Models for Antitubercular Activity of 5′-O-[(N-Acyl)sulfamoyl]adenosines

The relationship between topological indices and antitubercular activity of 5′-O-[(N-Acyl)sulfamoyl]adenosines has been investigated. A data set consisting of 31 analogues of 5′-O-[(N-Acyl)sulfamoyl]adenosines was selected for the present study. The values of numerous topostructural and topochemical indices for each of 31 differently substituted analogues of the data set were computed using an in-house computer program. Resulting data was analyzed and suitable models were developed through decision tree, random forest and moving average analysis (MAA). The goodness of the models was assessed by calculating overall accuracy of prediction, sensitivity, specificity and Mathews correlation coefficient. Pendentic eccentricity index – a novel highly discriminating, non-correlating pendenticity based topochemical descriptor – was also conceptualized and successfully utilized for the development of a model for antitubercular activity of 5′-O-[(N-Acyl)sulfamoyl]adenosines. The proposed index exhibited not only high sensitivity towards both the presence as well as relative position(s) of pendent/heteroatom(s) but also led to significant reduction in degeneracy. Random forest correctly classified the analogues into active and inactive with an accuracy of 67.74%. A decision tree was also employed for determining the importance of molecular descriptors. The decision tree learned the information from the input data with an accuracy of 100% and correctly predicted the cross-validated (10 fold) data with accuracy up to 77.4%. Statistical significance of proposed models was also investigated using intercorrelation analysis. Accuracy of prediction of proposed MAA models ranged from 90.4 to 91.6%

A brain and a head for a different habitat : Size variation in four morphs of Arctic charr (Salvelinus alpinus(L.)) in a deep oligotrophic lake

Adaptive radiation is the diversification of species to different ecological niches and has repeatedly occurred in different salmonid fish of postglacial lakes. In Lake Tinnsjoen, one of the largest and deepest lakes in Norway, the salmonid fish, Arctic charr (Salvelinus alpinus(L.)), has likely radiated within 9,700 years after deglaciation into ecologically and genetically segregated Piscivore, Planktivore, Dwarf, and Abyssal morphs in the pelagial, littoral, shallow-moderate profundal, and deep-profundal habitats. We compared trait variation in the size of the head, the eye and olfactory organs, as well as the volumes of five brain regions of these four Arctic charr morphs. We hypothesised that specific habitat characteristics have promoted divergent body, head, and brain sizes related to utilized depth differing in environmental constraints (e.g., light, oxygen, pressure, temperature, and food quality). The most important ecomorphological variables differentiating morphs were eye area, habitat, and number of lamellae. The Abyssal morph living in the deepest areas of the lake had the smallest brain region volumes, head, and eye size. Comparing the olfactory bulb with the optic tectum in size, it was larger in the Abyssal morph than in the Piscivore morph. The Piscivore and Planktivore morphs that use more illuminated habitats have the largest optic tectum volume, followed by the Dwarf. The observed differences in body size and sensory capacities in terms of vision and olfaction in shallow and deepwater morphs likely relates to foraging and mating habitats in Lake Tinnsjoen. Further seasonal and experimental studies of brain volume in polymorphic species are needed to test the role of plasticity and adaptive evolution behind the observed differences.Peer reviewe

An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential

Mutagenicity presents a challenging problem in modeling despite the addition of modern prediction methods and easier access to data. Previous studies have focused mainly on treatment of all mutagenic compound classes, while some have focused on a very small sets of alerting compounds such as aromatic amines with quantitative mutagenicity data. Data currently available at Novartis provide a large, unique set of mutagenicity data originating from one laboratory, providing compounds connected to the discovery and production of medicinal compounds rather than compounds associated with agricultural, environmental and foodstuff concern. We were especially interested in predicting the The performance of commonly used descriptors and methods performed quite poorly for the set of aromatic amines, while using the reaction energy to produce a reactive intermediate provides a prediction accuracy of at least 70% across multiple data sets. Whereas many papers have represented the study of aromatic amines and Ames results as a platform for study of prediction methods with good performance, we show that the set is quite difficult. The performance of methods in our hands will be compared with previously compiled datasets and reported models

Review of QSAR Models and Software Tools for Predicting of Genotoxicity and Carcinogenicity

This review of QSARs for genotoxicity and carcinogenicity was performed in a broad sense, considering both models available in software tools and models that are published in the literature. The review considered the potential applicability of diverse models to pesticides as well as to other types of regulated chemicals and pharmaceuticals. The availability of models and information on their applicability is summarised in tables, and a range of illustrative or informative examples are described in more detail in the text. In many cases, promising models were identified but they are still at the research stage. For routine application in a regulatory setting, further efforts will be needed to explore the applicability of such models for specific purposes, and to implement them in a practically useful form (i.e. user-friendly software). It is also noted that a range of software tools are research tools suitable for model development, and these require more specialised expertise than other tools that are aimed primarily at end-users such as risk assessors. It is concluded that the most useful models are those which are implemented in software tools and associated with transparent documentation on the model development and validation process. However, it is emphasised that the assessment of model predictions requires a reasonable amount of QSAR knowledge, even if it is not necessary to be a QSAR practitioner.JRC.DG.I.6-Systems toxicolog

Near-infrared raman spectroscopy with recursive partitioning techniques for precancer and cancer detection

Master'sMASTER OF ENGINEERIN

Adaptive radiation of Arctic charr (Salvelinus alpinus) in three Norwegian lakes - niche segregation, phenotypic and genetic variation

