, encoding three different beta-1, 3-glucanases, were isolated. FaBG2-1 was comprised of two exons and one intron. The first exon of FaBG2-1 encodes the major part of a signal peptide. Results of Southern blotting analysis indicated that the strawberry genome contains several copies of FaBG2-1 or related genes. FaBG2-2 appears to be an intronless gene and does not encode a signal peptide. FaBG2-3, like FaBG2-1, also encodes a signal peptide, but is different from FaBG2-1 in 3\u27 and 5\u27 non-coding regions. The proteins encoded by these three genes share a high degree of sequence homology to plant class II beta-1, 3-glucanases. The expression of FaBG2-1 and FaBG2-3 in strawberry plants infected with Colletotrichum fragariae and Colletotrichum acutatum, two important strawberry fungal pathogens, were examined. High levels of induction of both genes were observed in plants infected with C. fragariae, whereas lower levels of induction were observed in plants infected with C. acutatum. Moreover, the expression of FaBG2-3 was much greater than FaBG2-1 in both the uninfected and the infected plants. The expressions of FaBG2-1 and FaBG2-3 in leaves, crowns, and roots were examined at different time points during a 7 month growth period. Different organs showed different expression patterns for the two genes. Furthermore, the total beta-1, 3-glucanase activity and isozyme pattern were analyzed. The isozyme patterns were different between the uninfected and the infected plants. Also, the differences were observed between young plants and older plants. This research shows that beta-1, 3-glucanase in strawberry plant may play roles in plant defense and plant development

Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors

Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids’ synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.Instituto de Investigaciones Bioquímicas de La Plat

STEM Undergraduate Research Symposium 2016 Full Program

Full Program of the 2016 LSSF STEM Undergraduate Research Conference

In silico investigation of glossina morsitans promoters

Philosophiae Doctor - PhDTsetse flies (Glossina spp) are the biological vectors for Trypanosomes, the causative magents of Human African Trypanosomiasis (HAT). HAT is a debilitating disease that continues to present a major public health problem and a key factor limiting rural development in vast regions of tropical Africa. To augment vector control efforts, the International Glossina Genome Initiative (IGGI) was established in 2004 with the ultimate goal of generating a fully annotated whole genome sequence for Glossina morsitans. A working draft genome of Glossina morsitans was availed in 2011. In this thesis, transcriptional regulatory features in Glossina morsitans were analysed using the draft genome. A method for TSS identification in the newly sequenced Glossina morsitans genome was developed using TSS-seq tags sampled from two developmental stages of Glossina morsitans. High throughput next generation sequencing reads obtained from Glossina morsitans larvae and pupae were used to locate transcription start sites (TSS) in the Glossina morsitans genome. TSS-seq tag clusters, defined as a minimum number of reads at the 5’ predicted UTR or first coding exon, were used to define transcription start sites. A total of 3134 tag clusters were identified on the Glossina genome. Approximately 45.4% (1424) of the tag clusters mapped to the first coding exons or their proximal predicted 5’UTR regions and include 31 tag clusters that mapped to transposons. A total of 1101 (35.1%) tag clusters mapped outside the genic region and/or scaffolds without gene predictions and may correspond to previously un-annotated transcripts or noncoding RNA TSS. The core promoter regions were classified as narrow or broad based on the number of TSS positions within a TSS-seq cluster. Majority (95%) of the core promoters analysed in this study were of the broad type while only 5% were of the narrow type. Comparison of canonical core promoter motif occurences between random and bona fide core promoters showed that, generally, the number of motifs in biologically functional genomic windows in the true dataset exceeded those in the random dataset (p <= 0.00164, 0.00135, 0.00185 for the narrow, broad with peak and broad without peak categories respectively). Frequency of motif co-occurrence in core promoter was found to be fundamentally different across various initiation patterns. Narrow core promoters recorded higher frequency of the TATA-box and INR motifs and two-way motif co-occurrence showed that the TATA-box-INR pair is over-represented in the narrow category. Broad core promoters showed higher frequency of the BREd and MTE motifs and two-way motif co-occurrence showed that the MTE-DPE pair is over-represented in broad core promoters. TATA-less promoters account for 77% of the core promoters in this analysis. TATA-less core promoters showed a higher frequency of the MTE and INR motifs in contrast to observations in Drosophila where the DPE motif has been reported to occur frequently in TATA-less promoters. These motif combinations suggest their equal importance to transcription in their corresponding promoter classes in Glossina morsitans

