Critical Role of FLRT1 Phosphorylation in the Interdependent Regulation of FLRT1 Function and FGF Receptor Signalling

Background Fibronectin leucine rich transmembrane (FLRT) proteins have dual properties as regulators of cell adhesion and potentiators of fibroblast growth factor (FGF) mediated signalling. The mechanism by which the latter is achieved is still unknown and is the subject of this investigation. Principal Findings Here we show that FLRT1 is a target for tyrosine phosphorylation mediated by FGFR1 and implicate a non-receptor Src family kinase (SFK). We identify the target tyrosine residues in the cytoplasmic domain of FLRT1 and show that these are not direct substrates for Src kinase suggesting that the SFK may exert effects via potentiation of FGFR1 kinase activity. We show that whilst FLRT1 expression results in a ligand-dependent elevation of MAP kinase activity, a mutant version of FLRT1, defective as an FGFR1 kinase substrate (Y3F-FLRT1), has the property of eliciting ligand-independent chronic activation of the MAP kinase pathway which is suppressed by pharmacological inhibition of either FGFR1 or Src kinase. Functional investigation of FGFR1 and FLRT1 signalling in SH-SY5Y neuroblastoma cells reveals that FLRT1 alone acts to induce a multi-polar phenotype whereas the combination of FLRT1 and FGFR activation, or expression of Y3F-FLRT1, acts to induce neurite outgrowth via MAPK activation. Similar results were obtained in a dendrite outgrowth assay in primary hippocampal neurons. We also show that FGFR1, FLRT1 and activated Src are co-localized and this complex is trafficked toward the soma of the cell. The presence of Y3F-FLRT1 rather than FLRT1 resulted in prolonged localization of this complex within the neuritic arbour. Conclusions This study shows that the phosphorylation state of FLRT1, which is itself FGFR1 dependent, may play a critical role in the potentiation of FGFR1 signalling and may also depend on a SFK-dependent phosphorylation mechanism acting via the FGFR. This is consistent with an ‘in vivo’ role for FLRT1 regulation of FGF signalling via SFKs. Furthermore, the phosphorylation-dependent futile cycle mechanism controlling FGFR1 signalling is concurrently crucial for regulation of FLRT1-mediated neurite outgrowth

Photon- and Charge-Management in Advanced Energy Materials: Combining 0D, 1D, and 2D Nanocarbons as well as Bulk Semiconductors with Organic Chromophores

In this contribution, seminal works in the area of photon- and charge-management are highlighted with focus on covalent electron donor-acceptor conjugates built around porphyrins (Ps), on one hand, and 0D, 1D, and 2D nanocarbons, on the other hand. Photons in these conjugates are managed by Ps, while 0D, 1D, and 2D nanocarbons serve as the active component, which enable managing charges. With a few leading examples, it can be explored much beyond the simple photon- and charge-management characterization and emphasize photovoltaics and photocatalysis to convert and store energy. This contribution concludes by highlighting recent progress in mixing and matching the unique charge-management features of nanocarbons in the design of multidimensional nanocarbons.Fil: Cadranel, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Inorgánica, Analítica y Química Física; Argentina. Universitat Erlangen-Nuremberg; AlemaniaFil: Haines, Philipp. Universitat Erlangen-Nuremberg; AlemaniaFil: Kaur, Ramandeep. Universitat Erlangen-Nuremberg; AlemaniaFil: Menon, Arjun. Universitat Erlangen-Nuremberg; AlemaniaFil: Münich, Peter W.. Universitat Erlangen-Nuremberg; AlemaniaFil: Schol, Peter R.. Universitat Erlangen-Nuremberg; AlemaniaFil: Guldi, Dirk. Universitat Erlangen-Nuremberg; Alemani

Using elemental chemostratigraphy on Mid-Late Frasnian platform-top successions from the Lennard Shelf outcrops, Canning Basin, Western Australia.

