Current knowledge on exosome biogenesis and release

Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed.     

Estimation procedures for understory biomass and fuel loads in sagebrush steppe invaded by woodlands

Regression equations were developed to predict biomass for 9 shrubs, 9 grasses, and 10 forbs that generally dominate sagebrush ecosystems in central Nevada. Independent variables included percent cover, average height, and plant volume. We explored 2 ellipsoid volumes: one with maximum plant height and 2 crown diameters and another with live crown height and 2 crown diameters. Dependent variables were total, live, leaf, and dead biomass. Simple, multiple, linear, and power equations were investigated. Models were chosen based on scatter plots, residual plots, and R 2 and SEE values. In general, simple power equations provided the best-fit regressions. For shrubs, the ellipsoid volume computed with maximum plant height best predicted total plant weight, and the ellipsoid volume computed with the live crown height best predicted shrub foliage weight. In addition to regression equations for biomass, ratios for division of that biomass into 1-, 10-, 100-, and 1000-hour fuels were derived for common large shrubs. Regression equations were also derived to relate litter mat sizes of major shrub species to litter weights. The equations in this paper could be used to predict biomass in other areas of the Great Basin if training data were taken to validate or adjust these models.     

IDEA: A Collaborative Organizational Design Process Integrating Innovation, Design, Engagement, and Action

This paper describes an innovative and successful 1-year organization change process. It captures a design-based inquiry that simultaneously applies creative, purposeful, and systemic thinking to a complex set of issues. Three significant findings result from this research. First, this paper discusses how the change process created the necessary and sufficient conditions allowing for the creation of an innovative organizational design that embeds both optimization and innovation. Second, Design Thinking was used to develop a 2-day participative design process we have called IDEA, an acronym for integrating innovation, design, engagement, and action. We believe that the IDEA organizational design process is replicable. Third, it describes an emergent and co-created change process. This paper concludes by raising questions for future transformative organizational design efforts.     

The DNA sequence, annotation and analysis of human chromosome 3

After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.     

Low electrical resistivity associated with plunging of the Nazca flat slab beneath Argentina

Beneath much of the Andes, oceanic lithosphere descends eastward into the mantle at an angle of about 30 degrees (ref. 1). A partially molten region is thought to form in a wedge between this descending slab and the overlying continental lithosphere as volatiles given off by the slab lower the melting temperature of mantle material. This wedge is the ultimate source for magma erupted at the active volcanoes that characterize the Andean margin. But between 28 degrees and 33 degrees S the subducted Nazca plate appears to be anomalously buoyant, as it levels out at about 100 km depth and extends nearly horizontally under the continent. Above this 'flat slab', volcanic activity in the main Andean Cordillera terminated about 9 million years ago as the flattening slab presumably squeezed out the mantle wedge. But it is unknown where slab volatiles go once this happens, and why the flat slab finally rolls over to descend steeply into the mantle 600 km further eastward. Here we present results from a magnetotelluric profile in central Argentina, from which we infer enhanced electrical conductivity along the eastern side of the plunging slab, indicative of the presence of partial melt. This conductivity structure may imply that partial melting occurs to at least 250 km and perhaps to more than 400 km depth, or that melt is supplied from the 410 km discontinuity, consistent with the transition-zone 'water-filter' model of Bercovici and Karato.     

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.     

Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor

Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.     

RNA metabolism in brain of suckling normal and hypothyroid rats

Resumen Se estudió la incorporación de radioactividad en RNAs de fracciones subcelulares de cerebro de ratas normales y neonatalmente tiroprivas de 10 días de edad, luego de la administración subcutánea de ácido orótico tritiado. El hipotiroidismo afecta la síntesis de RNA nuclear «ràpidamente marcado» y probablemente su transporte al citoplasma.

---

---

Supported by Grants from the Consejo Nacional de Investigaciones Cientificas y Técnicas (1003b) and the Institute Nacional de Bromatología y Farmacología, Argentina.     

Surprising dissimilarities in a newly formed pair of 'identical twin' stars

The mass and chemical composition of a star are the primary determinants of its basic physical properties-radius, temperature and luminosity-and how those properties evolve with time. Accordingly, two stars born at the same time, from the same natal material and with the same mass, are 'identical twins,' and as such might be expected to possess identical physical attributes. We have discovered in the Orion nebula a pair of stellar twins in a newborn binary star system. Each star in the binary has a mass of 0.41 +/- 0.01 solar masses, identical to within 2 per cent. Here we report that these twin stars have surface temperatures differing by approximately 300 K ( approximately 10 per cent) and luminosities differing by approximately 50 per cent, both at high confidence level. Preliminary results indicate that the stars' radii also differ, by 5-10 per cent. These surprising dissimilarities suggest that one of the twins may have been delayed by several hundred thousand years in its formation relative to its sibling. Such a delay could only have been detected in a very young, definitively equal-mass binary system. Our findings reveal cosmic limits on the age synchronization of young binary stars, often used as tests for the age calibrations of star-formation models.