Although situated ∼400 km from the east coast of Africa, Madagascar exhibits cultural, linguistic, and genetic traits from both Southeast Asia and Eastern Africa. The settlement history remains contentious; we therefore used a grid-based approach to sample at high resolution the genomic diversity (including maternal lineages, paternal lineages, and genome-wide data) across 257 villages and 2,704 Malagasy individuals. We find a common Bantu and Austronesian descent for all Malagasy individuals with a limited paternal contribution from Europe and the Middle East. Admixture and demographic growth happened recently, suggesting a rapid settlement of Madagascar during the last millennium. However, the distribution of African and Asian ancestry across the island reveals that the admixture was sex biased and happened heterogeneously across Madagascar, suggesting independent colonization of Madagascar from Africa and Asia rather than settlement by an already admixed population. In addition, there are geographic influences on the present genomic diversity, independent of the admixture, showing that a few centuries is sufficient to produce detectable genetic structure in human populations.

Background: Protease-activated receptor 1 (PAR1) and PAR4 mediate thrombin signaling in platelets. Results: Mutations in transmembrane helix 4 (TM4) of PAR1 or PAR4 disrupts ␣-thrombin-induced heterodimerization and PAR1-assisted PAR4 cleavage. Conclusion: PAR1-PAR4 heterodimers are required for efficient PAR4 cleavage. Significance: The dimerization of PAR1 and PAR4 may impact the effectiveness of PAR1 antagonists.

While admixed populations offer a unique opportunity to detect selection, the admixture in most of the studied populations occurred too recently to produce conclusive signals. By contrast, Malagasy populations originate from admixture between Asian and African populations that occurred ~27 generations ago, providing power to detect selection. We analyze local ancestry across the genomes of 700 Malagasy and identify a strong signal of recent positive selection, with an estimated selection coefficient >0.2. The selection is for African ancestry and affects 25% of chromosome 1, including the Duffy blood group gene. The null allele at this gene provides resistance to Plasmodium vivax malaria, and previous studies have suggested positive selection for this allele in the Malagasy population. This selection event also influences numerous other genes implicated in immunity, cardiovascular diseases, and asthma and decreases the Asian ancestry genome-wide by 10%, illustrating the role played by selection in recent human history.

An immunodetection study of protein tyrosine phosphatase 1B (PTP-1B), SHP-2, and Src in isolated mitochondria from different rat tissues (brain, muscle, heart, liver, and kidney) revealed their exclusive localization in the brain. Given this result, we sought whether mitochondria respond to ATP and to the general tyrosine phosphatase inhibitor orthovanadate and found little or no change in the tyrosine phosphorylation profile of mitochondria from muscle, heart, liver, and kidney. In contrast, ATP induced an enhancement in the tyrosine-phosphorylated protein profile of brain mitochondria, which was further greatly enhanced with orthovanadate and which disappeared when Src was inhibited with two inhibitors: PP2 and PP1. Importantly, we found that in brain mitochondria, ATP addition induced Src autophosphorylation at Tyr-416 in its catalytic site, leading to its activation, whereas the regulatory Tyr-527 site remained unphosphorylated. Functional implications were addressed by measurements of the enzymatic activity of each of the oxidative phosphorylation complexes in brain mitochondria in the presence of ATP. We found an increase in complex I, III, and IV activity and a decrease in complex V activity, partially reversed by Src inhibition, demonstrating that the complexes are Src substrates. These results complemented and reinforced our initial study showing that respiration of brain mitochondria was partially dependent on tyrosine phosphorylation. Therefore, the present data suggest a possible control point in the regulation of respiration by tyrosine phosphorylation of the complexes mediated by Src auto-activation.Mitochondria provide the energy necessary for cell growth and biological activities through oxidative phosphorylation (OxPhos). 4 This relies on electron transfer from oxidative substrates to oxygen, via a series of redox reactions, to generate water. In this process, protons are pumped from the matrix across the mitochondrial inner membrane, via respiratory complexes I, III, and IV. When protons return to the mitochondrial matrix, ATP is synthesized via complex V.As the energy demand of a cell depends on its function and activity, energy production is adjusted and controlled by different mechanisms (1-3). One major regulatory system is protein phosphorylation/dephosphorylation (4). Evidence indicates that mitochondrial proteins undergo posttranslational phosphorylation (2, 5, 6), and reports have unambiguously revealed the existence of several kinases within the mitochondria, such as cAMP-dependent protein kinase (7) and members of the Src kinase family (8). Protein phosphatases have also been described, such as Ser/Thr phosphatases, PP2C-␥ and PP2A (7), and tyrosine phosphatases, SHP-2 (9), PTP-1B (10), and PTPMT1, a dual-specific phosphatase (11), the latter found exclusively in mitochondria but not in the cytosol.As indicated by earlier reports, mitochondrial signaling enzyme distribution and stimulation may vary according to the tissue. In a preceding report, which also explored the presence of PTP...