High-resolution chronostratigraphic correlation using elemental chemostratigraphy in platform carbonates is typically difficult to achieve. Here, elemental chemostratigraphy is used to correlate between two platform-top, carbonate-dominated field sections from the narrow Lennard Shelf that existed on the NE margin of the Canning Basin, Western Australia, during the mid–late Frasnian. The correlation, constrained by magnetic polarity reversals and physical ground truthing, is based on recognition of distinctive cyclical ‘‘stacking patterns’’ defined by changes in concentrations of the trace element zirconium (Zr). Zr concentrations are controlled by the amount of the heavy mineral zircon in the sediments, which is derived from a terrigenous source and is diagenetically very stable. The stacking patterns in the lower part of the study sections display gradually upward-increasing values of Zr to a maximum, followed by an almost immediate fall to a minimum. In the upper part of the study interval, the cycles are more symmetrical, with both gradually increasing and decreasing portions. The point at which the change in Zr stacking pattern occurs in the two sections is synchronous and occurs in association with a supersequence maximum flooding surface. The correlation based on maximum and minimum Zr values throughout the two sections is demonstrated to be chronostratigraphic by comparison with correlations based upon paleomagnetism and physical ground truthing. When element ratios commonly used as provenance and paleoclimate proxies are plotted, the variations between closely spaced samples are greater than any systematic variations throughout the study intervals. Therefore, no isochemical chemozones can be defined, implying that during deposition of the study intervals, there were no long-lived changes in sediment provenance or paleoclimate that the elemental chemistry can detect. The work presented here shows that the standard approach of defining isochemical chemozones for chemostratigraphic correlation is not always appropriate. However, an approach using cyclical changes in elemental variables for chemostratigraphic correlation between two closely spaced sections is chronostratigraphically valid. The greater challenge is in application of the same approach to more widely spaced sections, potentially in different facies of a carbonate setting

Financing essential HIV services: a new economic agenda.

Anna Vassall and colleagues discuss the need for, and challenges facing, innovative and sustainable financing of the HIV response. Please see later in the article for the Editors' Summary

Prospects for local co-governance

British local authorities and their partners are increasingly developing new ways of working together with local communities. The nature of this co-working, however, is complex, multi-faceted and little understood. This article argues for greater clarity of thinking on the topic, by analysing this co-working as a form of political co-governance, and drawing attention in particular to issues of scale and democracy. Using evidence from a study of 43 local authority areas, 16 authorities are identified where co-governance is practised, following three main types of approach: service-influencing, service-delivering and parish council developing. It is concluded that strengthening political co-governance is essential for a healthy democracy

Early Science with the Large Millimeter Telescope: COOL BUDHIES I - a pilot study of molecular and atomic gas at z~0.2

An understanding of the mass build-up in galaxies over time necessitates tracing the evolution of cold gas (molecular and atomic) in galaxies. To that end, we have conducted a pilot study called CO Observations with the LMT of the Blind Ultra-Deep H I Environment Survey (COOL BUDHIES). We have observed 23 galaxies in and around the two clusters Abell 2192 (z = 0.188) and Abell 963 (z = 0.206), where 12 are cluster members and 11 are slightly in the foreground or background, using about 28 total hours on the Redshift Search Receiver (RSR) on the Large Millimeter Telescope (LMT) to measure the $^{12}$CO J = 1 --> 0 emission line and obtain molecular gas masses. These new observations provide a unique opportunity to probe both the molecular and atomic components of galaxies as a function of environment beyond the local Universe. For our sample of 23 galaxies, nine have reliable detections (S/N$\geq$3.6) of the $^{12}$CO line, and another six have marginal detections (2.0 < S/N < 3.6). For the remaining eight targets we can place upper limits on molecular gas masses roughly between $10^9$ and $10^{10} M_\odot$. Comparing our results to other studies of molecular gas, we find that our sample is significantly more abundant in molecular gas overall, when compared to the stellar and the atomic gas component, and our median molecular gas fraction lies about $1\sigma$ above the upper limits of proposed redshift evolution in earlier studies. We discuss possible reasons for this discrepancy, with the most likely conclusion being target selection and Eddington bias.Comment: MNRAS, submitte

High-Resolution Late Devonian Magnetostratigraphy From the Canning Basin, Western Australia: A Re-Evaluation

