Divergence-time estimates for hominins provide insight into encephalization and body mass trends in human evolution

Quantifying speciation times during human evolution is fundamental as it provides a timescale to test for the correlation between key evolutionary transitions and extrinsic factors such as climatic or environmental change. Here, we applied a total evidence dating approach to a hominin phylogeny to estimate divergence times under different topological hypotheses. The time-scaled phylogenies were subsequently used to perform ancestral state reconstructions of body mass and phylogenetic encephalization quotient (PEQ). Our divergence-time estimates are consistent with other recent studies that analysed extant species. We show that the origin of the genus Homo probably occurred between 4.30 and 2.56 million years ago. The ancestral state reconstructions show a general trend towards a smaller body mass before the emergence of Homo, followed by a trend towards a greater body mass. PEQ estimations display a general trend of gradual but accelerating encephalization evolution. The obtained results provide a rigorous temporal framework for human evolution

Mechanical Competence and Bone Quality Develop During Skeletal Growth.

Bone fracture risk is influenced by bone quality, which encompasses bone's composition as well as its multiscale organization and architecture. Aging and disease deteriorate bone quality, leading to reduced mechanical properties and higher fracture incidence. Largely unexplored is how bone quality and mechanical competence progress during longitudinal bone growth. Human femoral cortical bone was acquired from fetal (n = 1), infantile (n = 3), and 2- to 14-year-old cases (n = 4) at the mid-diaphysis. Bone quality was assessed in terms of bone structure, osteocyte characteristics, mineralization, and collagen orientation. The mechanical properties were investigated by measuring tensile deformation at multiple length scales via synchrotron X-ray diffraction. We find dramatic differences in mechanical resistance with age. Specifically, cortical bone in 2- to 14-year-old cases exhibits a 160% greater stiffness and 83% higher strength than fetal/infantile cases. The higher mechanical resistance of the 2- to 14-year-old cases is associated with advantageous bone quality, specifically higher bone volume fraction, better micronscale organization (woven versus lamellar), and higher mean mineralization compared with fetal/infantile cases. Our study reveals that bone quality is superior after remodeling/modeling processes convert the primary woven bone structure to lamellar bone. In this cohort of female children, the microstructural differences at the femoral diaphysis were apparent between the 1- to 2-year-old cases. Indeed, the lamellar bone in 2- to 14-year-old cases had a superior structural organization (collagen and osteocyte characteristics) and composition for resisting deformation and fracture than fetal/infantile bone. Mechanistically, the changes in bone quality during longitudinal bone growth lead to higher fracture resistance because collagen fibrils are better aligned to resist tensile forces, while elevated mean mineralization reinforces the collagen scaffold. Thus, our results reveal inherent weaknesses of the fetal/infantile skeleton signifying its inferior bone quality. These results have implications for pediatric fracture risk, as bone produced at ossification centers during children's longitudinal bone growth could display similarly weak points. © 2019 American Society for Bone and Mineral Research

Empirical Installation of Linear Algebra Shared-Memory Subroutines for Auto-Tuning

