The Red Sea, Coastal Landscapes, and Hominin Dispersals

This chapter provides a critical assessment of environment, landscape and resources in the Red Sea region over the past five million years in relation to archaeological evidence of hominin settlement, and of current hypotheses about the role of the region as a pathway or obstacle to population dispersals between Africa and Asia and the possible significance of coastal colonization. The discussion assesses the impact of factors such as topography and the distribution of resources on land and on the seacoast, taking account of geographical variation and changes in geology, sea levels and palaeoclimate. The merits of northern and southern routes of movement at either end of the Red Sea are compared. All the evidence indicates that there has been no land connection at the southern end since the beginning of the Pliocene period, but that short sea crossings would have been possible at lowest sea-level stands with little or no technical aids. More important than the possibilities of crossing the southern channel is the nature of the resources available in the adjacent coastal zones. There were many climatic episodes wetter than today, and during these periods water draining from the Arabian escarpment provided productive conditions for large mammals and human populations in coastal regions and eastwards into the desert. During drier episodes the coastal region would have provided important refugia both in upland areas and on the emerged shelves exposed by lowered sea level, especially in the southern sector and on both sides of the Red Sea. Marine resources may have offered an added advantage in coastal areas, but evidence for their exploitation is very limited, and their role has been over-exaggerated in hypotheses of coastal colonization

Kinetics and Ligand-Binding Preferences of Mycobacterium tuberculosis Thymidylate Synthases, ThyA and ThyX

Mycobacterium tuberculosis kills approximately 2 million people each year and presents an urgent need to identify new targets and new antitubercular drugs. Thymidylate synthase (TS) enzymes from other species offer good targets for drug development and the M. tuberculosis genome contains two putative TS enzymes, a conventional ThyA and a flavin-based ThyX. In M. tuberculosis, both TS enzymes have been implicated as essential for growth, either based on drug-resistance studies or genome-wide mutagenesis screens. To facilitate future small molecule inhibitors against these proteins, a detailed enzymatic characterization was necessary.After cloning, overexpression, and purification, the thymidylate-synthesizing ability of ThyA and ThyX gene products were directly confirmed by HPLC analysis of reaction products and substrate saturation kinetics were established. 5-Fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) was a potent inhibitor of both ThyA and ThyX, offering important clues to double-targeting strategies. In contrast, the folate-based 1843U89 was a potent inhibitor of ThyA but not ThyX suggesting that it should be possible to find ThyX-specific antifolates. A turnover-dependent kinetic assay, combined with the active-site titration approach of Ackermann and Potter, revealed that both M. tuberculosis enzymes had very low k(cat) values. One possible explanation for the low catalytic activity of M. tuberculosis ThyX is that its true biological substrates remain to be identified. Alternatively, this slow-growing pathogen, with low demands for TMP, may have evolved to down-regulate TS activities by altering the turnover rate of individual enzyme molecules, perhaps to preserve total protein quantities for other purposes. In many organisms, TS is often used as a part of larger complexes of macromolecules that control replication and DNA repair.Thus, the present enzymatic characterization of ThyA and ThyX from M. tuberculosis provides a framework for future development of cell-active inhibitors and the biological roles of these TS enzymes in M. tuberculosis

Surgical treatment of premature sagittal synostosis Tratamento cirúrgico da fusão prematura da sutura sagital

A series of 50 consecutive children with premature sagittal synostosis is reported. All were treated surgically; 43 were male, 47 were leukodermic and two are siblings. In the pre-operative examination, the head shape, skull measurements and radiologic findings were evaluated; 38 children were operated on before six months of age and 12 of them, between six and 12 months of age. The surgical technique used was a wide biparietal craniectomy. Blood transfusions were occasional, being necessary for only six (12%) children. The children were admitted at the day of surgery and discharged between the second and the third post-operative day. No local or general complications were observed and no one died. The aesthetic result was considered good. The altered skull measurements before surgery reached normalization as far as the end of the first year after the treatment. It may be concluded that wide biparietal craniectomy is a procedure of great effectiveness in the treatment of the premature fusion of the sagittal suture.<br>É apresentada uma série de 50 crianças com fusão isolada e prematura da sutura sagital, tratadas cirurgicamente; 43 eram do sexo masculino, 47 leucodérmicas e duas irmãs. No pré-operatório foram avaliados o formato da cabeça, medidas do crânio e medidas radiológicas, 38 crianças foram operadas antes dos 6 meses de idade e 12 entre os 6 e 12 meses. A técnica cirúrgica usada foi a craniectomia parcial, ampla e biparietal. A transfusão sanguínea foi eventual, sendo necessária em somente 6 crianças (12%). As crianças foram admitidas no dia da cirurgia e receberam alta entre o segundo e terceiro dia após a cirurgia. Não foram observadas complicações locais ou gerais e não houve óbito. O resultado estético final foi considerado bom; as medidas do crânio, alteradas antes da cirurgia, se normalizaram até um ano após o tratamento. Conclui-se que a craniectomia parcial, ampla e biparietal é eficiente no tratamento da fusão isolada e prematura da sutura sagital, até o primeiro ano de vida

IRF6 Is Involved in the Regulation of Cell Proliferation and Transformation in MCF10A Cells Downstream of Notch Signaling

IRF6, a member of Interferon Regulatory Factors (IRF) family, is involved in orofacial and epidermal development. In breast cancer cell lines ectopic expression of IRF6 reduces cell numbers suggesting a role as negative regulator of cell cycle. IRF6 is a direct target of canonical Notch signaling in keratinocyte differentiation. Notch is involved in luminal cell fate determination and stem cell regulation in the normal breast and is implicated as an oncogene in breast cancer. Notch activation is sufficient to induce proliferation and transformation in non-tumorigenic breast epithelial cell line, MCF10A. ΔNp63, which is downregulated by Notch activation in the breast, regulates IRF6 expression in keratinocytes. In this report, we investigate Notch-IRF6 and ΔNp63-IRF6 interactions in MCF10A and MDA MB 231 cells. We observed that in these cells, IRF6 expression is partially regulated by canonical Notch signaling and ΔNp63 downregulation. Furthermore, we demonstrate that IRF6 abrogation impairs Notch-induced proliferation and transformation in MCF10A cells. Thus, we confirm the previous findings by showing a tissue independent regulation of IRF6 by Notch signaling, and extend them by proposing a context dependent role for IRF6, which acts as a positive regulator of proliferation and transformation in MCF10A cells downstream of Notch signaling