Late Devonian time was a period of rapid upheaval in the Earth system, including climate change, sea level changes, widespread ocean anoxia, and the Frasnian-Famennian mass extinction; the cause(s) of these changes remain(s) uncertain. The Lennard Shelf of the Canning Basin in Western Australia contains carbonate reef sections spanning much of the Late Devonian Epoch and has been sampled for paleomagnetic analysis with studies by Hansma and colleagues in 2015 and Playton and colleagues in 2016. However, previous paleomagnetic directions were scattered and their use for magnetostratigraphy has been questioned. Here, rock magnetic data and magnetostratigraphy for a late Devonian drill-core from the Lennard Shelf were analyzed. Three magnetostratigraphic interpretations were made using different paleopoles that showed good correlation with each other and the earlier interpretations by Playton and colleagues in 2016. Additionally, the rock magnetic data revealed the samples contain various mixtures of detrital and diagenetic minerals, the former of which should be viable recorders of primary magnetic signatures. Even in samples with these detrital phases, paleomagnetic data were often noisy and produced ambiguous polarity assignments, likely due to the anomalously weak Devonian field. Because of this ambiguity and the absence of a robust paleopole, broader correlations for this critical time-period will be difficult without additional paleomagnetic data from the late Devonian Period. Expanded data for this interval could eventually shed light on the timing, causes, and rates of the Frasnian-Famennian mass extinction and other environmental shifts in the late Devonian Epoch

Integrated stratigraphic correlation of Upper Devonian platform-to-basin carbonate sequences, Lennard Shelf, Canning Basin, Western Australia: advances in carbonate margin-to-slope sequence stratigraphy and stacking patterns

High-resolution, time-significant correlations are integral to meaningful stratigraphic frameworks in depositional systems, but may be difficult to achieve using traditional sequence stratigraphic or biostratigraphic approaches alone, particularly in geologically complex settings. In steep, reefal carbonate margin-to-slope systems, such correlations are essential to unravel shelf-to-basin transitions, characterize strike variability, and develop predictive sequence stratigraphic models – concepts which are currently poorly understood in these heterogeneous settings. The Canning Basin Chronostratigraphy Project (CBCP) integrates multiple independent datasets (including biostratigraphy, magnetostratigraphy, stable isotope chemostratigraphy, and sequence stratigraphy) extracted from Upper Devonian (Frasnian and Famennian) reefal platform exposures along the Lennard Shelf, Canning Basin, Western Australia. These were used to generate a well-constrained stratigraphic framework and shelf-to-basin composite reconstruction of the carbonate system. The resultant integrated framework allows for unprecedented analysis of carbonate margin-to-slope heterogeneity, depositional architecture, and sequence stratigraphy along the Lennard Shelf. Systems tract architecture, facies partitioning, and stacking patterns of margin to lower-slope environments were assessed for six composite-scale sequences that form part of a transgressive-to-regressive supersequence and span the Frasnian-Famennian (F-F) biotic crisis. Variations are apparent in margin styles, foreslope facies proportions, dominant resedimentation processes, downslope contributing sediment factories, and vertical rock successions, related to hierarchical accommodation signals and ecological changes associated with F-F boundary. We present these results in the form of carbonate margin-to-basin sequence stratigraphic models and associations that link seismic-scale architecture to fine-scale facies heterogeneity. These models provide a predictive foundation for characterization of steep-sided flanks of reefal carbonate platform systems that is useful for both industry and academia. This study emphasizes the utility of an integrated stratigraphic approach and the insights gained from better-constrained facies and stratal architecture analysis; insights that were not achievable with traditional sequence stratigraphic or biostratigraphic techniques alone

Prevention and early detection of prostate cancer

This Review was sponsored and funded by the International Society of Cancer Prevention (ISCaP), the European Association of Urology (EAU), the National Cancer Institute, USA (NCI) (grant number 1R13CA171707-01), Prostate Cancer UK, Cancer Research UK (CRUK) (grant number C569/A16477), and the Association for International Cancer Research (AICR