Efficient targeting to storage granules of human proinsulins with altered propeptide domain.

In neuronal and endocrine cells, peptide hormones are selectively segregated into storage granules, while other proteins are exported continuously without storage. Sorting of hormones by cellular machinery involves the recognition of specific structural domains on prohormone molecules. Since the propeptide of insulin is known to play an important role in its three-dimensional structure, it is reasonable to speculate that targeting of proinsulin to storage granules would require a functional connecting peptide. To test this hypothesis, we constructed two mutations in human proinsulin with different predicted structures. In one mutation, Ins delta C, the entire C peptide was deleted, resulting in an altered insulin in which the B and the A chains are joined contiguously. In the other mutation, Ins/IGF, the C peptide of proinsulin was replaced with the unrelated 12-amino acid connecting peptide of human insulin-like growth factor-I; this substitution should permit correct folding of the B and A chains to form a tertiary structure similar to that of proinsulin. By several biochemical and morphological criteria, we found that Ins/IGF is efficiently targeted to storage granules, suggesting that the C peptide of proinsulin does not contain necessary sorting information. Unexpectedly, Ins delta C, which presumably cannot fold properly, is also targeted to granules at a high efficiency. These results imply that either the targeting machinery can tolerate changes in the tertiary structure of transported proteins, or that the B and A chains of insulin can form a relatively intact three-dimensional structure even in the absence of C peptide

Early and efficient detection of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures.

Early, efficient and inexpensive methods for the detection of pulmonary tuberculosis are urgently needed for effective patient management as well as to interrupt transmission. These methods to detect M. tuberculosis in a timely and affordable way are not yet widely available in resource-limited settings. In a developing-country setting, we prospectively evaluated two methods for culturing and detecting M. tuberculosis in sputum. Sputum samples were cultured in liquid assay (micro broth culture) in microplate wells and growth was detected by microscopic observation, or in Löwenstein-Jensen (LJ) solid media where growth was detected by visual inspection for colonies. Sputum samples were collected from 321 tuberculosis (TB) suspects attending Bugando Medical Centre, in Mwanza, Tanzania, and were cultured in parallel. Pulmonary tuberculosis cases were diagnosed using the American Thoracic Society diagnostic standards. There were a total of 200 (62.3%) pulmonary tuberculosis cases. Liquid assay with microscopic detection detected a significantly higher proportion of cases than LJ solid culture: 89.0% (95% confidence interval [CI], 84.7% to 93.3%) versus 77.0% (95% CI, 71.2% to 82.8%) (p = 0.0007). The median turn around time to diagnose tuberculosis was significantly shorter for micro broth culture than for the LJ solid culture, 9 days (interquartile range [IQR] 7-13), versus 21 days (IQR 14-28) (p<0.0001). The cost for micro broth culture (labor inclusive) in our study was US $4.56 per sample, versus US$11.35 per sample for the LJ solid culture. The liquid assay (micro broth culture) is an early, feasible, and inexpensive method for detection of pulmonary tuberculosis in resource limited settings

La vie et la mort en peinture

L'abstraction visuelle ne constituerait pas d'abord une réflexion sur la nature du beau en soi, mais une approche cognitive renvoyant aux épistémologies et aux idéologies des époques où elle se manifeste. L'étude de différents discours tenus sur l'abstraction picturale au XIXe et au XXe siècles permet de suivre les valeurs attribuées à cette notion, notamment autour de l'opposition entre le vitalisme et la mort à partir des réflexions d'A. Riegl et W. Worringer. La différenciation entre l'abstrait et le concret, le sujet et l'objet se voit ainsi constamment relancée, dans la possibilité de leur réversibilité.Visual abstraction is not, at least not in the first place, a reflection upon the nature of beauty as such, but rather a cognitive approach to the world that bears witness to the epistemologies and ideologies of those periods of history where it appeared. The study of some of the discourses that have been held about pictural abstraction during the 19th and 20th centuries, notably the opposition between vitalism and death founded on the works of A. Riegl and W. Worringer, allows us to understand the various values that have been given to the notion. The distinction between abstraction and concreteness, subject and object, can here be seen, in regard to the possibility of their reversibility, as an ever-open question

Three-body interactions with cold polar molecules

We show that polar molecules driven by microwave fields give naturally rise to strong three-body interactions, while the two-particle interaction can be independently controlled and even switched off. The derivation of these effective interaction potentials is based on a microscopic understanding of the underlying molecular physics, and follows from a well controlled and systematic expansion into many-body interaction terms. For molecules trapped in an optical lattice, we show that these interaction potentials give rise to Hubbard models with strong nearest-neighbor two-body and three-body interaction. As an illustration, we study the one-dimensional Bose-Hubbard model with dominant three-body interaction and derive its phase diagram.Comment: 8 pages, 4 figure

Developmental and evolutionary significance of the zygomatic bone

International audienc

Cirsium species show disparity in patterns of genetic variation at their range-edge, despite similar patterns of reproduction and isolation

