The social significance of Neolithic stone bead technologies at Çatalhöyük

This project aims to better understand the social significance of stone bead production and use, from a technological perspective, at the large Neolithic settlement of Çatalhöyük, Turkey. This is done by closely examining technological practices and choices, reconstructing the manufacturing process, and analysing production contexts in order to determine the organization of production at Çatalhöyük, and the presence of craft specialization, all based on a large dataset providing both synchronic and diachronic perspectives of life at Çatalhöyük. Specifically, contexts with production evidence are identified and examined, manufacture marks on finished and unfinished beads are analysed, perforating tools are examined for use-wear, and some basic bead making experiments are also conducted. More importantly, the reasons behind the presence of craft specialization, and what factors may have propelled it, are also discussed. Technology is a fundamental aspect of daily life for Neolithic people, whether it is obtaining raw materials, manipulating them into finished products, using them, or exchanging them; technology is therefore a tangible form of constructing, maintaining, and propagating social ideologies. Stone bead technologies at Çatalhöyük provide important information regarding what regions the people of Çatalhöyük were interacting with, the skillsets they possessed, and why beads were made they way they were and what significance these beads had to both bead makers, bead consumers, and Neolithic society in general. Similarly, depositional practices and contextual analyses of contexts with evidence of bead use, such as burials and placed deposits, support the idea that stone beads were multipurpose, socially valued goods that became integral to daily, ritual, and social life at Neolithic Çatalhöyük, performing important functions such as the communication of ideas, the forging of relationships, marking important transitions in the lives of people and households, and creating, maintaining and propagating identities, both communal and personal. Stone beads conspicuously performed an integral social role at Çatalhöyük; the story of their manufacture and use is inextricably linked to all aspects of Neolithic life at Çatalhöyük, including identity, technology and symbolism and ritual

Molecular Diversity and Population Structure at the CYP3A5 gene in Africa

The CYP450 superfamily of enzymes metabolise ~90% of all therapeutic drug. CYP3A5 is involved in the metabolism of multiple drugs and endogenous compounds. Enzyme expression is highly variable and associated with differential efficacy of therapeutic drugs and risk of adverse drug reactions (ADRs). Four functionally important CYP3A5 variants: CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5* , have been identified in broad human population surveys. CYP3A5*1 produces a functional protein while CYP3A5*3, CYP3A5*6 and CYP3A5*7 define variants which reduce enzyme expression. Reduced CYP3A5 expression is associated with ADRs. Conversely elevated CYP3A5*3 frequencies are observed in non-equatorial populations and have been reported to protect against the onset of salt-sensitive hypertension. Little is known about CYP3A5 variability in Africa; a region that has more genetic diversity than the rest of the world combined. The main objectives of this thesis were to characterise intra-African variation in the CYP3A5 gene; identify likely implications of CYP3A5 variability on African healthcare; and examine evidence of selection on the gene. Appreciable African frequencies of CYP3A5*6 (12-33%) and CYP3A5*7 (3-22%) were identified and are likely to contribute to variable CYP3A5 expression across the continent. CYP3A5*6 was observed in every genotyped African population; CYP3A5*7 was observed almost exclusively in Niger-Congo speaking populations. Evidence of positive selection acting on CYP3A5 was found and coalescent dates of low/non-expresser CYP3A5 variants indicate that CYP3A5*3 is likely to have undergone a recent, rapid, increase in frequency in non-African populations. Re-sequencing of a ~12kb CYP3A5 region in five Ethiopian populations; and a ~4.5kb region in eight additional African populations, identified additional variants which may cause low/non-expression of CYP3A5. Considerable intra-African differences in CYP3A5 allele frequencies and haplotype structure were identified. Intra-African CYP3A5 variability suggests that there is likely to be differential efficacy of CYP3A5 metabolised drugs, and associated susceptibility to ADRs between individuals and groups across the continent

Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa.

Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago

Contrasting exome constancy and regulatory region variation in the gene encoding CYP3A4: an examination of the extent and potential implications.

OBJECTIVE: CYP3A4 expression varies up to 100-fold among individuals, and, to date, genetic causes remain elusive. As a major drug-metabolizing enzyme, elucidation of such genetic causes would increase the potential for introducing personalized dose adjustment of therapies involving CYP3A4 drug substrates. The foetal CYP3A isoform, CYP3A7, is reported to be expressed in ∼10% of European adults and may thus contribute towards the metabolism of endogenous substances and CYP3A drug substrates. However, little is known about the distribution of the variant expressed in the adult. METHODS: We resequenced the exons, flanking introns, regulatory elements and 3'UTR of CYP3A4 in five Ethiopian populations and incorporated data from the 1000 Genomes Project. Using bioinformatic analysis, we assessed likely consequences of observed CYP3A4 genomic variation. We also conducted the first extensive geographic survey of alleles associated with adult expression of CYP3A7 - that is, CYP3A7*1B and CYP3A7*1C. RESULTS AND CONCLUSION: Ethiopia contained 60 CYP3A4 variants (26 novel) and more variants (>1%) than all non-African populations combined. No nonsynonymous mutation was found in the homozygous form or at more than 2.8% in any population. Seventy-nine per cent of haplotypes contained 3'UTR and/or regulatory region variation with striking pairwise population differentiation, highlighting the potential for interethnic variation in CYP3A4 expression. Conversely, coding region variation showed that significant interethnic variation is unlikely at the protein level. CYP3A7*1C was found at up to 17.5% in North African populations and in significant linkage disequilibrium with CYP3A5*3, indicating that adult expression of the foetal isoform is likely to be accompanied by reduced or null expression of CYP3A5

