45 research outputs found
Real-time imaging of Leishmania mexicana-infected early phagosomes: a study using primary macrophages generated from green fluorescent protein-Rab5 transgenic mice
The small GTPase Rab5 is a key regulator of endosome/phagosome maturation and in intravesicular infections marks a phagosome stage at which decisions over pathogen replication or destruction are integrated. It is currently unclear whether Leishmania-infected phagosomes uniformly pass through a Rab5+ stage on their intracellular path to compartments with late endosomal/early lysosomal characteristics. Differences in routes and final compartments could have consequences for accessibility to antileishmanial drugs. Here, we generated a unique gfp-rab5 transgenic mouse model to visualize Rab5 recruitment to early parasite-containing phagosomes in primary host cells. Using real-time fluorescence imaging of phagosomes carrying Leishmania mexicana, we determined that parasite-infested phagosomes follow a uniform sequence of transient Rab5 recruitment. Residence in Rab5+ compartments was much shorter compared with phagosomes harboring latex beads. Furthermore, a comparative analysis of parasite life-cycle stages and mutants deficient in lpg1, the gene encoding the enzyme required for synthesis of the dominant surface lipophosphoglycan, indicated that parasite surface ligands and host cell receptors modulate pathogen residence times in Rab5+ phagosomes, but, as far as tested, had no significant effect on intracellular L. mexicana survival or replication.—Lippuner, C., Paape, D., Paterou, A., Brand, J., Richardson, M., Smith, A. J., Hoffmann, K., Brinkmann, V., Blackburn, C., Aebischer, T. Real-time imaging of Leishmania mexicana-infected early phagosomes: a study using primary macrophages generated from green fluorescent protein-Rab5 transgenic mice
Different response to eccentric and concentric training in older men and women
Sarcopenia is the age-related loss of muscle mass and strength and has been associated with an increased risk of falling and the development of metabolic diseases. Various training protocols, nutritional and hormonal interventions have been proposed to prevent sarcopenia. This study explores the potential of continuous eccentric exercise to retard age-related loss of muscle mass and function. Elderly men and women (80.6±3.5years) were randomized to one of three training interventions demanding a training effort of two sessions weekly for 12weeks: cognitive training (CT; n=16), conventional resistance training (RET; n=23) and eccentric ergometer training (EET; n=23). Subjects were tested for functional parameters and body composition. Biopsies were collected from M. vastus lateralis before and after the intervention for the assessment of fiber size and composition. Maximal isometric leg extension strength (MEL: +8.4±1.7%) and eccentric muscle coordination (COORD: −43±4%) were significantly improved with EET but not with RET (MEL: +2.3±2.0%; COORD: −13±3%) and CT (MEL: −2.3±2.5%; COORD: −12±5%), respectively. We observed a loss of body fat (−5.0±1.1%) and thigh fat (−6.9±1.5%) in EET subjects only. Relative thigh lean mass increased with EET (+2.5±0.6%) and RET (+2.0±0.3%) and correlated negatively with type IIX/type II muscle fiber ratios. It was concluded that both RET and EET are beneficial for the elderly with regard to muscle functional and structural improvements but differ in their spectrum of effects. A training frequency of only two sessions per week seems to be the lower limit for a training stimulus to reveal measurable benefit
Biologically relevant sex differences for fitness-related parameters in active octogenarians
The number of elderly people is growing in western populations, but only few maximal performance data exist for people >75years, in particular for European octogenarians. This study was performed to characterize maximal performance of 55 independently living subjects (32 women, 81.1±3.4years; 23 men, 81.7±2.9years) with a focus on sex differences. Maximal performance was determined in a ramp test to exhaustion on a bicycle ergometer with ergospirometry, electrocardiogram and blood lactate measurements. Maximal isometric extension strength of the legs (MEL) was measured on a force platform in a seated position. Body composition was quantified by X-ray absorptiometry. In >25% of the subjects, serious cardiac abnormalities were detected during the ramp test with men more frequently being affected than women. Maximal oxygen consumption and power output were 18.2±3.2 versus 25.9±5.9mlmin−1kg−1 and 66±12 versus 138±40W for women versus men, with a significant sex difference for both parameters. Men outperformed women for MEL with 19.0±3.8 versus 13.6±3.3Nkg−1. Concomitantly, we found a higher proportion of whole body fat in women (32.1±6.2%) compared to men (20.5±4.4%). Our study extends previously available maximal performance data for endurance and strength to independently living European octogenarians. As all sex-related differences were still apparent after normalization to lean body mass, it is concluded that it is essential to differentiate between female and male subjects when considering maximal performance parameters in the oldest segment of our populatio
A Bibliometric Analysis of Fragility Fractures: Top 50.