Genetic variation was assessed across the UK geographical range of Cirsium acaule and Cirsium heterophyllum. A decline in genetic diversity and increase in population divergence approaching the range edge of these species was predicted based on parallel declines in population density and seed production reported seperately. Patterns were compared with UK populations of the widespread Cirsium arvense.Populations were sampled along a latitudinal transect in the UK and genetic variation assessed using microsatellite markers. Cirsium acaule shows strong isolation by distance, a significant decline in diversity and an increase in divergence among range-edge populations. Geographical structure is also evident in C. arvense, whereas no such patterns are seen in C.heterophyllum. There is a major disparity between patterns of genetic variation in C. acaule and C. heterophyllum despite very similar patterns in seed production and population isolation in these species. This suggests it may be misleading to make assumptions about the geographical structure of genetic variation within species based solely on the present-day reproduction and distribution of populations

Fine-grained bit-flip protection for relaxation methods

[EN] Resilience is considered a challenging under-addressed issue that the high performance computing community (HPC) will have to face in order to produce reliable Exascale systems by the beginning of the next decade. As part of a push toward a resilient HPC ecosystem, in this paper we propose an error-resilient iterative solver for sparse linear systems based on stationary component-wise relaxation methods. Starting from a plain implementation of the Jacobi iteration, our approach introduces a low-cost component-wise technique that detects bit-flips, rejecting some component updates, and turning the initial synchronized solver into an asynchronous iteration. Our experimental study with sparse incomplete factorizations from a collection of real-world applications, and a practical GPU implementation, exposes the convergence delay incurred by the fault-tolerant implementation and its practical performance.This material is based upon work supported in part by the U.S. Department of Energy (Award Number DE-SC-0010042) and NVIDIA. E. S. Quintana-Orti was supported by project CICYT TIN2014-53495-R of MINECO and FEDER.Anzt, H.; Dongarra, J.; Quintana Ortí, ES. (2019). Fine-grained bit-flip protection for relaxation methods. Journal of Computational Science. 36:1-11. https://doi.org/10.1016/j.jocs.2016.11.013S11136Chow, E., & Patel, A. (2015). Fine-Grained Parallel Incomplete LU Factorization. SIAM Journal on Scientific Computing, 37(2), C169-C193. doi:10.1137/140968896Karpuzcu, U. R., Kim, N. S., & Torrellas, J. (2013). Coping with Parametric Variation at Near-Threshold Voltages. IEEE Micro, 33(4), 6-14. doi:10.1109/mm.2013.71Bronevetsky, G., & de Supinski, B. (2008). Soft error vulnerability of iterative linear algebra methods. Proceedings of the 22nd annual international conference on Supercomputing - ICS ’08. doi:10.1145/1375527.1375552Sao, P., & Vuduc, R. (2013). Self-stabilizing iterative solvers. Proceedings of the Workshop on Latest Advances in Scalable Algorithms for Large-Scale Systems - ScalA ’13. doi:10.1145/2530268.2530272Calhoun, J., Snir, M., Olson, L., & Garzaran, M. (2015). Understanding the Propagation of Error Due to a Silent Data Corruption in a Sparse Matrix Vector Multiply. 2015 IEEE International Conference on Cluster Computing. doi:10.1109/cluster.2015.101Chazan, D., & Miranker, W. (1969). Chaotic relaxation. Linear Algebra and its Applications, 2(2), 199-222. doi:10.1016/0024-3795(69)90028-7Frommer, A., & Szyld, D. B. (2000). On asynchronous iterations. Journal of Computational and Applied Mathematics, 123(1-2), 201-216. doi:10.1016/s0377-0427(00)00409-xDuff, I. S., & Meurant, G. A. (1989). The effect of ordering on preconditioned conjugate gradients. BIT, 29(4), 635-657. doi:10.1007/bf01932738Aliaga, J. I., Barreda, M., Dolz, M. F., Martín, A. F., Mayo, R., & Quintana-Ortí, E. S. (2014). Assessing the impact of the CPU power-saving modes on the task-parallel solution of sparse linear systems. Cluster Computing, 17(4), 1335-1348. doi:10.1007/s10586-014-0402-

Scratching Beneath the Surface : Intentionality in Great Ape Signal production

Despite important similarities having been found between human and animal communication systems, surprisingly little research effort has focussed on whether the cognitive mechanisms underpinning these behaviours are also similar. In particular, it is highly debated whether signal production is the result of reflexive processes, or can be characterised as intentional. Here, we critically evaluate the criteria that are used to identify signals produced with different degrees of intentionality, and discuss recent attempts to apply these criteria to the vocal, gestural, and multimodal communicative signals of great apes and more distantly related species. Finally, we outline the necessary research tools, such as physiologically validated measures of arousal, and empirical evidence that we believe would propel this debate forward and help unravel the evolutionary origins of human intentional communication

Avoiding Costly Conservation Mistakes: The Importance of Defining Actions and Costs in Spatial Priority Setting

Background: The typical mandate in conservation planning is to identify areas that represent biodiversity targets within the smallest possible area of land or sea, despite the fact that area may be a poor surrogate for the cost of many conservation actions. It is also common for priorities for conservation investment to be identified without regard to the particular conservation action that will be implemented. This demonstrates inadequate problem specification and may lead to inefficiency: the cost of alternative conservation actions can differ throughout a landscape, and may result in dissimilar conservation priorities