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Mechanical power describes the complex interaction between a patient’s lungs and the ventilator and may be useful in predicting lung injury. However, its behavior in obesity and during dynamic surgical conditions is not understood. We comprehensively quantified ventilation bioenergetics and effects of body habitus and common surgical conditions. These data show body habitus is a prime determinant of intraoperative mechanical power and provide quantitative context for future translation toward a useful perioperative prognostic measurement.

Funding: The LUNGSCOT study is funded by the Chief Scientists Office of the Scottish Government, reference HIPS/19/52. Introduction Targeted lung cancer screening is effective in reducing lung cancer and all-cause mortality according to major trials in the United Kingdom and Europe. However, the best ways of implementing screening in local communities requires an understanding of the population the programme will serve. We undertook a study to explore the views of those potentially eligible for, and to identify potential barriers and facilitators to taking part in, lung screening, to inform the development of a feasibility study. Methods Men and women aged 45–70, living in urban and rural Scotland, and either self-reported people who smoke or who recently quit, were invited to take part in the study via research agency Taylor McKenzie. Eleven men and 14 women took part in three virtual focus groups exploring their views on lung screening. Focus group transcripts were transcribed and analysed using thematic analysis, assisted by QSR NVivo. Findings Three overarching themes were identified: (1) Knowledge, awareness and acceptability of lung screening, (2) Barriers and facilitators to screening and (3) Promoting screening and implementation ideas. Participants were largely supportive of lung screening in principle and described the importance of the early detection of cancer. Emotional and psychological concerns as well as system-level and practical issues were discussed as posing barriers and facilitators to lung screening. Conclusions Understanding the views of people potentially eligible for a lung health check can usefully inform the development of a further study to test the feasibility and acceptability of lung screening in Scotland. Patient or Public Contribution The LUNGSCOT study has convened a patient advisory group to advise on all aspects of study development and implementation. Patient representatives commented on the focus group study design, study materials and ethics application, and two representatives read the focus group transcripts. Publisher PDF

A temperature-induced structural phase transition is reported in layered hybrid perovskite (MA)2PbI2−xBrx(SCN)2 (0 ≤ x ≤ 1.2). The observed transition temperature decreases with Br substitution, suggesting a weakening of bonding interaction between the molecular ions.

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies., Combined methylmalonic acidemia (MMA) and hyperhomocysteinemias are inborn errors of vitamin B12 metabolism, and mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) underlie some forms of these disorders. Here the authors generated mouse models of a human syndrome due to mutations in RONIN (THAP11) and HCFC1, and show that this syndrome is both an inborn error of vitamin B12 metabolism and displays some features of ribosomopathy.

Supplementary Figure S3 shows comprehensive multi-omics correlation analysis and assessment of the magnitude of improvement in inter-omic correlations as the cells switched from a steady state to a dynamic state induced by iFGFR1 activation.

Supplementary Table S1 provides expression data of RNA, ribosome occupancy and protein used for multi-omics correlation analysis as well as complete lists of TE UP, TE DOWN and background genes.

Cooperativity between WNT and FGF signaling is well documented in embryonic development and cancer progression, but the molecular mechanisms underlying this cross-talk remain elusive. In this study, we interrogated the dynamics of RNA levels, ribosome occupancy, and protein expression as a function of inducible FGF signaling in mouse mammary glands with constitutive WNT hyperactivation. Multiomics correlation analysis revealed a substantial discrepancy between RNA and ribosome occupancy levels versus protein levels. However, this discrepancy decreased as cells became premalignant and dynamically responded to FGF signaling, implicating the importance of stringent gene regulation in nontransformed cells. Analysis of individual genes demonstrated that acute FGF hyperactivation increased translation of many stem cell self-renewal regulators, including WNT signaling components, and decreased translation of genes regulating cellular senescence. WNT pathway components translationally upregulated by FGF signaling had long and structured 5′ UTRs with a high frequency of polypurine sequences, several of which harbored (CGG)4 motifs that can fold into either stable G-quadruplexes or other stable secondary structures. The FGF-mediated increase in translation of WNT pathway components was compromised by silvestrol, an inhibitor of EIF4A that clamps EIF4A to polypurine sequences to block 43S scanning and inhibits its RNA-unwinding activity important for translation initiation. Moreover, silvestrol treatment significantly delayed FGF-WNT–driven tumorigenesis. Taken together, these results suggest that FGF signaling selectively enhances translation of structured mRNAs, particularly WNT signaling components, and highlight their vulnerability to inhibitors that target the RNA helicase EIF4A.Significance: The RNA helicase EIF4A may serve as a therapeutic target for breast cancers that require FGF and WNT signaling. Cancer Res; 78(15); 4229–40. ©2018 AACR.

