Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy.

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-length Manduca sexta sGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO

Late Pleistocene human genome suggests a local origin for the first farmers of central Anatolia

Anatolia was home to some of the earliest farming communities. It has been long debated whether a migration of farming groups introduced agriculture to central Anatolia. Here, we report the first genome-wide data from a 15,000-year-old Anatolian hunter-gatherer and from seven Anatolian and Levantine early farmers. We find high genetic continuity (~80–90%) between the hunter-gatherers and early farmers of Anatolia and detect two distinct incoming ancestries: an early Iranian/Caucasus related one and a later one linked to the ancient Levant. Finally, we observe a genetic link between southern Europe and the Near East predating 15,000 years ago. Our results suggest a limited role of human migration in the emergence of agriculture in central Anatolia

An exploratory trial implementing a community-based child oral health promotion intervention for Australian families from refugee and migrant backgrounds: a protocol paper for Teeth Tales

Introduction: Inequalities are evident in early childhood caries rates with the socially disadvantaged experiencing greater burden of disease. This study builds on formative qualitative research, conducted in the Moreland/Hume local government areas of Melbourne, Victoria 2006–2009, in response to community concerns for oral health of children from refugee and migrant backgrounds. Development of the community-based intervention described here extends the partnership approach to cogeneration of contemporary evidence with continued and meaningful involvement of investigators, community, cultural and government partners. This trial aims to establish a model for child oral health promotion for culturally diverse communities in Australia.<p></p> Methods and analysis: This is an exploratory trial implementing a community-based child oral health promotion intervention for Australian families from refugee and migrant backgrounds. Families from an Iraqi, Lebanese or Pakistani background with children aged 1–4 years, residing in metropolitan Melbourne, were invited to participate in the trial by peer educators from their respective communities using snowball and purposive sampling techniques. Target sample size was 600. Moreland, a culturally diverse, inner-urban metropolitan area of Melbourne, was chosen as the intervention site. The intervention comprised peer educator led community oral health education sessions and reorienting of dental health and family services through cultural Competency Organisational Review (CORe).<p></p> Ethics and dissemination: Ethics approval for this trial was granted by the University of Melbourne Human Research Ethics Committee and the Department of Education and Early Childhood Development Research Committee. Study progress and output will be disseminated via periodic newsletters, peer-reviewed research papers, reports, community seminars and at National and International conferences.<p></p&gt

Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases

The lymphatic clearance pathways of the brain are different compared to the other organs of the body and have been the subject of heated debates. Drainage of brain extracellular fluids, particularly interstitial fluid (ISF) and cerebrospinal fluid (CSF), is not only important for volume regulation, but also for removal of waste products such as amyloid beta (A?). CSF plays a special role in clinical medicine, as it is available for analysis of biomarkers for Alzheimer’s disease. Despite the lack of a complete anatomical and physiological picture of the communications between the subarachnoid space (SAS) and the brain parenchyma, it is often assumed that A? is cleared from the cerebral ISF into the CSF. Recent work suggests that clearance of the brain mainly occurs during sleep, with a specific role for peri- and para-vascular spaces as drainage pathways from the brain parenchyma. However, the direction of flow, the anatomical structures involved and the driving forces remain elusive, with partially conflicting data in literature. The presence of A? in the glia limitans in Alzheimer’s disease suggests a direct communication of ISF with CSF. Nonetheless, there is also the well-described pathology of cerebral amyloid angiopathy associated with the failure of perivascular drainage of A?. Herein, we review the role of the vasculature and the impact of vascular pathology on the peri- and para-vascular clearance pathways of the brain. The different views on the possible routes for ISF drainage of the brain are discussed in the context of pathological significance

Monitoring the assembly-disassembly-organisation-reassembly process of germanosilicate UTL through in situ pair distribution function analysis