SOX11 interactome analysis: Implication in transcriptional control and neurogenesis

Somatische Stammzellen können sich durch mitotische Teilung vermehren, was eine Regeneration vieler Gewebe nach Verletzungen oder Infektion ermöglicht. Im adulten Säugerhirn kann der Verlust von post-mitotischen Neuronen jedoch nicht kompensiert werden. Eine Ausnahme bildet die das gesamte erwachsene Leben andauernde Differenzierung von Neuronen aus einem Pool von neuronalen Stammzellen. Dieser Prozess, bezeichnet als adulte Neurogenese, ist auf einige spezielle Bereiche des Gehirns, die neurogenen Nischen beschränkt. Dessen Regulierung unterliegt einer komplexen Maschinerie aus extrinsischen und intrinsischen Mechanismen. Bei den intrazellulären Prozessen der adulten Neurogenese spielen die Proteine aus der Familie der SOX Transkriptionsfaktoren eine entscheidende Rolle. Das SOXC Protein SOX11 stellt einen essentiellen Faktor während der Festlegung des neuronalen Schicksals von Vorläuferzellen und der Initiierung von frühen neuronalen Expressionsprogrammen dar. Aktuelle Modelle deuten darauf hin, dass sowohl die Erhaltung der Stammzelleigenschaften als auch die Differenzierung von zentralen Transkriptionsnetzwerken reguliert werden. Diese bestehen aus interagierenden Transkriptionsfaktoren, welche zusammen Genexpressionsprogramme kontrollieren. Aufgrund dieser Erkenntnisse, wurde die Studie darauf ausgelegt, regulatorische Prozesse der späten neuronalen Differenzierung und Reifung zu identifizieren, welche die frühe neuronale Identität innerhalb der unreifen Neuronen definieren. Durch seine zentrale Bedeutung für die neuronale Differenzierung und die Initiierung der Expression neuronaler Marker, wurde SOX11 als Ausgangspunkt für die Analyse des zu Grunde liegenden Transkriptionsnetzwerks gewählt. SOX11-spezifische monoklonale Antikörper wurden zur Detektion des Proteins auf Western Blot Ebene generiert und validiert. Das SOX11-assoziierte Transkriptionsnetzwerk wurde durch die Bestimmung des SOX11-Interaktoms in Neuro2a Zellen mithilfe von Affinitätsaufreinigung und quantitativer Massenspektrometrie erstellt. Das identifizierte SOX11-spezifische Interaktom wies eine signifikante Anreicherung von Transkriptionsfaktoren und anderen Regulatoren auf Transkriptionsebene auf. Literaturrecherche und GO Term Analyse verifizierten darüber hinaus einige der Interaktoren als modulierende Proteine während der Neurogenese. Ein Protein-Protein Interaktionsnetzwerk, in dem die experimentell bestimmten Daten mit Informationen aus öffentlichen Interaktionsdatenbanken vervollständigt wurden, zeigt die Interaktionen zwischen den Proteinen, sowie die Konnektivität einzelner Faktoren. Ausgewählte SOX11 Interaktoren wurden mithilfe von Promotorstudien funktionell charakterisiert. Analysiert wurde der Einfluss auf die durch SOX11 aktivierten Promotoren von DCX und Stathmin1, zwei Markerproteine der frühen neuronalen Identität. Zwei Transkriptionsfaktoren, MYT1 und YY1, zeigten einen kooperativen Effekt mit SOX11 auf die Promotoren beider Gene. In silico Promotoranalysen für DCX und Stathmin1 ergaben benachbarte Bindungssequenzen sowohl für MYT1 und SOX11, als auch für YY1 und SOX11 innerhalb des DCX Promotors und für MYT1 und SOX11 innerhalb des Stathmin1 Promotors, durch welche die Kooperation der Transkriptionsfaktoren auf den Promotoren ermöglicht wird. Zudem ergab das Genom-weite Bindungsprofil von MYT1 und SOX11 eine Anreicherung von in die Neurogenese involvierten Genen. Die proteomische Analyse des SOX11-Transkriptionsnetzwerks in Kombination mit funktionellen Promotorstudien identifizierte neue Faktoren, die eine Rolle bei der intrinsischen Modulierung der späten Neurogenese spielen und deckte die kooperative Aktivität von MYT1 und YY1 mit SOX11 in Bezug auf die Regulierung früher neuronaler Markern auf. Zusätzlich wurden einige Kandidaten identifiziert, die möglicherweise Strategien zur Reprogrammierung von somatischen Zellen in funktionelle Neuronen verbessern können und damit einen Beitrag zur regenerativen Medizin leisten