Interocular yoking in human saccades examined by mutual information analysis

International audienceABSTRACT : BACKGROUND : Saccadic eye movements align the two eyes precisely to foveate a target. Trial-by-trial variance of eye movement is always observed within an identical experimental condition. This has often been treated as experimental error without addressing its significance. The present study examined statistical linkages between the two eyes' movements, namely interocular yoking, for the variance of eye position and velocity. METHODS : Horizontal saccadic movements were recorded from twelve right-eye-dominant subjects while they decided on saccade direction in Go-Only sessions and on both saccade execution and direction in Go/NoGo sessions. We used infrared corneal reflection to record simultaneously and independently the movement of each eye. Quantitative measures of yoking were provided by mutual information analysis of eye position or velocity, which is sensitive to both linear and non-linear relationships between the eyes' movements. Our mutual information analysis relied on the variance of the eyes movements in each experimental condition. The range of movements for each eye varies for different conditions so yoking was further studied by comparing GO-Only vs. Go/NoGo sessions, leftward vs. rightward saccades. RESULTS : Mutual information analysis showed that velocity yoking preceded positional yoking. Cognitive load increased trial variances of velocity with no increase in velocity yoking, suggesting that cognitive load may alter neural processes in areas to which oculomotor control is not tightly linked. The comparison between experimental conditions showed that interocular linkage in velocity variance of the right eye lagged that of the left eye during saccades. CONCLUSIONS : We conclude quantitative measure of interocular yoking based on trial-to-trial variance within a condition, as well as variance between conditions, provides a powerful tool for studying the binocular movement mechanism

Restructuring of Pancreatic Islets and Insulin Secretion in a Postnatal Critical Window

Function and structure of adult pancreatic islets are determined by early postnatal development, which in rats corresponds to the first month of life. We analyzed changes in blood glucose and hormones during this stage and their association with morphological and functional changes of alpha and beta cell populations during this period. At day 20 (d20), insulin and glucose plasma levels were two- and six-fold higher, respectively, as compared to d6. Interestingly, this period is characterized by physiological hyperglycemia and hyperinsulinemia, where peripheral insulin resistance and a high plasmatic concentration of glucagon are also observed. These functional changes were paralleled by reorganization of islet structure, cell mass and aggregate size of alpha and beta cells. Cultured beta cells from d20 secreted the same amount of insulin in 15.6 mM than in 5.6 mM glucose (basal conditions), and were characterized by a high basal insulin secretion. However, beta cells from d28 were already glucose sensitive. Understanding and establishing morphophysiological relationships in the developing endocrine pancreas may explain how events in early life are important in determining adult islet physiology and metabolism

Modeling Structure-Function Relationships in Synthetic DNA Sequences using Attribute Grammars

Recognizing that certain biological functions can be associated with specific DNA sequences has led various fields of biology to adopt the notion of the genetic part. This concept provides a finer level of granularity than the traditional notion of the gene. However, a method of formally relating how a set of parts relates to a function has not yet emerged. Synthetic biology both demands such a formalism and provides an ideal setting for testing hypotheses about relationships between DNA sequences and phenotypes beyond the gene-centric methods used in genetics. Attribute grammars are used in computer science to translate the text of a program source code into the computational operations it represents. By associating attributes with parts, modifying the value of these attributes using rules that describe the structure of DNA sequences, and using a multi-pass compilation process, it is possible to translate DNA sequences into molecular interaction network models. These capabilities are illustrated by simple example grammars expressing how gene expression rates are dependent upon single or multiple parts. The translation process is validated by systematically generating, translating, and simulating the phenotype of all the sequences in the design space generated by a small library of genetic parts. Attribute grammars represent a flexible framework connecting parts with models of biological function. They will be instrumental for building mathematical models of libraries of genetic constructs synthesized to characterize the function of genetic parts. This formalism is also expected to provide a solid foundation for the development of computer assisted design applications for synthetic biology

Recombination and Population Structure in Salmonella enterica

Salmonella enterica is a bacterial pathogen that causes enteric fever and gastroenteritis in humans and animals. Although its population structure was long described as clonal, based on high linkage disequilibrium between loci typed by enzyme electrophoresis, recent examination of gene sequences has revealed that recombination plays an important evolutionary role. We sequenced around 10% of the core genome of 114 isolates of enterica using a resequencing microarray. Application of two different analysis methods (Structure and ClonalFrame) to our genomic data allowed us to define five clear lineages within S. enterica subspecies enterica, one of which is five times older than the other four and two thirds of the age of the whole subspecies. We show that some of these lineages display more evidence of recombination than others. We also demonstrate that some level of sexual isolation exists between the lineages, so that recombination has occurred predominantly between members of the same lineage. This pattern of recombination is compatible with expectations from the previously described ecological structuring of the enterica population as well as mechanistic barriers to recombination observed in laboratory experiments. In spite of their relatively low level of genetic differentiation, these lineages might therefore represent incipient species