Å forstå hvordan økologiske og fysiske faktorer fører til opprinnelsen av nye arter, og hvilke faktorer som former ny intraspesifikk diversitet, er den “hellige gral” i evolusjonær biologi. Adaptiv radiasjon er den evolusjonære prosessen som kan føre til diversifisering av fenotyper og genotyper i ulike miljøer, og som kan splitte en forfaders form eller linje i nye former og arter. I den økologiske artsdannelsesprosessen vil lokal tilpasning gjennom naturlig seleksjon drive oppsplittingen av populasjoner, noe som vil føre til evolusjon av reproduktiv isolasjon og dermed dannelsen av nye økotyper, morfer, populasjoner og til slutt arter. Et godt eksempel på en polymorf art er røya (Salvelinus alpinus) som kan ha ulike nisjer (det vil si tilpasning til spesifikke abiotiske og biotiske forhold) i en innsjø. Spesialiseringen til en bestemt nisje kan favorisere divergensen mellom morfene, noe som kan lede til forskjeller i utseende, vekst, kjønnsmodning, gytetid og sted, og over tid utvikle reproduktive barrierer mellom morfene. Denne doktorgradsavhandlingen fokuserer på fenotypisk og genetisk divergens av røyemorfer. Hovedmålet er å undersøke nisjesegregering på trofisk nivå (det vil si diettvalg og habitatbruk), ved å studere morfologiske og genetiske forskjeller mellom røyemorfer fra tre forskjellige ferskvannsystemer i Norge (Tinnsjøen, Tårnvatn og Skøvatn). To røyemorfer ble funnet eksisterende sammen i Skøvatn, tre morfer i Tårnvatn, og fire i Tinnsjøen. To nye morfer ble funnet i Tinnsjøen og Skøvatn. Alle morfene viste forskjeller i livshistorie, genetikk, fenotype, diettvalg og habitatbruk. De fiskespisende morfene ernærte seg hovedsakelig av fisk, og ble funnet i den profundale delen av Tinnsjøen og Tårnvatn. Planktivore morfer spiste hovedsakelig dyreplankton, og ble funnet i flere ulike habitater i disse tre innsjøene. Livshistoriekarakterer og habitatbruk var lignende hos de småvokste dypvannsmorfene, men morfen i Skøvatn viste forskjeller i diettvalg sammenlignet med morfen fra Tårnvatn. Den nye dypvannsmorfen som ble funnet i den dypere delen av Tinnsjøen har likhetstrekk med hulefisk som hvitt skinn, underutviklede øyne og små hjerneregioner. Parallell evolusjon kan være en forklaring for likhetene som er funnet blant noen av morfene i disse tre ferskvannssystemene. Funnene viser hvordan seleksjonspress kan føre til lignende resultater i samme miljøer, der fenotypisk plastisitet også kan være en viktig mekanisme i tidlige stadier av nisjespesialisering. Disse morfene er sannsynligvis i en økologisk artsdannelsesprosess, der naturlig seleksjon spiller en viktig rolle i den adaptive divergensen av morfer, og bidrar til reproduktiv isolasjon. Adaptiv radiasjon kan forklare tilpasninger og diversitet hos den polymorfe røya i ulike vann.Abstract Understanding the ecological and physical factors driving the origin of species, and which ones are shaping new intraspecific diversity, are the “holy grail” of evolutionary biology. Adaptive radiation is the evolutionary process that can generate diversification of phenotypes and genotypes across different environments, differentiating a single ancestor into different forms and species. Under ecological speciation, local adaptation through natural selection drives the divergence of populations, evolving reproductive isolation and leading to the formation of new eco morphs, populations, and ultimately, species. A good example of polymorphic species is Arctic charr (Salvelinus alpinus), which has the flexibility to occupy different niches (i.e. a specific range of abiotic and biotic factors that a species has specialised) in a lake. For example, in fish, the specialisation into a specific niche can favour divergence among morphs, showing differences in morphology, growth, maturity, spawning time and site, developing reproductive barriers among the morphs. This thesis focuses on phenotypic and genetic divergence of Arctic charr morphs. The main objectives are to investigate trophic niche segregation (i.e. diet choice and habitat use), morphological and genetic differences among sympatric Arctic charr morphs from three different lakes in Norway (Tinnsjøen, Tårnvatn and Skøvatn). Two Arctic charr morphs were found coexisting in Lake Skøvatn, three morphs in Lake Tårnvatn and four morphs in Lake Tinnsjøen. Two novel morphs were found in Lake Tinnsjøen and Skøvatn. All morphs showed divergence in life history, genetics, phenotype, diet and habitat use. The piscivore morphs fed mainly on fish and were found in the profundal habitat of Lake Tinnsjøen and Tårnvatn. The planktivore morphs were feeding mainly on zooplankton, and were found across different habitats from these three lakes. Life-history traits and habitat use was similar among the small-sized profundal morphs, but the morph in Skøvatn presented differences in diet choice compared to the morph from Lake Tårnvatn. Finally, the Abyssal morph was found in the deepprofundal habitat in Lake Tinnsjøen, presenting similarities with cave fish such as white coloration, reduced eyes and small brain regions. Parallel evolution could be responsible for the similarities found among some of the Arctic charr morphs across these three lakes. These findings show how selection pressures can sometimes lead to similar outcomes in similar environments. However, phenotypic plasticity may also be an important component during the early stages of niche specialization. These morphs are likely under ecological speciation, where natural selection could play an important role in the adaptive divergence of morphs, contributing to reproductive isolation. Arctic charr polymorphism could be a case of adaptive radiation, explaining their diversity across different freshwater systems