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Abstract The Aria cryogenic distillation plant, located in Sardinia, Italy, is a key component of the DarkSide-20k experimental program for WIMP dark matter searches at the INFN Laboratori Nazionali del Gran Sasso, Italy. Aria is designed to purify the argon, extracted from underground wells in Colorado, USA, and used as the DarkSide-20k target material, to detector-grade quality. In this paper, we report the first measurement of argon isotopic separation by distillation with the 26 m tall Aria prototype. We discuss the measurement of the operating parameters of the column and the observation of the simultaneous separation of the three stable argon isotopes: $${}^{36}\hbox {Ar}$$ 36 Ar , $${}^{38}\textrm{Ar}$$ 38 Ar , and $${}^{40}\textrm{Ar}$$ 40 Ar . We also provide a detailed comparison of the experimental results with commercial process simulation software. This measurement of isotopic separation of argon is a significant achievement for the project, building on the success of the initial demonstration of isotopic separation of nitrogen using the same equipment in 2019.

Introduction Acute clinical deterioration in hospital inpatients can be caused by a range of factors including dementia, delirium, substance withdrawal and psychiatric disturbance, creating challenges in diagnosis, often requiring a management plan with input from multiple disciplines. Staff forums and broader literature have confirmed that healthcare staff working in non-mental health settings, may not be as skilled in recognising and managing early signs of emerging and/or escalating clinical agitation. The BoC RRT is a consultation service within the Division of Medicine and CL Psychiatry. Staffed by Medical Registrars and Mental Health Nurses, the collaboration provides a unique healthcare response to acute general wards. The BoC RRT has been implemented to address the rising number of incidences whereby staff and patient safety are compromised. Using evidence-based skills the team aimed to: respond to episodes of clinical agitation that require an internal security response, assist ward referrals by exploring biopsychosocial contributants to behaviour, develop individual patient support plans and review and reduce restrictive intervention practices. Objectives To determine if the rapid response model has influenced: - The impact on staff/patient safety - Frequency of emergency responses for aggression - Frequency of restrictive intervention use Methods This project was approved as a quality assurance project (QA2022018). The patients within scope of the BoC RRT include inpatients in medical and surgical wards. It excludes patients in Emergency Departments, mental health units, outpatient clinics, and visitors. The evaluation of the pilot has used a PDSA (Plan, Do, Study, Act) cycle when implementing new improvements. A mixed methods approach explored the impact of the BoC RRT. Staff consultation will identify challenges in responding to scenarios whereby there is risk of harm to staff and patients. Staff feedback and the emergency response data was monitored. Results In 2021, there was approx. 720 code greys per month, requiring a security response. Since the implementation of BoC RRT, these numbers have reduced to 527. Reviewing restrictive intrvention practices has identified areas for policy review and need for education. Staff consultation found that nurses were confident caring for those patients exhibiting clinical agitation associated with delirium and dementia. However, caring for people with mental health or substance use disorders were more challenging. Conclusions These interim results indicate that BoC RRT has been generally well received by clinical staff. The decline in code grey responses indicates that it is likely having a positive impact in early identification and management of clinical agitation for hospital inpatients. There is support for this response model to continue beyond the pilot phase and further area for research. Disclosure of Interest None Declared

73Ge(n,γ) cross sections were measured at the neutron time-of-flight facility n_TOF at CERN up to neutron energies of 300 keV, providing for the first time experimental data above 8 keV. Results indicate that the stellar cross section at kT=30 keV is 1.5 to 1.7 times higher than most theoretical predictions. The new cross sections result in a substantial decrease of 73Ge produced in stars, which would explain the low isotopic abundance of 73Ge in the solar system. Keywords: Nucleosynthesis, Neutron capture, s process, Germanium, n_TOF

