On the ground electronic states of copper silicide and its ions

The low-lying electronic states of SiCu, SiCu^+, and SiCu^− have been studied using a variety of high-level ab initio techniques. As expected on the basis of simple orbital occupancy and bond forming for Si(s^2p^2)+Cu(s^1) species, ^2Π_r, ^1Σ^+, and ^3Σ^− states were found to be the ground electronic states for SiCu, SiCu^+, and SiCu^−, respectively; the ^2Π_r state is not that suggested in most recent experimental studies. All of these molecules were found to be quite strongly bound although the bond lengths, bond energies, and harmonic frequencies vary slightly among them, as a result of the nonbonding character of the 2π-MO (molecular orbital) [composed almost entirely of the Si 3p-AO (atomic orbital)], the occupation of which varies from 0 to 2 within the ^1Σ^+, ^2Π_r, and ^3Σ^− series. The neutral SiCu is found to have bound excited electronic states of ^4Σ^−, ^2Δ, ^2Σ^+, and ^2Π_i symmetry lying 0.5, 1.2, 1.8, and 3.2 eV above the ^2Π_r ground state. It is possible but not yet certain that the ^2Π_i state is, in fact, the “B state” observed in the recent experimental studies by Scherer, Paul, Collier, and Saykally

Is Alpha-Synuclein Loss-of-Function a Contributor to Parkinsonian Pathology? Evidence from Non-human Primates

Accumulation of alpha-synuclein (α-syn) in Lewy bodies and neurites of midbrain dopamine neurons is diagnostic for Parkinson’s disease (PD), leading to the proposal that PD is a toxic gain-of-function synucleinopathy. Here we discuss the alternative viewpoint that α-syn displacement from synapses by misfolding and aggregation results in a toxic loss-of-function. In support of this hypothesis we provide evidence from our pilot study demonstrating that knockdown of endogenous α-syn in dopamine neurons of nonhuman primates reproduces the pattern of nigrostriatal degeneration characteristic of PD

Emerging roles of ATG7 in human health and disease

The cardinal stages of macroautophagy are driven by core autophagy-related (ATG) proteins, whose ablation largely abolishes intracellular turnover. Disrupting ATG genes is paradigmatic of studying autophagy deficiency, yet emerging data suggest that ATG proteins have extensive biological importance beyond autophagic elimination. An important example is ATG7, an essential autophagy effector enzyme that in concert with other ATG proteins, also regulates immunity, cell death and protein secretion, and independently regulates the cell cycle and apoptosis. Recently, a direct association between ATG7 dysfunction and disease was established in patients with biallelic ATG7 variants and childhood-onset neuropathology. Moreover, a prodigious body of evidence supports a role for ATG7 in protecting against complex disease states in model organisms, although how dysfunctional ATG7 contributes to manifestation of these diseases, including cancer, neurodegeneration and infection, in humans remains unclear. Here, we systematically review the biological functions of ATG7, discussing the impact of its impairment on signalling pathways and human pathology. Future studies illuminating the molecular relationship between ATG7 dysfunction and disease will expedite therapies for disorders involving ATG7 deficiency and/or impaired autophagy.Peer reviewe

Renaturing cities using a regionally-focused biodiversity-led multifunctional benefits approach to urban green infrastructure

If a ‘Renaturing of Cities’ strategy is to maximise the ecosystem service provision of urban green infrastructure (UGI), then detailed consideration of a habitat services, biodiversity-led approach and multifunctionality are necessary rather than relying on the assumed benefits of UGI per se. The paper presents preliminary data from three case studies, two in England and one in Germany, that explore how multifunctionality can be achieved, the stakeholders required, the usefulness of an experimental approach for demonstrating transformation, and how this can be fed back into policy. We argue that incorporating locally contextualised biodiversity-led UGI design into the planning and policy spheres contributes to the functioning and resilience of the city and provides the adaptability to respond to locally contextualised challenges, such as overheating, flooding, air pollution, health and wellbeing as well as biodiversity loss. Framing our research to encompass both the science of biodiversity-led UGI and co-developing methods for incorporating a strategic approach to implementation of biodiversity-led UGI by planners and developers addresses a gap in current knowledge and begins to address barriers to UGI implementation. By combining scientific with policy learning and defined urban environmental targets with community needs, our research to date has begun to demonstrate how nature-based solutions to building resilience and adaptive governance can be strategically incorporated within cities through UGI

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Background and aims: Esophageal adenocarcinoma (EAC) is chemoresistant in the majority of cases. The tumor-promoting biology of cancer associated fibroblasts (CAF) make them a target for novel therapies. Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to regulate the activated fibroblast phenotype in benign disease. We investigated the potential for CAF modulation in EAC using PDE5i to enhance the efficacy of chemotherapy. Methods: EAC fibroblasts were treated with PDE5i and phenotypic effects examined using immunoblotting, immunohistochemistry, gel contraction, transwell invasion, organotypics, single cell RNAseq and shotgun proteomics. The combination of PDE5i with standard-of-care chemotherapy (Epirubicin, 5-Fluorouracil and Cisplatin) was tested for safety and efficacy in validated near-patient model systems (3D tumor growth assays (3D-TGAs) and patient derived xenograft (PDX) mouse models). Results: PDE5i treatment reduced alpha-SMA expression in CAFs by 50% (p<0.05), associated with a significant reduction in the ability of CAFs to contract collagen-1 gels and induce cancer cell invasion, (p<0.05). RNAseq and proteomic analysis of CAF and EAC cell lines revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. 3D-TGA assays confirmed the importance of stromal cells to chemoresistance in EAC, which could be attenuated by PDE5i. Chemotherapy+PDE5i in PDX-bearing mice was safe and significantly reduced PDX tumor volume (p<0.05). Conclusion: PDE5 is a candidate for clinical trials to alter the fibroblast phenotype in esophageal cancer. We demonstrate the specificity of PDE5i for fibroblasts to prevent transdifferentiation and revert the CAF phenotype. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient in vitro and in vivo PDX-based model systems