The final publication is available at Springer via http://dx.doi.org/10.1007/s10766-013-0249-6The introduction of auto-tuning techniques in linear algebra shared-memory routines is analyzed. Information obtained in the installation of the routines is used at running time to take some decisions to reduce the total execution time. The study is carried out with routines at different levels (matrix multiplication, LU and Cholesky factorizations and linear systems symmetric or general routines) and with calls to routines in the LAPACK and PLASMA libraries with multithread implementations. Medium NUMA and large cc-NUMA systems are used in the experiments. This variety of routines, libraries and systems allows us to obtain general conclusions about the methodology to use for linear algebra shared-memory routines auto-tuning. Satisfactory execution times are obtained with the proposed methodology.Partially supported by Fundacion Seneca, Consejeria de Educacion de la Region de Murcia, 08763/PI/08, PROMETEO/2009/013 from Generalitat Valenciana, the Spanish Ministry of Education and Science through TIN2012-38341-C04-03, and the High-Performance Computing Network on Parallel Heterogeneus Architectures (CAPAP-H). The authors gratefully acknowledge the computer resources and assistance provided by the Supercomputing Centre of the Scientific Park Foundation of Murcia and by the Centre de Supercomputacio de Catalunya.Cámara, J.; Cuenca, J.; Giménez, D.; García, LP.; Vidal Maciá, AM. (2014). Empirical Installation of Linear Algebra Shared-Memory Subroutines for Auto-Tuning. International Journal of Parallel Programming. 42(3):408-434. https://doi.org/10.1007/s10766-013-0249-6S408434423Agullo, E., Demmel, J., Dongarra, J., Hadri, B., Kurzak, J., Langou, J., Ltaief, H., Luszczek, P., Tomov, S.: Numerical linear algebra on emerging architectures: the PLASMA and MAGMA projects. J. Phys. Conf. Ser. 180(1), 1–5 (2009)Alberti, P., Alonso, P., Vidal, A.M., Cuenca, J., Giménez, D.: Designing polylibraries to speed up linear algebra computations. Int. J. High Perform. Comput. Netw. 1/2/3(1), 75–84 (2004)Anderson, E., Bai, Z., Bischof, C., Demmel, J., Dongarra, J.J., Du Croz, J., Grenbaum, A., Hammarling, S., McKenney, A., Ostrouchov, S., D. Sorensen, S.: LAPACK User’s Guide. Society for Industrial and Applied Mathematics, Philadelphia (1995)Bernabé, G., Cuenca, J., Giménez, D.: Optimization techniques for 3D-FWT on systems with manycore GPUs and multicore CPUs. In: ICCS (2013)Buttari, A., Langou, J., Kurzak, J., Dongarra, J.: A class of parallel tiled linear algebra algorithms for multicore architectures. Parallel Comput. 35(1), 38–53 (2009)Cámara, J., Cuenca, J., Giménez, D., Vidal. A.M.: Empirical autotuning of two-level parallel linear algebra routines on large cc-NUMA systems. In: ISPA (2012)Caron, E., Desprez, F., Suter, F.: Parallel extension of a dynamic performance forecasting tool. Scalable Comput. Pract. Exp. 6(1), 57–69 (2005)Chen, Z., Dongarra, J., Luszczek, P., Roche, K.: Self adapting software for numerical linear algebra and LAPACK for clusters. Parallel Comput. 29, 1723–1743 (2003)Cuenca, J., Giménez, D., González, J.: Achitecture of an automatic tuned linear algebra library. Parallel Comput. 30(2), 187–220 (2004)Cuenca, J., García, L.P., Giménez, D.: Improving linear algebra computation on NUMA platforms through auto-tuned nested parallelism. In: Proceedings of the 2012 EUROMICRO Conference on Parallel, Distributed and Network Processing (2012)Frigo, M.: FFTW: An adaptive software architecture for the FFT. In: Proceedings of the ICASSP Conference, vol. 3, p. 1381 (1998)Golub, G., Van Loan, C.F.: Matrix Computations, 3rd edn. The John Hopkins University Press, Baltimore (1996)Im, E.-J., Yelick, K., Vuduc, R.: Sparsity: optimization framework for sparse matrix kernels. Int. J. High Perform. Comput. Appl. (IJHPCA) 18(1), 135–158 (2004)Intel MKL web page.: http://software.intel.com/en-us/intel-mkl/Jerez, S., Montávez, J.-P., Giménez, D.: Optimizing the execution of a parallel meteorology simulation code. In: Proceedings of the 23rd IEEE International Parallel and Distributed Processing Symposium. IEEE (2009)Katagiri, T., Kise, K., Honda, H., Yuba, T.: Fiber: a generalized framework for auto-tuning software. Springer LNCS 2858, 146–159 (2003)Katagiri, T., Kise, K., Honda, H., Yuba, T.: ABCLib-DRSSED: a parallel eigensolver with an auto-tuning facility. Parallel Comput. 32(3), 231–250 (2006)Kurzak, J., Tomov, S., Dongarra, J.: Autotuning gemm kernels for the FERMI GPU. IEEE Trans. Parallel Distrib. Syst. 23(11), 2045–2057 (2012)Lastovetsky, A.L., Reddy, R., Higgins, R.: Building the functional performance model of a processor. In: SAC, pp. 746–753 (2006)Li, J., Skjellum, A., Falgout, R.D.: A poly-algorithm for parallel dense matrix multiplication on two-dimensional process grid topologies. Concurrency Pract. Exp. 9(5), 345–389 (1997)Naono, K., Teranishi, K., Cavazos, J., Suda, R., (eds.): Software Automatic Tuning. From Concepts to State-of-the-Art Results. Springer, Berlin (2010)Nath, R., Tomov, S., Dongarra, J.: An improved MAGMA gemm for FERMI graphics processing units. IJHPCA 24(4), 511–515 (2010)Petitet, A., Blackford, L.S., Dongarra, J., Ellis, B., Fagg, G.E., Roche, K., Vadhiyar, S.S.: Numerical libraries and the grid. IJHPCA 15(4), 359–374 (2001)PLASMA.: http://icl.cs.utk.edu/plasma/Püschel, M., Moura, J.M.F., Singer, B., Xiong, J., Johnson, J.R., Padua, D.A., Veloso, M.M., Johnson, R.W.: Spiral: a generator for platform-adapted libraries of signal processing algorithms. IJHPCA 18(1), 21–45 (2004)Seshagiri, L., Wu, M.-S., Sosonkina, M., Zhang, Z., Gordon, M.S., Schmidt, M.W.: Enhancing adaptive middleware for quantum chemistry applications with a database framework. In: IPDPS Workshops, pp. 1–8 (2010)Tanaka, T., Katagiri, T., Yuba, T.: d-Spline based incremental parameter estimation in automatic performance tuning. In: PARA, pp. 986–995 (2006)Vuduc, R., Demmel, J., Bilmes, J.: Statistical models for automatic performance tuning. In: International Conference on Computational Science (1), pp. 117–126 (2001)Whaley, R.C., Petitet, A., Dongarra, J.: Automated empirical optimizations of software and the ATLAS project. Parallel Comput. 27(1–2), 3–35 (2001