This work reports on accurate, high-resolution measurements of the 25Mg(n,γ)26Mg and 25Mg(n,tot) cross sections in the neutron energy range from thermal to about 300 keV, leading to a significantly improved 25Mg(n,γ)26Mg parametrization. The relevant resonances for n+25Mg were characterized from a combined R-matrix analysis of the experimental data. This resulted in an unambiguous spin/parity assignment of the corresponding excited states in 26Mg. With this information experimental upper limits of the reaction rates for 22Ne(α,n)25Mg and 22Ne(α,γ)26Mg were established, potentially leading to a significantly higher (α,n)/(α,γ) ratio than previously evaluated. The impact of these results has been studied for stellar models in the mass range 2 to 25 M⊙.

Sentinel-1A was launched in April 2014, and has been collecting data routinely over more than one year. Sentinel-1B is set for launch on 22 April 2016. The Sentinel-1 constellation has several advantages over previous radar missions for InSAR applications: (1) Data are being acquired systematically for tectonic and volcanic areas, (2) Images cover a wide footprint, 250 km from near to far range in Interferometric Wide Swath (TOPS) mode, (3) Small perpendicular and temporal baselines greatly improve interferometric coherence at C-band, (4) Data are freely available to all users, (5) The mission is planned to be operational for 20 years, with 1C and 1D planned for future launches. These features enable us to map geological processes occurring in any place at anytime using InSAR. We will review progress within COMET towards our ultimate goal of building a fully-automated processing system that provides deformation results and derived products to the wide InSAR and Geophysics communities. In addition to high-resolution-ECMWFbased atmospheric correction model, we will show results of a systematic analysis of interferometric coherence in tectonic and volcanic areas, and discuss the future goals and timeline for the COMET InSAR automated processing system.

N-alkylated C2-symmetric amino acid amide derivatives were shown to catalyse the Michael addition of 2-hydroxy-1,4-napthoquinone to β-nitrostyrene, achieving a maximum ee of 44%. The corresponding trifluoroacetic acid salts also catalysed the aldol reaction between 4-nitrobenzaldehyde and hydroxyacetone, leading to the formation of predominantly syn-aldol products in up to 55% ee. Aspects of the solvent dependence of the aldol reaction and the H-bonding of the catalyst were investigated.

Abstract Many cellular processes are governed by protein–protein interactions that require tight spatial and temporal regulation. Accordingly, it is necessary to understand the dynamics of these interactions to fully comprehend and elucidate cellular processes and pathological disease states. To map de novo protein–protein interactions with time resolution at an organelle-wide scale, we developed a quantitative mass spectrometry method, time-resolved interactome profiling (TRIP). We apply TRIP to elucidate aberrant protein interaction dynamics that lead to the protein misfolding disease congenital hypothyroidism. We deconvolute altered temporal interactions of the thyroid hormone precursor thyroglobulin with pathways implicated in hypothyroidism pathophysiology, such as Hsp70-/90-assisted folding, disulfide/redox processing, and N-glycosylation. Functional siRNA screening identified VCP and TEX264 as key protein degradation components whose inhibition selectively rescues mutant prohormone secretion. Ultimately, our results provide novel insight into the temporal coordination of protein homeostasis, and our TRIP method should find broad applications in investigating protein-folding diseases and cellular processes.

Atraumatic splenic rupture is a rare complication of a pancreatic pseudocyst (PP), described in the setting of chronic pancreatitis. There is common understanding, within the literature, that an inflammatory process at the tail of the pancreas may disrupt the spleen and result in such splenic complications. The authors present a case report of a 29-year-old male with a PP, associated with chronic pancreatitis. The patient had a history of excessive alcohol intake and presented to the emergency department with a short history of abdominal pain and vomiting. He denied any significant history of trauma and serum amylase levels were normal. An admission computed tomography (CT) scan of the abdomen confirmed the presence of a PP in direct contact with the spleen. The CT also demonstrated a heterogenous hypodense area of the splenic hilum, along with perisplenic fluid. The patient was admitted for observation. His abdominal pain progressed, and he became haemodynamically unstable. An emergency ultrasound scan (USS) at this time revealed intra-abdominal haemorrhage. A subsequent CT confirmed splenic rupture, which was managed surgically with a full recovery. Few such cases are documented within the literature and more understanding of preempting such events is needed.