The authors would like to thank: The EPSRC (grants: EP/K025112/1; EP/K005499/1; EP/K503162/1) for funding opportunities and beam line I15 at the Diamond Light Source. Phoebe Allan is acknowledged for her help and knowledge of PDF refinement. M.M. and R.E.M. would like to acknowledge OP VVV "Excellent Research Teams", project No. CZ.02.1.01/0.0/0.0/15_003/0000417 - CUCAM.A study into the disassembly and organisation steps of the ADOR process has been undertaken through in situ Pair Distribution Function (PDF) analysis. Three aqueous systems (water, 6 M HCl and 12 M HCl) were introduced to a parent zeolite germanosilicate UTL in a cell. Hydrolysis could be clearly seen when UTL was exposed to water over a period of 8 hr, forming the disorded layered material, IPC-1P. In hydrochloric acid, the hydrolysis step is too quick to observe and a Ge-Cl containing species could be seen. In 6 M HCl, the rearrangement of the interlayer region began after an induction period of 8 hr, with the process still occuring after 15 hr. In 12 M HCl, the rearrangement appears to have come to an end after only 6 hr.PostprintPeer reviewe

Rheumatoid leptomeningitis presenting with an acute neuropsychiatric disorder

Leptomeningitis is a rare central nervous system manifestation of rheumatoid arthritis, generally in patients with established chronic rheumatoid disease. We report a 41-year-old man without previous rheumatoid arthritis or psychiatric disorder who presented with an acute neuropsychiatric disturbance and polyarthralgia. His MR scan of brain showed asymmetric bifrontal leptomeningitis, confirmed on (18F)-fluoro-D-glucose-positron emission tomography. Other investigations showed highly positive serum and cerebrospinal fluid anti-cyclic citrullinated peptide. A leptomeningeal biopsy showed necrotising leptomeningeal inflammation with ill-defined granulomas and lymphoplasmacytic infiltrate without organisms. Prolonged high-dose corticosteroids and then rituximab resulted in recovery. Chronic leptomeningitis can present with an acute neuropsychiatric disorder. We highlight that early rheumatoid disease can, rarely, cause a chronic leptomeningitis, reversible with immunotherapy

The preparation route and final form of V-MXenes override the effect of the O/F ratio on their magnetic properties

This work was supported by OP VVV “Excellent Research Teams” project no. CZ.02.1.01/0.0/0.0/15_003/0000417 – CUCAM. P. E. would like to also acknowledge the Czech Science Foundation for the ExPro project (19-27551X). Computational resources and low-temperature infrastructure were supplied by the projects “e-Infrastruktura CZ” (e-INFRA CZ LM2018140) and MGML (LM2023065) supported by the Ministry of Education, Youth and Sports of the Czech Republic.Transition metal carbides and nitrides (MXenes) show a high potential for electrochemical energy storage in batteries and supercapacitors and for electrocatalysis. Their excellent electronic and magnetic characteristics have been highlighted in several theoretical studies. However, experimental research on MXenes is yet to confirm their predicted properties as candidates for controllable magnetic 2D materials. Here, we report our theoretical and experimental study of V2CTx MXenes (T = O, OH, F), providing key insights into their magnetism. Based on our density functional theory (DFT) analysis, we predicted ferromagnetic (FM) and antiferromagnetic (AFM) states of V2CTx, which are determined by the O/F ratio of surface functional groups. Accordingly, we prepared V2CTx MXenes in the form of multilayered powders and thin films with different O/F ratios. No experimental evidence of FM or AFM properties was found in any material. Nevertheless, powders and films with almost identical chemical compositions (in terms of O/F ratio) displayed different magnetic properties, whereas films with disparate chemical compositions revealed a similar magnetic character. Therefore, the preparation route and form of the final V2CTx material override the effect of the O/F ratio, which is often overestimated in theoretical studies. Moreover, these findings underscore the importance of preparing MXene materials to experimentally confirm their theoretically predicted properties.Peer reviewe

Post-synthesis incorporation of Al into germanosilicate ITH zeolites: the influence of treatment conditions on the acidic properties and catalytic behavior in tetrahydropyranylation