High-resolution record reveals climate-driven environmental and sedimentary changes in an active rift

Young rifts are shaped by combined tectonic and surface processes and climate, yet few records exist to evaluate the interplay of these processes over an extended period of early rift-basin development. Here, we present the longest and highest resolution record of sediment flux and paleoenvironmental changes when a young rift connects to the global oceans. New results from International Ocean Discovery Program (IODP) Expedition 381 in the Corinth Rift show 10s–100s of kyr cyclic variations in basin paleoenvironment as eustatic sea level fluctuated with respect to sills bounding this semi-isolated basin, and reveal substantial corresponding changes in the volume and character of sediment delivered into the rift. During interglacials, when the basin was marine, sedimentation rates were lower (excepting the Holocene), and bioturbation and organic carbon concentration higher. During glacials, the basin was isolated from the ocean, and sedimentation rates were higher (~2–7 times those in interglacials). We infer that reduced vegetation cover during glacials drove higher sediment flux from the rift flanks. These orbital-timescale changes in rate and type of basin infill will likely influence early rift sedimentary and faulting processes, potentially including syn-rift stratigraphy, sediment burial rates, and organic carbon flux and preservation on deep continental margins worldwide

High-resolution record revealsclimate-driven environmental andsedimentary changes in an active rift

Young rifts are shaped by combined tectonic and surface processes and climate, yet few records exist to evaluate the interplay of these processes over an extended period of early rift-basin development. Here, we present the longest and highest resolution record of sediment flux and paleoenvironmental changes when a young rift connects to the global oceans. New results from International Ocean Discovery Program (IODP) Expedition 381 in the Corinth Rift show 10s–100s of kyr cyclic variations in basin paleoenvironment as eustatic sea level fluctuated with respect to sills bounding this semi-isolated basin, and reveal substantial corresponding changes in the volume and character of sediment delivered into the rift. During interglacials, when the basin was marine, sedimentation rates were lower (excepting the Holocene), and bioturbation and organic carbon concentration higher. During glacials, the basin was isolated from the ocean, and sedimentation rates were higher (~2–7 times those in interglacials). We infer that reduced vegetation cover during glacials drove higher sediment flux from the rift flanks. These orbital-timescale changes in rate and type of basin infill will likely influence early rift sedimentary and faulting processes, potentially including syn-rift stratigraphy, sediment burial rates, and organic carbon flux and preservation on deep continental margins worldwide.publishedVersio

Expedition 381 Summary

The primary objective of International Ocean Discovery Program Expedition 381 was to retrieve a record of early continental rifting and basin evolution from the Corinth rift, central Greece. Continental rifting is fundamental for the formation of ocean basins, and active rift zones are dynamic regions of high geohazard potential. However, the detailed spatial and temporal evolution of a complete rift system needed to understand rift development from the fault to plate scale is poorly resolved. In the active Corinth rift, deformation rates are high, the recent synrift succession is preserved and complete offshore, and earlier rift phases are preserved onshore. Additionally, a dense seismic database provides high-resolution imaging of the fault network and seismic stratigraphy around the basin. As the basin has subsided, its depositional environment has been affected by fluctuating global sea level and its absolute position relative to sea level, and the basin sediments record this changing environment through time. In Corinth, we can therefore achieve an unprecedented precision of timing and spatial complexity of rift-fault system development, rift-controlled drainage system evolution, and basin fill in the first few million years of rift history. The following are the expedition themes: High-resolution fault slip and rift evolution history, Surface processes in active rifts, High-resolution late Quaternary Eastern Mediterranean paleoclimate and paleoenvironment of a developing rift basin, and Geohazard assessment in an active rift. These objectives were and will be accomplished as a result of successful drilling, coring, and logging at three sites in the Gulf of Corinth, which collectively yielded 1645 m of recovered core over a 1905 m cored interval. Together, these cores provide (1) a long rift history (Sites M0078 and M0080), (2) a high-resolution record of the most recent phase of rifting (Site M0079), and (3) the spatial variation of rift evolution (comparison of sites in the central and eastern rift). The sediments contain a rich and complex record of changing sedimentation, sediment and pore water geochemistry, and environmental conditions from micropaleontological assemblages. The preliminary chronology developed by shipboard analyses will be refined and improved during postexpedition research, providing a high-resolution chronostratigraphy down to the orbital timescale for a range of tectonic, sedimentological, and paleoenvironmental studies. This chronology will provide absolute timing of key rift events, rates of fault movement, rift extension and subsidence, and the spatial variations of these parameters. The core data will also allow us to investigate the relative roles of and feedbacks between tectonics, climate, and eustasy in sediment flux, basin evolution, and basin environment. Finally, the Corinth rift boreholes will provide the first long Quaternary record of Mediterranean-type climate in the region. The potential range of scientific applications for this unique data set is very large, encompassing tectonics, sedimentary processes, paleoenvironment, paleoclimate, paleoecology, geochemistry, and geohazards