Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.     

Bifidobacteria and the infant gut: an example of co-evolution and natural selection

Throughout the human life, the gut microbiota interacts with us in a number of different ways, thereby influencing our health status. The acquisition of such an interactive gut microbiota commences at birth. Medical and environmental factors including diet, antibiotic exposure and mode of delivery are major factors that shape the composition of the microbial communities in the infant gut. Among the most abundant members of the infant microbiota are species belonging to the Bifidobacterium genus, which are believed to confer beneficial effects upon their host. Bifidobacteria may be acquired directly from the mother by vertical transmission and their persistence in the infant gut is associated with their saccharolytic activity toward glycans that are abundant in the infant gut. Here, we discuss the establishment of the infant gut microbiota and the contribution of bifidobacteria to this early life microbial consortium.     

Structural diversity and African origin of the 17q21.31 inversion polymorphism

The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08-1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2') lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps.     

Conserved amino acids participate in the structure networks deputed to intramolecular communication in the lutropin receptor

The luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) particularly susceptible to spontaneous pathogenic gain-of-function mutations. Protein structure network (PSN) analysis on wild-type LHR and two constitutively active mutants, combined with in vitro mutational analysis, served to identify key amino acids that are part of the regulatory network responsible for propagating communication between the extracellular and intracellular poles of the receptor. Highly conserved amino acids in the rhodopsin family GPCRs participate in the protein structural stability as network hubs in both the inactive and active states. Moreover, they behave as the most recurrent nodes in the communication paths between the extracellular and intracellular sides in both functional states with emphasis on the active one. In this respect, non-conservative loss-of-function mutations of these amino acids is expected to impair the most relevant way of communication between activating mutation sites or hormone-binding domain and G protein recognition regions.     

Mitochondria dynamism: of shape,transport and cell migration

Mitochondria are highly dynamic and functionally versatile organelles that continuously fragment and fuse in response to different physiological needs of the cell. The list of proteins that strictly regulate the morphology of these organelles is constantly growing, adding new players every day and new pieces to the comprehension and elucidation of this complex machinery. The structural complexity of mitochondria is only paralled by their functional versatility. Indeed, changes in mitochondria shape play critical roles in vertebrate development programmed cell death and in various processes of normal cell physiology, such as calcium signaling, reactive oxygen species production, and lifespan. Here, we present the latest findings on the regulation of mitochondrial dynamics and some of their physiological roles, focusing on cell migration. In cells where migration represents a crucial function in their physiology, such as T and tumoral metastatic cells, mitochondria need to be fragmented and recruited to specific subcellular regions to make movement possible. In depth analysis of this role of mitochondrial dynamics should help in identifying potential targeted therapy against cancer or in improving the immune system’s efficiency.     

A consideration of Babylonian astronomy within the historiography of science

This paper traces the reception of Babylonian astronomy into the history of science, beginning in early to mid twentieth century when cuneiform astronomical sources became available to the scholarly public. The dominant positivism in philosophy of science of this time influenced criteria employed in defining and demarcating science by historians, resulting in a persistently negative assessment of the nature of knowledge evidenced in cuneiform sources. Ancient Near Eastern astronomy (and astrology) was deemed pre- or non-scientific, and even taken to reflect a stage in the evolution of thought before the emergence of science (in ancient Greece). Two principal objections are examined: first, that the Near East produced merely practical as opposed to theoretical knowledge and, second, that astronomy was in the service of astrology and religion. As the notion of a universal scientific method has been dismantled by post-positivists and constructivists of the second half of the twentieth century, an interest in varieties of intellectual and cultural contexts for science has provided a new ground for the re-consideration of Babylonian astronomical texts as science developed here.     

Geological record of fluid flow and seismogenesis along an erosive subducting plate boundary

Tectonic erosion of the overriding plate by the downgoing slab is believed to occur at half the Earth's subduction zones. In situ investigation of the geological processes at active erosive margins is extremely difficult owing to the deep marine environment and the net loss of forearc crust to deeper levels in the subduction zone. Until now, a fossil erosive subduction channel-the shear zone marking the plate boundary-has not been recognized in the field, so that seismic observations have provided the only information on plate boundary processes at erosive margins. Here we show that a fossil erosive margin is preserved in the Northern Apennines of Italy. It formed during the Tertiary transition from oceanic subduction to continental collision, and was preserved by the late deactivation and fossilization of the plate boundary. The outcropping erosive subduction channel is approximately 500 m thick. It is representative of the first 5 km of depth, with its deeper portions reaching approximately 150 degrees C. The fossil zone records several surprises. Two décollements were simultaneously active at the top and base of the subduction channel. Both deeper basal erosion and near-surface frontal erosion occurred. At shallow depths extension was a key deformation component within this erosive convergent plate boundary, and slip occurred without an observable fluid pressure cycle. At depths greater than about 3 km a fluid cycle is clearly shown by the development of veins and the alternation of fast (co-seismic) and slow (inter-seismic) slip. In the deepest portions of the outcropping subduction channel, extension is finally overprinted by compressional structures. In modern subduction zones the onset of seismic activity is believed to occur at approximately 150 degrees C, but in the fossil channel the onset occurred at cooler palaeo-temperatures.