Late shellmound occupation in southern Brazil: A multi-proxy study of the Galheta IV archaeological site.

Brazilian coastal archaeology is renowned for its numerous and large shellmounds (sambaquis), which had been continuously occupied from at least 8000 to 1000 years cal BP. However, changes in their structure and material culture in the late Holocene have led to different hypotheses concerning their ecological and cultural changes. The archaeological site Galheta IV (ca.

24.0 kyr cal BP stone artefact from Vale da Pedra Furada, Piauí, Brazil: Techno-functional analysis.

Current archaeological paradigm proposes that the first peopling of the Americas does not exceed the Last Glacial Maximum period. In this context, the acceptance of the anthropogenic character of the earliest stone artefacts generally rests on the presence of projectile points considered no more as typocentric but as typognomonic, since it allows, by itself, to certify the human character of the other associated artefacts. In other words, without this presence, nothing is certain.

A method for complete plant taxon and site inventories in large forest areas with the help of orienteering maps, as exemplified by target forests in Switzerland.

Complete plant inventories of large areas of forests in the moderate and boreal zone have thus far been infeasible and have also not been published. The use of orienteering maps (O-maps) for sampling for inventories was tested. In the sampling method presented herein, the "O-map/way method", O-maps were used for controlled and systematic inspection and sampling, making it possible to carry out successfully complete plant taxon and site inventories of large forest areas (1 to 100 ha).

Covariation of the endocranium and splanchnocranium during great ape ontogeny.

That great ape endocranial shape development persists into adolescence indicates that the splanchnocranium succeeds brain growth in driving endocranial development. However, the extent of this splanchnocranial influence is unknown. We applied two-block partial least squares analyses of Procrustes shape variables on an ontogenetic series of great ape crania to explore the covariation of the endocranium (the internal braincase) and splanchnocranium (face, or viscerocranium).

Reconstructing the Deep Population History of Central and South America.

We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least ∼9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America.

Early human dispersals within the Americas.

Studies of the peopling of the Americas have focused on the timing and number of initial migrations. Less attention has been paid to the subsequent spread of people within the Americas. We sequenced 15 ancient human genomes spanning from Alaska to Patagonia; six are ≥10,000 years old (up to ~18× coverage).

Functional characterization and phenotypic monitoring of human hematopoietic stem cell expansion and differentiation of monocytes and macrophages by whole-cell mass spectrometry.

The different facets of macrophages allow them to play distinct roles in tissue homeostasis, tissue repair and in response to infections. Individuals displaying dysregulated macrophage functions are proposed to be prone to inflammatory disorders or infections. However, this being a cause or a consequence of the pathology remains often unclear.

Evolutionary population history of early Paleoamerican cranial morphology.

The nature and timing of the peopling of the Americas is a subject of intense debate. In particular, it is unclear whether high levels of between-group craniometric diversity in South America result from multiple migrations or from local diversification processes. Previous attempts to explain this diversity have largely focused on testing alternative dispersal or gene flow models, reaching conflicting or inconclusive results.

Comparative analysis of solar pasteurization versus solar disinfection for the treatment of harvested rainwater.

Background: Numerous pathogens and opportunistic pathogens have been detected in harvested rainwater. Developing countries, in particular, require time- and cost-effective treatment strategies to improve the quality of this water source. The primary aim of the current study was thus to compare solar pasteurization (SOPAS; 70 to 79 °C; 80 to 89 °C; and ≥90 °C) to solar disinfection (SODIS; 6 and 8 hrs) for their efficiency in reducing the level of microbial contamination in harvested rainwater.

Early South Americans Cranial Morphological Variation and the Origin of American Biological Diversity.

Recent South Americans have been described as presenting high regional cranial morphological diversity when compared to other regions of the world. This high diversity is in accordance with linguistic and some of the molecular data currently available for the continent, but the origin of this diversity has not been satisfactorily explained yet. Here we explore if this high morphological variation was already present among early groups in South America, in order to refine our knowledge about the timing and origins of the modern morphological diversity.

The Oldest Case of Decapitation in the New World (Lapa do Santo, East-Central Brazil).

We present here evidence for an early Holocene case of decapitation in the New World (Burial 26), found in the rock shelter of Lapa do Santo in 2007. Lapa do Santo is an archaeological site located in the Lagoa Santa karst in east-central Brazil with evidence of human occupation dating as far back as 11.7-12.

The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold.

Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune diseases such as rheumatoid arthritis. Cancer Osaka thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a serine-threonine (ST) kinase and is a key regulator in the production of pro-inflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective, and potent inhibitors for the treatment of autoimmune disorders and cancer.

The cranial morphology of the Botocudo Indians, Brazil.

The Botocudo Indians were hunter-gatherer groups that occupied the East-Central regions of Brazil decimated during the colonial period in the country. During the 19th century, craniometric studies suggested that the Botocudo resembled more the Paleoamerican population of Lagoa Santa than typical Native Americans groups. These results suggest that the Botocudo Indians might represent a population that retained the biological characteristics of early groups of the continent, remaining largely isolated from groups that gave origin to the modern Native South American variation.

2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes.

The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, ε, η, θ (in particular PKCε/η, and display a 10-100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCθ-dependent pathways in vitro and in vivo.

A simple protocol for amino acid type selective isotope labeling in insect cells with improved yields and high reproducibility.

An easy to use and robust approach for amino acid type selective isotope labeling in insect cells is presented. It relies on inexpensive commercial media and can be implemented in laboratories without sophisticated infrastructure. In contrast to previous protocols, where either high protein amounts or high incorporation ratios were obtained, here we achieve both at the same time.

Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery.

Bisphosphonates are potent inhibitors of farnesyl pyrophosphate synthase (FPPS) and are highly efficacious in the treatment of bone diseases such as osteoporosis, Paget's disease and tumor-induced osteolysis. In addition, the potential for direct antitumor effects has been postulated on the basis of in vitro and in vivo studies and has recently been demonstrated clinically in early breast cancer patients treated with the potent bisphosphonate zoledronic acid. However, the high affinity of bisphosphonates for bone mineral seems suboptimal for the direct treatment of soft-tissue tumors.

Craniometric similarities within and between human populations in comparison with neutral genetic data.

The statement that pairs of individuals from different populations are often more genetically similar than pairs from the same population is a widespread idea inside and outside the scientific community. Witherspoon et al. ["Genetic similarities within and between human populations," Genetics 176:351-359 (2007)] proposed an index called the dissimilarity fraction (omega) to access in a quantitative way the validity of this statement for genetic systems.

Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay.

Allosteric inhibitors of Bcr-Abl have emerged as a novel therapeutic option for the treatment of CML. Using fragment-based screening, a search for novel Abl inhibitors that bind to the myristate pocket was carried out. Here we show that not all myristate ligands are functional inhibitors, but that the conformational state of C-terminal helix_I is a structural determinant for functional activity.

Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site.

The ATP-competitive inhibitors dasatinib and nilotinib, which bind to catalytically different conformations of the Abl kinase domain, have recently been approved for the treatment of imatinib-resistant CML. These two new drugs, albeit very efficient against most of the imatinib-resistant mutants of Bcr-Abl, fail to effectively suppress the Bcr-Abl activity of the T315I (or gatekeeper) mutation. Generating new ATP site-binding drugs that target the T315I in Abl has been hampered, amongst others, by target selectivity, which is frequently an issue when developing ATP-competitive inhibitors.

Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model.