Supplementary Methods and Figure Legends provide further details of the study methods and legends for supplementary figures and tables.

Ternary nitride materials hold promise for many optical, electronic, and refractory applications yet their preparation via solid-state synthesis remains challenging. Often, high pressures or reactive gasses are used to manipulate the effective chemical potential of nitrogen, yet these strategies require specialized equipment. Here we report on a simple two-step synthesis using ion-exchange reactions that yield rocksalt-derived MgZrN$_2$ and Mg$_2$NbN$_3$, as well as layered MgMoN$_2$. All three compounds show nearly temperature-independent and weak paramagnetic responses to an applied magnetic field at cryogenic temperatures indicating phase pure products. The key to synthesizing these ternary materials is an initial low-temperature step (300-450 $^{\circ}$C) to promote Mg-M-N bond formation. Then the products are annealed (800-900 $^{\circ}$C) to increase crystalline domains of the ternary product. Calorimetry experiments reveal that initial reaction temperatures are determined by phase transitions of reaction precursors, whereas heating directly to high temperatures results in decomposition. These two-step reactions provide a rational guide to material discovery of other bulk ternary nitrides.

One possibility for detecting low-amplitude pulsational variations is through gravitational microlensing. During a microlensing event, the temporary brightness increase leads to improvement in the signal-to-noise ratio, and thereby better detectability of pulsational signatures in light curves. We explore this possibility under two primary considerations. The first is when the standard point-source and point-lens approximation applies. In this scenario, dividing the observed light curve by the best-fitted microlensing model leads to residuals that result in pulsational features with improved uncertainties. The second is for transit events (single lens) or caustic crossing (binary lens). The point-source approximation breaks down, and residuals relative to a simple best-fitted microlensing model display more complex behavior. We employ a Monte-Carlo simulation of microlensing of pulsating variables toward the Galactic bulge for the surveys of OGLE and of KMTNet. We demonstrate that the efficiency for detecting pulsational signatures with intrinsic amplitudes of $350$, is $\sim 50-60\%$. The maximum efficiency occurs for pulsational periods $P \simeq 0.1-0.3$ days. We also study the possibility that high-magnification microlensing events of non-radially pulsating stars (NRPs) could be misinterpreted as planetary or binary microlensing events. We conclude that small asymmetric features around lightcurve peaks due to stellar pulsations could be misdiagnosed with crossing (or passing close to) small caustic curves., Comment: 11 pages, 4 Figures, 4 Tables

Targeted lung cancer screening is effective in reducing mortality by upwards of twenty percent. However, screening is not universally available and uptake is variable and socially patterned. Understanding screening behaviour is integral to designing a service that serves its population and promotes equitable uptake. We sought to review the literature to identify barriers and facilitators to screening to inform the development of a pilot lung screening study in Scotland.We used Arksey and O'Malley's scoping review methodology and PRISMA-ScR framework to identify relevant literature to meet the study aims. Qualitative, quantitative and mixed methods primary studies published between January 2000 and May 2021 were identified and reviewed by two reviewers for inclusion, using a list of search terms developed by the study team and adapted for chosen databases.Twenty-one articles met the final inclusion criteria. Articles were published between 2003 and 2021 and came from high income countries. Following data extraction and synthesis, findings were organised into four categories: Awareness of lung screening, Enthusiasm for lung screening, Barriers to lung screening, and Facilitators or ways of promoting uptake of lung screening. Awareness of lung screening was low while enthusiasm was high. Barriers to screening included fear of a cancer diagnosis, low perceived risk of lung cancer as well as practical barriers of cost, travel and time off work. Being health conscious, provider endorsement and seeking reassurance were all identified as facilitators of screening participation.Understanding patient reported barriers and facilitators to lung screening can help inform the implementation of future lung screening pilots and national lung screening programmes.