Generating Performance Portable Code using Rewrite Rules: From High-Level Functional Expressions to High-Performance OpenCL Code

Computers have become increasingly complex with the emergence of heterogeneous hardware combining multicore CPUs and GPUs. These parallel systems exhibit tremendous computational power at the cost of increased programming effort resulting in a tension between performance and code portability. Typically, code is either tuned in a low-level imperative language using hardware-specific optimizations to achieve maximum performance or is written in a high-level, possibly functional, language to achieve portability at the expense of performance. We propose a novel approach aiming to combine high-level programming, code portability, and high-performance. Starting from a high-level functional expression we apply a simple set of rewrite rules to transform it into a low-level functional representation, close to the OpenCL programming model, from which OpenCL code is generated. Our rewrite rules define a space of possible implementations which we automatically explore to generate hardware-specific OpenCL implementations. We formalize our system with a core dependently-typed λ-calculus along with a denotational semantics which we use to prove the correctness of the rewrite rules. We test our design in practice by implementing a compiler which generates high performance imperative OpenCL code. Our experiments show that we can automatically derive hardware-specific implementations from simple functional high-level algorithmic expressions offering performance on a par with highly tuned code for multicore CPUs and GPUs written by experts

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one‐third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling‐centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes

Enhanced ion acceleration from transparency-driven foils demonstrated at two ultraintense laser facilities

Laser-driven ion sources are a rapidly developing technology producing high energy, high peak current beams. Their suitability for applications, such as compact medical accelerators, motivates development of robust acceleration schemes using widely available repetitive ultraintense femtosecond lasers. These applications not only require high beam energy, but also place demanding requirements on the source stability and controllability. This can be seriously affected by the laser temporal contrast, precluding the replication of ion acceleration performance on independent laser systems with otherwise similar parameters. Here, we present the experimental generation of >60 MeV protons and >30 MeV u-1 carbon ions from sub-micrometre thickness Formvar foils irradiated with laser intensities >1021 Wcm2. Ions are accelerated by an extreme localised space charge field ≳30 TVm-1, over a million times higher than used in conventional accelerators. The field is formed by a rapid expulsion of electrons from the target bulk due to relativistically induced transparency, in which relativistic corrections to the refractive index enables laser transmission through normally opaque plasma. We replicate the mechanism on two different laser facilities and show that the optimum target thickness decreases with improved laser contrast due to reduced pre-expansion. Our demonstration that energetic ions can be accelerated by this mechanism at different contrast levels relaxes laser requirements and indicates interaction parameters for realising application-specific beam delivery