Different modes of state transitions determine pattern in the Phosphatidylinositide-Actin system

<p>Abstract</p> <p>Background</p> <p>In a motile polarized cell the actin system is differentiated to allow protrusion at the front and retraction at the tail. This differentiation is linked to the phosphoinositide pattern in the plasma membrane. In the highly motile <it>Dictyostelium </it>cells studied here, the front is dominated by PI3-kinases producing PI(3,4,5)tris-phosphate (PIP3), the tail by the PI3-phosphatase PTEN that hydrolyses PIP3 to PI(4,5)bis-phosphate. To study de-novo cell polarization, we first depolymerized actin and subsequently recorded the spontaneous reorganization of actin patterns in relation to PTEN.</p> <p>Results</p> <p>In a transient stage of recovery from depolymerization, symmetric actin patterns alternate periodically with asymmetric ones. The switches to asymmetry coincide with the unilateral membrane-binding of PTEN. The modes of state transitions in the actin and PTEN systems differ. Transitions in the actin system propagate as waves that are initiated at single sites by the amplification of spontaneous fluctuations. In PTEN-null cells, these waves still propagate with normal speed but loose their regular periodicity. Membrane-binding of PTEN is induced at the border of a coherent PTEN-rich area in the form of expanding and regressing gradients.</p> <p>Conclusions</p> <p>The state transitions in actin organization and the reversible transition from cytoplasmic to membrane-bound PTEN are synchronized but their patterns differ. The transitions in actin organization are independent of PTEN, but when PTEN is present, they are coupled to periodic changes in the membrane-binding of this PIP3-degrading phosphatase. The PTEN oscillations are related to motility patterns of chemotaxing cells.</p

Genomic Diversity and Evolution of the Lyssaviruses

Lyssaviruses are RNA viruses with single-strand, negative-sense genomes responsible for rabies-like diseases in mammals. To date, genomic and evolutionary studies have most often utilized partial genome sequences, particularly of the nucleoprotein and glycoprotein genes, with little consideration of genome-scale evolution. Herein, we report the first genomic and evolutionary analysis using complete genome sequences of all recognised lyssavirus genotypes, including 14 new complete genomes of field isolates from 6 genotypes and one genotype that is completely sequenced for the first time. In doing so we significantly increase the extent of genome sequence data available for these important viruses. Our analysis of these genome sequence data reveals that all lyssaviruses have the same genomic organization. A phylogenetic analysis reveals strong geographical structuring, with the greatest genetic diversity in Africa, and an independent origin for the two known genotypes that infect European bats. We also suggest that multiple genotypes may exist within the diversity of viruses currently classified as ‘Lagos Bat’. In sum, we show that rigorous phylogenetic techniques based on full length genome sequence provide the best discriminatory power for genotype classification within the lyssaviruses

Osteoclast Activated FoxP3+ CD8+ T-Cells Suppress Bone Resorption in vitro

BACKGROUND: Osteoclasts are the body's sole bone resorbing cells. Cytokines produced by pro-inflammatory effector T-cells (T(EFF)) increase bone resorption by osteoclasts. Prolonged exposure to the T(EFF) produced cytokines leads to bone erosion diseases such as osteoporosis and rheumatoid arthritis. The crosstalk between T-cells and osteoclasts has been termed osteoimmunology. We have previously shown that under non-inflammatory conditions, murine osteoclasts can recruit naïve CD8 T-cells and activate these T-cells to induce CD25 and FoxP3 (Tc(REG)). The activation of CD8 T-cells by osteoclasts also induced the cytokines IL-2, IL-6, IL-10 and IFN-γ. Individually, these cytokines can activate or suppress osteoclast resorption. PRINCIPAL FINDINGS: To determine the net effect of Tc(REG) on osteoclast activity we used a number of in vitro assays. We found that Tc(REG) can potently and directly suppress bone resorption by osteoclasts. Tc(REG) could suppress osteoclast differentiation and resorption by mature osteoclasts, but did not affect their survival. Additionally, we showed that Tc(REG) suppress cytoskeletal reorganization in mature osteoclasts. Whereas induction of Tc(REG) by osteoclasts is antigen-dependent, suppression of osteoclasts by Tc(REG) does not require antigen or re-stimulation. We demonstrated that antibody blockade of IL-6, IL-10 or IFN-γ relieved suppression. The suppression did not require direct contact between the Tc(REG) and osteoclasts. SIGNIFICANCE: We have determined that osteoclast-induced Tc(REG) can suppress osteoclast activity, forming a negative feedback system. As the CD8 T-cells are activated in the absence of inflammatory signals, these observations suggest that this regulatory loop may play a role in regulating skeletal homeostasis. Our results provide the first documentation of suppression of osteoclast activity by CD8 regulatory T-cells and thus, extend the purview of osteoimmunology

Prime Focus Spectrograph (PFS) for the Subaru telescope: Its start of the last development phase