Sociobiology, universal Darwinism and their transcendence: An investigation of the history, philosophy and critique of Darwinian paradigms, especially gene-Darwinism, process-Darwinism, and their types of reductionism towards a theory of the evolution of evolutionary processes, evolutionary freedom and ecological idealism

Based on a review of different Darwinian paradigms, particularly sociobiology, this work, both, historically and philosophically, develops a metaphysic of gene-Darwinism and process-Darwinism, and then criticises and transcends these Darwinian paradigms in order to achieve a truly evolutionary theory of evolution. Part I introduces essential aspects of current sociobiology as the original challenge to this investigation. The claim of some sociobiologists that ethics should become biologized in a gene-egoistic way, is shown to be tied to certain biological views, which ethically lead to problematic results. In part II a historical investigation into sociobiology and Darwinism in general provides us, as historical epistemology', with a deeper understanding of the structure and background of these approaches. Gene-Darwinism, which presently dominates sociobiology and is linked to Dawkins' selfish gene view of evolution, is compared to Darwin's Darwinism and the evolutionary' synthesis and becomes defined more strictly. An account of the external history of Darwinism and its subparadigms shows how cultural intellectual presuppositions, like Malthusianism or the Newtonian concept of the unchangeable laws of nature, also influenced biological theory' construction. In part III universal 'process-Darwinism' is elaborated based on the historical interaction of Darwinism with non-biological subject areas. Building blocks for this are found in psychology, the theory of science and economics. Additionally, a metaphysical argument for the universality of process- Darwinism, linked to Hume's and Popper's problem of induction, is proposed. In part IV gene-Darwinism and process-Darwinism are criticised. Gene-Darwinism—despite its merits—is challenged as being one-sided in advocating 'gene-atomism', 'germ-line reductionism' and 'process-monism'. My alternative proposals develop and try to unify different criticisms often found. In respect of gene-atomism I advocate a many-level approach, opposing the necessary radical selfishness of single genes. I develop the concept of higher-level genes, propose a concept of systemic selection, which may stabilise group properties, without relying on permanent group selection and extend the applicability of a certain group selectionist model generally to small open groups. Proposals of mine linked to the critique of germ-line reductionism are: 'exformation', phenotypes as evolutionary factors and a field theoretic understanding of causa formalis (resembling Aristotelian hylemorphism). Finally the process-monism of gene-Darwinism, process-Darwinism and, if defined strictly, Darwinism in general is criticised. 1 argue that our ontology and ethics would be improved by replacing the Newtoman-Paleyian deist metaphor of an eternal and unchangeable law of nature, which lies at tire very heart of Darwinism, by a truly evolutionary understanding of evolution where new processes may gain a certain autonomy. All this results in a view that I call 'ecological idealism', which, although still very much based on Darwinism, clearly transcends a Darwinian world view