Background and Objectives: The population is aging and fragility fractures are a research topic of steadily growing importance. Therefore, a systematic bibliometric review was performed to identify the 50 most cited articles in the field of fragility fractures analyzing their qualities and characteristics. Materials and Methods: From the Core Collection database in the Thomson Reuters Web of Knowledge, the most influential original articles with reference to fragility fractures were identified in February 2021 using a multistep approach. Year of publication, total number of citations, average number of citations per year since year of publication, affiliation of first and senior author, geographic origin of study population, keywords, and level of evidence were of interest. Results: Articles were published in 26 different journals between 1997 and 2020. The number of total citations per article ranged from 12 to 129 citations. In the majority of publications, orthopedic surgeons and traumatologists (66%) accounted for the first authorship, articles mostly originated from Europe (58%) and the keyword mostly used was "hip fracture". In total, 38% of the articles were therapeutic studies level III followed by prognostic studies level I. Only two therapeutic studies with level I could be identified. Conclusions: This bibliometric review shows the growing interest in fragility fractures and raises awareness that more high quality and interdisciplinary studies are needed
Parthenon -- a performance portable block-structured adaptive mesh refinement framework
On the path to exascale the landscape of computer device architectures and
corresponding programming models has become much more diverse. While various
low-level performance portable programming models are available, support at the
application level lacks behind. To address this issue, we present the
performance portable block-structured adaptive mesh refinement (AMR) framework
Parthenon, derived from the well-tested and widely used Athena++ astrophysical
magnetohydrodynamics code, but generalized to serve as the foundation for a
variety of downstream multi-physics codes. Parthenon adopts the Kokkos
programming model, and provides various levels of abstractions from
multi-dimensional variables, to packages defining and separating components, to
launching of parallel compute kernels. Parthenon allocates all data in device
memory to reduce data movement, supports the logical packing of variables and
mesh blocks to reduce kernel launch overhead, and employs one-sided,
asynchronous MPI calls to reduce communication overhead in multi-node
simulations. Using a hydrodynamics miniapp, we demonstrate weak and strong
scaling on various architectures including AMD and NVIDIA GPUs, Intel and AMD
x86 CPUs, IBM Power9 CPUs, as well as Fujitsu A64FX CPUs. At the largest scale
on Frontier (the first TOP500 exascale machine), the miniapp reaches a total of
zone-cycles/s on 9,216 nodes (73,728 logical GPUs) at ~92%
weak scaling parallel efficiency (starting from a single node). In combination
with being an open, collaborative project, this makes Parthenon an ideal
framework to target exascale simulations in which the downstream developers can
focus on their specific application rather than on the complexity of handling
massively-parallel, device-accelerated AMR.Comment: 17 pages, 11 figures, accepted for publication in IJHPCA, Codes
available at https://github.com/parthenon-hpc-la
Catching Element Formation In The Act
Gamma-ray astronomy explores the most energetic photons in nature to address
some of the most pressing puzzles in contemporary astrophysics. It encompasses
a wide range of objects and phenomena: stars, supernovae, novae, neutron stars,
stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays
and relativistic-particle acceleration, and the evolution of galaxies. MeV
gamma-rays provide a unique probe of nuclear processes in astronomy, directly
measuring radioactive decay, nuclear de-excitation, and positron annihilation.
The substantial information carried by gamma-ray photons allows us to see
deeper into these objects, the bulk of the power is often emitted at gamma-ray
energies, and radioactivity provides a natural physical clock that adds unique
information. New science will be driven by time-domain population studies at
gamma-ray energies. This science is enabled by next-generation gamma-ray
instruments with one to two orders of magnitude better sensitivity, larger sky
coverage, and faster cadence than all previous gamma-ray instruments. This
transformative capability permits: (a) the accurate identification of the
gamma-ray emitting objects and correlations with observations taken at other
wavelengths and with other messengers; (b) construction of new gamma-ray maps
of the Milky Way and other nearby galaxies where extended regions are
distinguished from point sources; and (c) considerable serendipitous science of
scarce events -- nearby neutron star mergers, for example. Advances in
technology push the performance of new gamma-ray instruments to address a wide
set of astrophysical questions.Comment: 14 pages including 3 figure
Direct Visualization of Peptide/MHC Complexes at the Surface and in the Intracellular Compartments of Cells Infected In Vivo by Leishmania major
Protozoa and bacteria infect various types of phagocytic cells including macrophages, monocytes, dendritic cells and eosinophils. However, it is not clear which of these cells process and present microbial antigens in vivo and in which cellular compartments parasite peptides are loaded onto Major Histocompatibility Complex molecules. To address these issues, we have infected susceptible BALB/c (H-2d) mice with a recombinant Leishmania major parasite expressing a fluorescent tracer. To directly visualize the antigen presenting cells that present parasite-derived peptides to CD4+ T cells, we have generated a monoclonal antibody that reacts to an antigenic peptide derived from the parasite LACK antigen bound to I-Ad Major Histocompatibility Complex class II molecule. Immunogold electron microscopic analysis of in vivo infected cells showed that intracellular I-Ad/LACK complexes were present in the membrane of amastigote-containing phagosomes in dendritic cells, eosinophils and macrophages/monocytes. In both dendritic cells and macrophages, these complexes were also present in smaller vesicles that did not contain amastigote. The presence of I-Ad/LACK complexes at the surface of dendritic cells, but neither on the plasma membrane of macrophages nor eosinophils was independently confirmed by flow cytometry and by incubating sorted phagocytes with highly sensitive LACK-specific hybridomas. Altogether, our results suggest that peptides derived from Leishmania proteins are loaded onto Major Histocompatibility Complex class II molecules in the phagosomes of infected phagocytes. Although these complexes are transported to the cell surface in dendritic cells, therefore allowing the stimulation of parasite-specific CD4+ T cells, this does not occur in other phagocytic cells. To our knowledge, this is the first study in which Major Histocompatibility Complex class II molecules bound to peptides derived from a parasite protein have been visualized within and at the surface of cells that were infected in vivo