Author(s): Wustrow, A; Huang, G; McDermott, MJ; O'Nolan, D; Liu, CH; Tran, GT; McBride, BC; Dwaraknath, SS; Chapman, KW; Billinge, SJL; Persson, KA; Thornton, K; Neilson, JR | Abstract: Low-temperature synthesis routes are necessary for selectively synthesizing many metastable solid-state materials. Here, we identify a cooperative effect that starting materials have in lowering temperatures in solid-state metathesis reactions by studying the formation of yttrium manganese oxide. Previous studies have shown that YMnO3 can be synthesized by ternary metathesis with an alkali halide being produced as a secondary product. In this contribution, we show that by using alkaline earth metals instead of alkali metals, the polymorph selectivity of the reaction is changed, as orthorhombic YMnO3 forms at lower temperatures than the hexagonal polymorph. Reactions were studied using ex post facto synchrotron X-ray diffraction. These experiments reveal that reactions using alkaline earth manganese oxides as a starting material require high temperatures to progress. Reaction temperatures can be lowered from 700 to 550 °C while maintaining phase selectivity by reacting both MgMn2O4 and CaMn2O4 with YOCl in a cooperative "cometathesis"reaction. The nascent halide salts appear to improve the reaction kinetics. Since the onset temperature for YMnO3 formation falls 50 °C below the MgCl2-CaCl2 liquidus, the enhanced reactivity is consistent with the surface melting of a nasscent salt byproduct at the interfaces. Cometathesis routes have similar phase selectivity and temperature reduction in reactions that form TbMnO3, ErMnO3, and DyMnO3. Cometathesis lowers reaction temperatures while preserving the reaction selectivity of the end members, making it a valuable approach for synthesizing metastable targets.

A cloud-hosted web-based software application, nmfMapping, for carrying out a nonnegative matrix factorization of a set of powder diffraction or atomic pair distribution function datasets is described. This app allows structure scientists to rapidly find trends in sets of related data such as from in situ and operando diffraction experiments. The application is easy to use and does not require any programming expertise. It is available at the pdfitc.org website., Comment: 19 Pages, 7 Figures, submitted to Acta Crystallographica Section A

The COVID-19 pandemic significantly disrupted daily life for undergraduates and introduced new stressors (e.g., campus closures). How individuals respond to stressors can interact with stress to increase disorder risk in both unique and transdiagnostic ways. The current study examined how maladaptive and adaptive stress response styles moderated the perceived severity of COVID-related stressors effect on general and specific internalizing dimensions at the beginning of the COVID-19 pandemic in a combined undergraduate sample across two universities (N = 451) using latent bifactor modeling and LASSO modeling to identify optimal predictors. Results showed that perceived stress severity and maladaptive response styles (not adaptive response styles or interactions between stress and response styles) were associated with both common and specific internalizing dimensions. Results suggest additive associations of stress severity and maladaptive coping with internalizing symptoms during the pandemic's beginning, and provide important insights for screening, prevention, and intervention during future public health crises.The online version contains supplementary material available at 10.1007/s10862-022-09975-7.

The layered perovskite (MA)2PbI2(SCN)2 (MA = CH3NH3+) is a member of an emerging series of compounds derived from hybrid organic-inorganic perovskites. Here, we successfully synthesized (MA)2PbI2-xBrx(SCN)2 (0 ≤ x < 1.6) by using a solid-state reaction. Despite smaller bromide substitution for iodine, 1% linear expansion along the a axis was observed at x ∼ 0.4 due to a change of the orientation of the SCN- anions. Diffuse reflectance spectra reveal that the optical band gap increases by the bromide substitution, which is supported by the DFT calculations. Curiously, bromine-rich compounds where x ≥ 0.8 are light sensitive, leading to partial decomposition after ∼24 h. This study demonstrates that the layered perovskite (MA)2PbI2(SCN)2 tolerates a wide range of bromide substitution toward tuning the band gap energy.

International audience; Background: Global HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identified worldwide, but their contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015.Methods: We assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched the PubMed, Embase (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) databases for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data were collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses were done for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, CRD42017067164.Findings: Our global data collection yielded an HIV-1 molecular epidemiology database of 383 519 samples from 116 countries in 1990-2015. We found that the proportion of recombinants increased over time, both globally and in most regions, reaching 22·8% (7 978 517 of 34 921 639) of global HIV-1 infections in 2010-15. Both the proportion and the number of distinct CRFs detected increased over time to 16·7% and 57 CRFs in 2010-15. The global and regional distribution of HIV-1 recombinants was diverse and evolved over time, and we found large regional variation in the numbers (0-44 CRFs), types (58 distinct CRFs), and proportions (0-80·5%) of HIV-1 recombinants. Globally, CRF02_AG was the most prevalent recombinant, accounting for 33·9% (2 701 364 of 7 978 517) of all recombinant infections in 2010-15. URFs accounted for 26·7% (2 131 450 of 7 978 517), CRF01_AE for 23·0% (1 838 433), and other CRFs for 16·4% (1 307 270) of all recombinant infections in 2010-15. Although other CRFs accounted for small proportions of infections globally (