Abstract Eukaryotes produce a large number of cytochrome P450s that mediate the synthesis and degradation of diverse endogenous and exogenous metabolites. Yet, most of these P450s are uncharacterized and global tools to study these challenging, membrane-resident enzymes remain to be exploited. Here, we applied activity profiling of plant, mouse and fungal P450s with chemical probes that become reactive when oxidized by P450 enzymes. Identification by mass spectrometry revealed labeling of a wide range of active P450s, including six plant P450s, 40 mouse P450s and 13 P450s of the fungal wheat pathogen Zymoseptoria tritici. We next used transient expression of GFP-tagged P450s by agroinfiltration to show ER-targeting and NADPH-dependent, activity-based labeling of plant, mouse and fungal P450s. Both global profiling and transient expression can be used to detect a broad range of active P450s to study e.g. their regulation and discover selective inhibitors.

Abstract Record high temperatures were documented in the McMurdo Dry Valleys, Antarctica, on 18 March 2022, exceeding average temperatures for that day by nearly 30°C. Satellite imagery and stream gage measurements indicate that surface wetting coincided with this warming more than 2 months after peak summer thaw and likely exceeded thresholds for rehydration and activation of resident organisms that typically survive the cold and dry conditions of the polar fall in a freeze‐dried state. This weather event is notable in both the timing and magnitude of the warming and wetting when temperatures exceeded 0°C at a time when biological communities and streams have typically entered a persistent frozen state. Such events may be a harbinger of future climate conditions characterized by warmer temperatures and greater thaw in this region of Antarctica, which could influence the distribution, activity, and abundance of sentinel taxa. Here we describe the ecosystem responses to this weather anomaly reporting on meteorological and hydrological measurements across the region and on later biological observations from Canada Stream, one of the most diverse and productive ecosystems within the McMurdo Dry Valleys.

Clostridioides difficile is an important human pathogen, for which there are very limited treatment options, primarily the glycopeptide antibiotic vancomycin. In recent years, vancomycin resistance has emerged as a serious problem in several gram-positive pathogens, but high-level resistance has yet to be reported for C. difficile, although it is not known if this is due to constraints upon resistance evolution in this species. Here, we show that resistance to vancomycin can evolve rapidly under ramping selection but is accompanied by fitness costs and pleiotropic trade-offs, including sporulation defects that would be expected to severely impact transmission. We identified 2 distinct pathways to resistance, both of which are predicted to result in changes to the muropeptide terminal D-Ala-D-Ala that is the primary target of vancomycin. One of these pathways involves a previously uncharacterised D,D-carboxypeptidase, expression of which is controlled by a dedicated two-component signal transduction system. Our findings suggest that while C. difficile is capable of evolving high-level vancomycin resistance, this outcome may be limited clinically due to pleiotropic effects on key pathogenicity traits. Moreover, our data identify potential mutational routes to resistance that should be considered in genomic surveillance.

Abstract Pseudomonas aeruginosa is a major nosocomial pathogen that causes severe disease including sepsis. Carbapenem-resistant P. aeruginosa is recognised by the World Health Organisation as a priority 1 pathogen, with urgent need for new therapeutics. As such, there is renewed interest in using bacteriophages as a therapeutic. However, the dynamics of treating pan-resistant P. aeruginosa with phage in vivo are poorly understood. Using a pan-resistant P. aeruginosa in vivo infection model, phage therapy displays strong therapeutic potential, clearing infection from the blood, kidneys, and spleen. Remaining bacteria in the lungs and liver displays phage resistance due to limiting phage adsorption. Yet, resistance to phage results in re-sensitisation to a wide range of antibiotics. In this work, we use phage steering in vivo, pre-exposing a pan resistant P. aeruginosa infection with a phage cocktail to re-sensitise bacteria to antibiotics, clearing the infection from all organs.