PFS (Prime Focus Spectrograph), a next generation facility instrument on the Subaru telescope, is now being tested on the telescope. The instrument is equipped with very wide (1.3 degrees in diameter) field of view on the Subaru’s prime focus, high multiplexity by 2394 reconfigurable fibers, and wide waveband spectrograph that covers from 380nm to 1260nm simultaneously in one exposure. Currently engineering observations are ongoing with Prime Focus Instrument (PFI), Metrology Camera System (MCS), the first spectrpgraph module (SM1) with visible cameras and the first fiber cable providing optical link between PFI and SM1. Among the rest of the hardware, the second fiber cable has been already installed on the telescope and in the dome building since April 2022, and the two others were also delivered in June 2022. The integration and test of next SMs including near-infrared cameras are ongoing for timely deliveries. The progress in the software development is also worth noting. The instrument control software delivered with the subsystems is being well integrated with its system-level layer, the telescope system, observation planning software and associated databases. The data reduction pipelines are also rapidly progressing especially since sky spectra started being taken in early 2021 using Subaru Nigh Sky Spectrograph (SuNSS), and more recently using PFI during the engineering observations. In parallel to these instrumentation activities, the PFS science team in the collaboration is timely formulating a plan of large-sky survey observation to be proposed and conducted as a Subaru Strategic Program (SSP) from 2024. In this article, we report these recent progresses, ongoing developments and future perspectives of the PFS instrumentation

Prime Focus Spectrograph (PFS) for Subaru Telescope: progressing final steps to science operation

The instrumentation of the Prime Focus Spectrograph (PFS), a next generation facility instrument on the Subaru telescope, is now in the final phase of its commissioning process and its general, open-use operations for sciences will provisionally start in 2025. The instrument enables simultaneous spectroscopy with 2386 individual fibers distributed over a very wide (∼1.3 degrees in diameter) field of view on the Subaru’s prime focus. The spectra cover a wide range of wavelengths from 380nm to 1260nm in one exposure in the Low-Resolution (LR) mode (while the visible red channel has the Medium-Resolution (MR) mode as well that covers 710−885nm). The system integration activities at the observatory on Maunakea in Hawaii have been continuing since the arrival of the Metrology Camera System in 2018. On-sky engineering tests and observations have also been carried out continually since September 2021 and, despite various difficulties in interlacing commissioning processes with development activities on the schedule and addressing some major issues on hardware and software, the team successfully observed many targeted stars as intended over the entire field of view (Engineering First Light) in September 2022. Then in parallel to the arrival, integration and commissioning of more hardware components, validations and optimizations of the performance and operation of the instrument are ongoing. The accuracy of the fiber positioning process and the speed of the fiber reconfiguration process have been recently confirmed to be ∼ 20−30μm for 95% of allocated fibers, and ∼130 seconds, respectively. While precise quantitative analyses are still in progress, the measured throughput has been confirmed to be consistent with the model where the information from various sub-components and sub-assemblies is integrated. Long integration of relatively faint objects are being taken to validate an expected increase of signal-to-noise ratio as more exposures are taken and co-added without any serious systematic errors from, e.g., sky subtraction process. The PFS science operation will be carried out in a queue mode by default and various developments, implementations and validations have been underway accordingly in parallel to the instrument commissioning activities. Meetings and sessions are arranged continually with the communities of potential PFS users on multiple scales, and discussions are iterated for mutual understanding and possible optimization of the rules and procedures over a wide range of processes such as proposal submission, observation planning, data acquisition and data delivery. The end-to-end processes of queue observations including successive exposures with updated plans based on assessed qualities of the data from past observations are being tested during engineering observations, and further optimizations are being undertaken. In this contribution, a top-level summary of these achievements and ongoing progresses and future perspectives will be provided

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Biochronostratigraphy and paleoenvironment analysis of Neogene deposits from the Pelotas Basin (well 2-TG-96-RS), Southernmost Brazil

This paper presents the integration of micropaleontological (palynology and foraminifera) and isotopic (87Sr/86Sr) analysis of a selected interval from the well 2-TG-96-RS, drilled on the onshore portion of the Pelotas Basin, Rio Grande do Sul, Brazil. A total of eight samples of the section between 140.20 and 73.50 m in depth was selected for palynological analysis, revealing diversified and abundant palynomorph associations. Species of spores, pollen grains and dinoflagellate cysts are the most common palynomorphs found. Planktic and benthic calcareous foraminifera were recovered from the lowest two levels of the section (140.20 and 134.30 m). Based on the stratigraphic range of the species of dinoflagellate cysts and sporomorphs, a span age from Late Miocene to Early Pliocene is assigned. The relative age obtained from the 87Sr/86Sr ratio in shells of calcareous foraminifers indicates a Late Miocene (Messinian) correspondence, corroborating the biostratigraphic positioning performed with palynomorphs. Paleoenvironmental interpretations based on the quantitative distribution of organic components (palynomorphs, phytoclasts and amorphous organic matter) throughout the section and on foraminiferal associations indicate a shallow marine depositional environment for the section. Two palynologicals intervals were recognized based on palynofacies analysis, related to middle to outer shelf (140.20 to 128.90 m) and inner shelf (115.75 to 73.50 m) conditions