In the synthesis of complex oxides, solid-state metathesis provides low-temperature reactions where product selectivity can be achieved through simple changes in precursor composition. The influence of precursor structure, however, is less understood in solid-state synthesis. Here we present the ternary metathesis reaction (LiMnO2 + YOCl → YMnO3 + LiCl) to target two yttrium manganese oxide products, hexagonal and orthorhombic YMnO3, when starting from three different LiMnO2 precursors. Using temperature-dependent synchrotron X-ray and neutron diffraction, we identify the relevant intermediates and temperature regimes of reactions along the pathway to YMnO3. Manganese-containing intermediates undergo a charge disproportionation into a reduced Mn(II,III) tetragonal spinel and oxidized Mn(III,IV) cubic spinel, which lead to hexagonal and orthorhombic YMnO3, respectively. Density functional theory calculations confirm that the presence of Mn(IV) caused by a small concentration of cation vacancies (∼2.2%) in YMnO3 stabilizes the orthorhombic polymorph over the hexagonal. Reactions over the course of 2 weeks yield o-YMnO3 as the majority product at temperatures below 600 °C, which supports an equilibration of cation defects over time. Controlling the composition and structure of these defect-accommodating intermediates provides new strategies for selective synthesis of complex oxides at low temperatures.

Although initial studies on hybrid perovskites for photovoltaic applications focused on simple compositions, the most technologically relevant perovskites are heavily substituted. The influence of ...

Paraffin fouling deposition is a common issue in oil production that leads to constrictions within the system wherever the system temperature drops below the wax appearance temperature (WAT). Chemical mitigation of these issues often relies on various laboratory equipment for product selection, but often the test conditions chosen are not representative of the field; therefore, the resulting deposit generated may give misleading results. In this article, our aim is to investigate how the use of different laboratory techniques can be utilized to generate a field-representative wax deposit. Our study includes the traditional cold finger (CF) apparatus, the coaxial shear cold finger (CSCF), and the dynamic paraffin deposition cell (DPDC), a test method developed in house. The pieces of equipment use similar temperature-driven deposit formation to measure fouling but with very different mixing conditions. The study of paraffin deposition at narrow temperature gradients with these techniques showed similar trends for deposit weight when compared to the fouling factor obtained using a common oil and the Para-window technique presented in a previous study. Significantly, it was observed that for all of the laboratory techniques used, different sample homogenization/mixing mechanisms did not affect the carbon chain distribution of the most insoluble and problematic high-molecular-weight wax (≥n-C35) but did affect the shorter chain composition (i.e., those that are most prevalent in the parent crude oil). The results confirm that temperature is the main driver dictating the nature of the most field-representative deposit characteristics using the laboratory test systems available. This presents the opportunity to gain better insights into paraffin deposition in the laboratory and prepares us to develop better screening capabilities in order to meet current and future paraffin challenges faced in the field.

Olivine Fe2GeS4 has been identified as a promising photovoltaic absorber material introduced as an alternate candidate to iron pyrite, FeS2. The compounds share similar benefits in terms of element...

Functional small molecules afford opportunities to direct solid-state inorganic reactions at low temperatures. Here, we use catalytic amounts of organosilicon molecules to influence the metathesis reaction: FeCl2 + Na2S2 → 2NaCl + FeS2. Specifically, hexaphenyldisiloxane ((C6H5)6Si2O) is shown to increase pyrite yields in metathesis reactions performed at 150 °C. In situ synchrotron X-ray diffraction (SXRD) paired with differential scanning calorimetry (DSC) reveals that diffusion-limited intermediates are circumvented in the presence of (C6H5)6Si2O. Control reactions suggest that the observed change in the reaction pathway is imparted by the Si–O functional group. 1H NMR supports catalytic behavior, as (C6H5)6Si2O is unchanged ex post facto. Taken together, we hypothesize that the polar Si–O functional group coordinates to iron chloride species when NaCl and Na2S4 form, forming an unidentified, transient intermediate. Further exploration of targeted small molecules in these metathesis reaction provides new strategies in controlling inorganic materials synthesis at low-temperatures.