Phage characterization for research and therapy can involve newly isolated phages propagated in pathogenic bacteria. If so, characterization requires safety-managing the bacteria. In the current study, we adapt a common and inexpensive reagent, PrimeStore (Longhorn Vaccines and Diagnostics, San Antonio, TX, USA), to safety-manage bacteria in 20 min by selectively inactivating the bacteria. No bacterial survivors are observed among >109 bacteria per ml for a representative of both Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Bacillus thuringiensis). This procedure causes no detected inactivation of podophage T3, myophage T4 and siphophage 0105phi7-2. Margins of safety for PrimeStore concentration exist for bacterial inactivation and phage non-inactivation. Thus, general applicability is expected. Subsequent dialysis is used to block long-term effects on phages. Nonetheless, comparable tests should be performed for each pathogenic bacterial strain/phage. Electron microscopy of thin sections reveals inactivation-altered bacterial cytoplasm and a non-disintegrated bacterial envelope (ghosts). Ghosting of E. coli includes re-arrangement of the cytoplasm and the release of endotoxin. The activity of the released endotoxin is >99% reduced after subsequent dialysis, which also removes PrimeStore components. Ghosting of B. thuringiensis includes apparent phase separation within the cytoplasm. The primary application envisaged is biophysical and other screening of phages for therapy of infectious disease.

The orbits of close-in exoplanets provide clues to their formation and evolutionary history. Many close-in exoplanets likely formed far out in their protoplanetary disks and migrated to their current orbits, perhaps via high-eccentricity migration (HEM), a process that can also excite obliquities. A handful of known exoplanets are perhaps caught in the act of HEM, as they are observed on highly eccentric orbits with tidal circularization timescales shorter than their ages. One such exoplanet is Kepler-1656 b, which is also the only known nongiant exoplanet ( 0.8 to have its obliquity constrained; expanding this population will help establish the degree to which orbital misalignment accompanies migration. Future work that constrains the mutual inclinations of outer perturbers will be key for distinguishing plausible mechanisms.

We confirm TOI-4201 b as a transiting Jovian-mass planet orbiting an early M dwarf discovered by the Transiting Exoplanet Survey Satellite. Using ground-based photometry and precise radial velocities from NEID and the Planet Finder Spectrograph, we measure a planet mass of ${2.59}_{-0.06}^{+0.07}$ M _J , making this one of the most massive planets transiting an M dwarf. The planet is ∼0.4% of the mass of its 0.63 M _⊙ host and may have a heavy-element mass comparable to the total dust mass contained in a typical class II disk. TOI-4201 b stretches our understanding of core accretion during the protoplanetary phase and the disk mass budget, necessitating giant planet formation to take place either much earlier in the disk lifetime or perhaps through alternative mechanisms like gravitational instability.

Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these ‘hypertension polypills’ were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.

Asteroseismology of dwarf stars cooler than the Sun is very challenging owing to the low amplitudes and rapid timescales of oscillations. Here we present the asteroseismic detection of solar-like oscillations at 4-minute timescales ( ${\nu }_{\max }\sim 4300$ μ Hz) in the nearby K dwarf σ Draconis using extreme-precision Doppler velocity observations from the Keck Planet Finder and 20 s cadence photometry from NASA’s Transiting Exoplanet Survey Satellite. The star is the coolest dwarf star to date with both velocity and luminosity observations of solar-like oscillations, having amplitudes of 5.9 ± 0.8 cm s ^−1 and 0.8 ± 0.2 ppm, respectively. These measured values are in excellent agreement with established luminosity−velocity amplitude relations for oscillations and provide further evidence that mode amplitudes for stars with T _eff < 5500 K diminish in scale following an ( L / M ) ^1.5 relation. By modeling the star’s oscillation frequencies from photometric data, we measure an asteroseismic age of 4.5 ± 0.9 (ran) ± 1.2 (sys) Gyr. The observations demonstrate the capability of next-generation spectrographs and precise space-based photometry to extend observational asteroseismology to nearby cool dwarfs, which are benchmarks for stellar astrophysics and prime targets for directly imaging planets using future space-based telescopes.