Post-synthesis alumination of germanosilicate medium-pore ITH zeolites was shown to be an effective procedure for tuning their acidity. Treatment of ITH zeolites synthesized with different chemical compositions (i.e. Si/Ge = 2.5, 4.4 and 5.8) with aqueous Al(NO3)(3) solution led to the formation of strong Bronsted and Lewis acid sites and an increasing fraction of ultramicro- and meso-pores in Ge-rich ITH samples (Si/Ge = 2.5 and 4.4). The concentration of Al incorporated into the framework increases with decreasing Si/Ge ratio of the parent ITH. The increasing temperature of alumination from 80 to 175 degrees C (HT conditions) resulted in (1) a 1.5-2-fold increase in the concentration of Bronsted acid sites formed and (2) a decreasing fraction of framework Al atoms detectable with base probe molecules (i.e. pyridine, 2,6-di-tert-butylpyridine), i.e. an increased concentration of the "inner" acid sites. The activity of prepared Al-substituted ITH zeolites in tetrahydropyranylation of alcohols is enhanced with increasing amount of accessible acid sites in bulky crystals (e.g. alumination at lower temperature) or with increasing total concentration of acid centres within tiny ITH crystals (e.g. alumination under HT conditions). This trend became more prominent with increasing kinetic diameter of the substrate molecules under investigation (methanol < 1-propanol < 1-hexanol).Post-synthesis alumination of germanosilicate medium-pore ITH zeolites was shown to be an effective procedure for tuning their acidity. Treatment of ITH zeolites synthesized with different chemical compositions (i.e.Si/Ge = 2.5, 4.4 and 5.8) with aqueous5529732984Czech Science Foundation [14-30898P, 13-17593P

Ab initio structure search and in situ 7Li NMR studies of discharge products in the Li-S battery system.

The high theoretical gravimetric capacity of the Li-S battery system makes it an attractive candidate for numerous energy storage applications. In practice, cell performance is plagued by low practical capacity and poor cycling. In an effort to explore the mechanism of the discharge with the goal of better understanding performance, we examine the Li-S phase diagram using computational techniques and complement this with an in situ (7)Li NMR study of the cell during discharge. Both the computational and experimental studies are consistent with the suggestion that the only solid product formed in the cell is Li2S, formed soon after cell discharge is initiated. In situ NMR spectroscopy also allows the direct observation of soluble Li(+)-species during cell discharge; species that are known to be highly detrimental to capacity retention. We suggest that during the first discharge plateau, S is reduced to soluble polysulfide species concurrently with the formation of a solid component (Li2S) which forms near the beginning of the first plateau, in the cell configuration studied here. The NMR data suggest that the second plateau is defined by the reduction of the residual soluble species to solid product (Li2S). A ternary diagram is presented to rationalize the phases observed with NMR during the discharge pathway and provide thermodynamic underpinnings for the shape of the discharge profile as a function of cell composition.Fellowship support to KAS from the ConvEne IGERT Program of the National Science Foundation (DGE 0801627) is gratefully acknowledged. AJM acknowledges the support from the Winton Programme for the Physics of Sus-tainability. PDM and DSW thank the UK-EPSRC for financial support. This research made use of the shared experimental facilities of the Materials Research Laboratory (MRL), sup-ported by the MRSEC Program of the NSF under Award No. DMR 1121053. The MRL is a member of the NSF-funded Mate-rials Research Facilities Network (www.mrfn.org). CPG and ML thank the U.S. DOE Office of Vehicle Technologies (Con-tract No. DE-AC02-05CH11231) and the EU ERC (via an Ad-vanced Fellowship to CPG) for funding.This is the final published version. It first appeared at http://pubs.acs.org/doi/abs/10.1021/ja508982p

Propagating spin-wave spectroscopy in nanometer-thick YIG films at millikelvin temperatures

Performing propagating spin-wave spectroscopy of thin films at millikelvin temperatures is the next step towards the realisation of large-scale integrated magnonic circuits for quantum applications. Here we demonstrate spin-wave propagation in a $100\,\mathrm{nm}$-thick yttrium-iron-garnet film at the temperatures down to $45 \,\mathrm{mK}$, using stripline nanoantennas deposited on YIG surface for the electrical excitation and detection. The clear transmission characteristics over the distance of $10\,\mu \mathrm{m}$ are measured and the subtracted spin-wave group velocity and the YIG saturation magnetisation agree well with the theoretical values. We show that the gadolinium-gallium-garnet substrate influences the spin-wave propagation characteristics only for the applied magnetic fields beyond $75\,\mathrm{mT}$, originating from a GGG magnetisation up to $47 \,\mathrm{kA/m}$ at $45 \,\mathrm{mK}$. Our results show that the developed fabrication and measurement methodologies enable the realisation of integrated magnonic quantum nanotechnologies at millikelvin temperatures.Comment: 6 pages, 5 figure