The emission of white light from a single material is atypical and is of interest for solid-state lighting applications. Broadband light emission has been observed in some layered perovskite derivatives, A₂PbBr₄ (A = R-NH₃⁺), and correlates with static structural distortions corresponding to out-of-plane tilting of the lead bromide octahedra. While materials with different organic cations can yield distinct out-of-plane tilts, the underlying origin of the octahedral tilting remains poorly understood. Using high energy resolution (e.g., quasi-elastic) neutron scattering, this contribution details the rotational dynamics of the organic cations in A₂PbBr₄ materials where A = n-butylammonium (nBA), 1,8-diaminooctammonium (ODA), and 4-aminobutyric acid (GABA). The organic cation dynamics differentiate (nBA)₂PbBr₄ from (ODA)PbBr₄ or (GABA)₂PbBr₄ in that the larger spatial extent of dynamics of nBA yields a larger effective cation radius. The larger effective volume of the nBA cation in (nBA)₂PbBr₄ yields a closer to ideal A-site geometry, preventing the out-of-plane tilt and broadband luminescence. In all three compounds, we observe hydrogen dynamics attributed to rotation of the ammonium headgroup and at a time scale faster than the white light photoluminescence studied by time-correlated single photon counting spectroscopy. This supports a previous assignment of the broadband emission as resulting from a single ensemble, such that the emissive excited state experiences many local structures faster than the emissive decay. The findings presented here highlight the role of the organic cation and its dynamics in hybrid organic–inorganic perovskites and white light emission.

Classical Cepheids are essential objects in the study of stellar evolution and cosmology; however, we know little about their magnetic properties. We report the detection of Stokes $V$ features interpreted as Zeeman signatures in four classical Cepheids using high-resolution spectropolarimetric observations obtained with ESPaDOnS at CFHT. Eight observations of $\eta$ Aql were acquired in 2017 covering its 7.2 d pulsation period, and single observations of Polaris, $\zeta$ Gem, $\delta$ Cep and RT Aur were obtained in 2020 as part of our ongoing systematic survey. We use mean circular polarization Stokes $V$ profiles generated using the Least-Squares Deconvolution procedure to diagnose Zeeman signatures and measure mean longitudinal field strengths $\langle B_{z}\rangle$. We detect magnetic signatures across all pulsation phases of $\eta$ Aql ($-0.89\pm0.47$ G$\, Comment: 11 pages, 6 figures, accepted for publication in MNRAS

Magnetic semiconductors may soon improve the energy efficiency of computers, but materials exhibiting these dual properties remain underexplored. Here, we report the computational prediction and realization of a new magnetic and semiconducting material, MnSnN$_2$, via combinatorial sputtering of thin films. Grazing incidence wide angle X-ray scattering and laboratory X-ray diffraction studies show a wide composition tolerance for this wurtzite-like MnSnN$_2$, ranging from $20\%

The field of dark matter detection is a highly visible and highly competitive one. In this paper, we propose recommendations for presenting dark matter direct detection results particularly suited for weak-scale dark matter searches, although we believe the spirit of the recommendations can apply more broadly to searches for other dark matter candidates, such as very light dark matter or axions. To translate experimental data into a final published result, direct detection collaborations must make a series of choices in their analysis, ranging from how to model astrophysical parameters to how to make statistical inferences based on observed data. While many collaborations follow a standard set of recommendations in some areas, for example the expected flux of dark matter particles (to a large degree based on a paper from Lewin and Smith in 1995), in other areas, particularly in statistical inference, they have taken different approaches, often from result to result by the same collaboration. We set out a number of recommendations on how to apply the now commonly used Profile Likelihood Ratio method to direct detection data. In addition, updated recommendations for the Standard Halo Model astrophysical parameters and relevant neutrino fluxes are provided. The authors of this note include members of the DAMIC, DarkSide, DARWIN, DEAP, LZ, NEWS-G, PandaX, PICO, SBC, SENSEI, SuperCDMS, and XENON collaborations, and these collaborations provided input to the recommendations laid out here. Wide-spread adoption of these recommendations will make it easier to compare and combine future dark matter results., 20 pages, 8 figures, 4 tables, version 2 to match publication

