Isotopic evolution of the terminal Neoproterozoic and early Cambrian carbon cycle on the northern Yangtze Platform, South China

Profound geotectonic, climatic and biological changes occur during the terminal Neoproterozoic and its transition into the early Cambrian. These are reflected in temporal variations of the chemical and isotopic composition of seawater. We are studying a sequence of sedimentary rocks at the Shatan section, northern Yangtze Platform, Sichuan Province of China. This succession comprises, in ascending stratigraphic order, predominantly calcareous sediments of the Sinian upper Dengying Formation and black shales of the lower Cambrian Guojiaba Formation (time equivalent of Niutitang Fm.). Paleoenvironmental setting represents shallow-water shelf deposits. The objective of our study is to provide temporal records for the isotopic compositions of organic and carbonate carbon throughout this time interval. Organic carbon isotope values display a range between -35.8‰ and -30.1‰ with clear stratigraphic variations. Carbonate carbon isotope data vary between -3.5‰ and +0.5‰. These secular variations are interpreted to reflect perturbations of the global carbon cycle, specifically changes in the fractional burial of organic carbon. However, local conditions have further affected the isotopic signals.     

'Rejuvenation' protects neurons in mouse models of Parkinson's disease

Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease.     

The unconventional secretion of stress-inducible protein 1 by a heterogeneous population of extracellular vesicles

The co-chaperone stress-inducible protein 1 (STI1) is released by astrocytes, and has important neurotrophic properties upon binding to prion protein (PrP^C). However, STI1 lacks a signal peptide and pharmacological approaches pointed that it does not follow a classical secretion mechanism. Ultracentrifugation, size exclusion chromatography, electron microscopy, vesicle labeling, and particle tracking analysis were used to identify three major types of extracellular vesicles (EVs) released from astrocytes with sizes ranging from 20–50, 100–200, and 300–400 nm. These EVs carry STI1 and present many exosomal markers, even though only a subpopulation had the typical exosomal morphology. The only protein, from those evaluated here, present exclusively in vesicles that have exosomal morphology was PrP^C. STI1 partially co-localized with Rab5 and Rab7 in endosomal compartments, and a dominant-negative for vacuolar protein sorting 4A (VPS4A), required for formation of multivesicular bodies (MVBs), impaired EV and STI1 release. Flow cytometry and PK digestion demonstrated that STI1 localized to the outer leaflet of EVs, and its association with EVs greatly increased STI1 activity upon PrP^C-dependent neuronal signaling. These results indicate that astrocytes secrete a diverse population of EVs derived from MVBs that contain STI1 and suggest that the interaction between EVs and neuronal surface components enhances STI1–PrP^C signaling.     

New data on isotopic composition of Jurassic-Early Cretaceous cephalopods

The aim of this paper is to reconstruct the Jurassic-Early Cretaceous climatic conditions using new isotopic data. Paleobotanical data indicate that a cooling occurred gradually just after Late Triassic, and a temperature minimum was reached in the Pliensbachian. This was followed by a climatic optimum in the early Toarcian, cooling in the late Toarcian and a second climatic optimum in the Oxfordian. Published isotopic thermometry data and our new results on isotopic composition of some Jurassic invertebrate shells from the Russian Platform, Poland, Germany and England generally confirm this pattern, and also indicate a third climatic optimum in the Middle Callovian. Middle-Late Mesozoic adult belemnites apparently lived during their spawning phase, in shallow waters similar to extant Nautilus. However, at least juvenile belemnoids, unlike ammonoids, engaged in significant short-term vertical migrations in the water column, reaching colder waters of the upper bathyal zone.     

Global variation in copy number in the human genome

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.     

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.     

Segregation of receptor and ligand regulates activation of epithelial growth factor receptor

Interactions between ligands and receptors are central to communication between cells and tissues. Human airway epithelia constitutively produce both a ligand, the growth factor heregulin, and its receptors--erbB2, erbB3 and erbB4 (refs 1-3). Although heregulin binding initiates cellular proliferation and differentiation, airway epithelia have a low rate of cell division. This raises the question of how ligand-receptor interactions are controlled in epithelia. Here we show that in differentiated human airway epithelia, heregulin-alpha is present exclusively in the apical membrane and the overlying airway surface liquid, physically separated from erbB2-4, which segregate to the basolateral membrane. This physical arrangement creates a ligand-receptor pair poised for activation whenever epithelial integrity is disrupted. Indeed, immediately following a mechanical injury, heregulin-alpha activates erbB2 in cells at the edge of the wound, and this process hastens restoration of epithelial integrity. Likewise, when epithelial cells are not separated into apical and basolateral membranes ('polarized'), or when tight junctions between adjacent cells are opened, heregulin-alpha activates its receptor. This mechanism of ligand-receptor segregation on either side of epithelial tight junctions may be vital for rapid restoration of integrity following injury, and hence critical for survival. This model also suggests a mechanism for abnormal receptor activation in diseases with increased epithelial permeability.