In sharp contrast to molecular synthesis, materials synthesis is generally presumed to lack selectivity. The few known methods of designing selectivity in solid-state reactions have limited scope, such as topotactic reactions or strain stabilization. This contribution describes a general approach for searching large chemical spaces to identify selective reactions. This novel approach explains the ability of a nominally "innocent" Na2CO3 precursor to enable the metathesis synthesis of single-phase Y2Mn2O7: an outcome that was previously only accomplished at extreme pressures and which cannot be achieved with closely related precursors of Li2CO3 and K2CO3 under identical conditions. By calculating the required change in chemical potential across all possible reactant-product interfaces in an expanded chemical space including Y, Mn, O, alkali metals, and halogens, using thermodynamic parameters obtained from density functional theory calculations, we identify reactions that minimize the thermodynamic competition from intermediates. In this manner, only the Na-based intermediates minimize the distance in the hyperdimensional chemical potential space to Y2Mn2O7, thus providing selective access to a phase which was previously thought to be metastable. Experimental evidence validating this mechanism for pathway-dependent selectivity is provided by intermediates identified from in situ synchrotron-based crystallographic analysis. This approach of calculating chemical potential distances in hyperdimensional compositional spaces provides a general method for designing selective solid-state syntheses that will be useful for gaining access to metastable phases and for identifying reaction pathways that can reduce the synthesis temperature, and cost, of technological materials.

The EXO-200 experiment searched for neutrinoless double-beta decay of $^{136}$Xe with a single-phase liquid xenon detector. It used an active mass of 110 kg of 80.6%-enriched liquid xenon in an ultra-low background time projection chamber with ionization and scintillation detection and readout. This paper describes the design and performance of the various support systems necessary for detector operation, including cryogenics, xenon handling, and controls. Novel features of the system were driven by the need to protect the thin-walled detector chamber containing the liquid xenon, to achieve high chemical purity of the Xe, and to maintain thermal uniformity across the detector., Manuscript updated in response to JINST reviewer comments

Background Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. Objective STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. Design STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group – the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. Setting Antenatal clinics in the UK and elsewhere in Europe. Participants Women with twin pregnancy at Interventions Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0–20+ 6 weeks’ gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. Main outcome measures Obstetric – all births before 34+ 0 weeks’ gestation following the spontaneous onset of labour; and neonatal – composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. Results A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal ‘easy’ or ‘fairly easy’ in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. Limitations There was the possibility of a type II error around smaller than anticipated benefit. Conclusions In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of Future work Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. Trial registration Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 44. See the NIHR Journals Library website for further project information.

Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here, we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm. SINE-deleted cells exhibit an activated unfolded protein response and PKR and markedly increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic inclusions. TDP-43 binds stronger to Malat1 without the SINE and is likely ‘hijacked’ by cytoplasmic Malat1 to the cytoplasm, resulting in the depletion of nuclear TDP-43 and redistribution of TDP-43 binding to repetitive element transcripts and mRNAs encoding mitotic and nuclear-cytoplasmic regulators. The SINE promotes Malat1 nuclear retention by facilitating Malat1 binding to HNRNPK, a protein that drives RNA nuclear retention, potentially through direct interactions of the SINE with KHDRBS1 and TRA2A, which bind to HNRNPK. Losing these RNA–protein interactions due to the SINE deletion likely creates more available TDP-43 binding sites on Malat1 and subsequent TDP-43 aggregation. These results highlight the significance of lncRNA TEs in TDP-43 proteostasis with potential implications in both cancer and neurodegenerative diseases.

This paper presents a novel approach to identify inerter-based suspension struts, which can provide significant performance enhancement for passenger vehicles. The inerter has been used on Formula 1 racing cars, and several beneficial devices incorporating inerters have also been identified for ride comfort enhancement. However, previous investigations either were limited to simple network configurations with moderate performance improvement, or resulted in complicated configurations with a large number of elements which are impractical for real-life applications. In addition, some important practical performance constraints have not been taken into consideration, such as high-frequency dynamic stiffness which influences the NVH performance, and frequency content consideration of the sprung mass acceleration which more directly relates to passenger perception. In this paper, a quarter-car model including top mount is studied, with the performance of a conventional suspension strut presented as baseline. The structure-immittance approach, which can cover all networks with pre-determined numbers of each element type, is adopted for the identification of the optimal suspension configurations. Several configurations with up to a 14.7% performance improvement are identified with all other practical performance indices to be no worse than the baseline. The suspension devices proposed in previous works are also considered for a sake of comparison, demonstrating significant advantages of the structure-immittance approach. Subsequently, a sensitivity analysis against the sprung and unsprung mass changes is carried out, which represents cargo and tyre weight variations, respectively. Time domain response and other reality checks are then conducted for the out-performing configurations, which reconfirm the ride comfort enhancement and ensure no unexpected behaviour occurs.