For solar-type stars, spots and their associated magnetic regions induce radial velocity perturbations through the Doppler rotation signal and the suppression of convective blueshift, collectively known as rotation modulation. We developed the Rotation–Convection (RC) model: a method of detrending and characterizing rotation modulation using only cross–correlation functions or one-dimensional spectra without the need for continuous high-cadence measurements. The RC method uses a simple model for the anomalous radial velocity induced by an active region and has two inputs: stellar flux (or a flux proxy) and the relative radial velocity between strongly and weakly absorbed wavelengths (analogous to the bisector–inverse slope). On NEID solar data (3 month baseline), the RC model lowers the amplitude of rotationally modulated stellar activity to below the meter–per–second level. For the standard star HD 26965, the RC model detrends the activity signal to the meter–per–second level for HARPS, EXPRES, and NEID observations, even though the temporal density and time span of the observations differ by an order of magnitude between the three data sets. In addition to detrending, the RC model also characterizes the rotation–modulation signal. From comparison with the Solar Dynamics Observatory, we confirmed that the model accurately recovers and separates the rotation and convection radial velocity components. We also mapped the amplitude of the rotation and convection perturbations as a function of height within the stellar atmosphere. Probing stellar atmospheres with our revised spot model will fuel future innovations in stellar activity mitigation, enabling robust exoplanet detection.

We present a new analysis of Kepler-21, the brightest ( V = 8.5) Kepler system with a known transiting exoplanet, Kepler-21 b. Kepler-21 b is a radius valley planet ( R = 1.6 ± 0.2 R _⊕ ) with an Earth-like composition (8.38 ± 1.62 g cm ^–3 ), though its mass and radius fall in the regime of possible “water worlds.” We utilize new Keck/High-Resolution Echelle Spectrometer and WIYN/NEID radial velocity (RV) data in conjunction with Kepler and Transiting Exoplanet Survey Satellite (TESS) photometry to perform a detailed study of activity mitigation between photometry and RVs. We additionally refine the system parameters, and we utilize Gaia astrometry to place constraints on a long-term RV trend. Our activity analysis affirms the quality of Kepler photometry for removing correlated noise from RVs, despite its temporal distance, though we reveal some cases where TESS may be superior. Using refined orbital parameters and updated composition curves, we rule out a water world scenario for Kepler-21 b, and we identify a long-period super-Jupiter planetary candidate, Kepler-21 (c).

The LHS 1610 system consists of a nearby ( d = 9.7 pc) M5 dwarf hosting a candidate brown dwarf companion in a 10.6 days, eccentric ( e ∼ 0.37) orbit. We confirm this brown dwarf designation and estimate its mass ( ${49.5}_{-3.5}^{+4.3}$ M _Jup ) and inclination (114.5° ${}_{-10.0}^{+7.4}$ ) by combining discovery radial velocities (RVs) from the Tillinghast Reflector Echelle Spectrograph and new RVs from the Habitable-zone Planet Finder with the available Gaia astrometric two-body solution. We highlight a discrepancy between the measurement of the eccentricity from the Gaia two-body solution ( e = 0.52 ± 0.03) and the RV-only solution ( e = 0.3702 ± 0.0003). We discuss possible reasons for this discrepancy, which can be further probed when the Gaia astrometric time series become available as part of Gaia Data Release 4. As a nearby mid-M star hosting a massive short-period companion with a well-characterized orbit, LHS 1610 b is a promising target to look for evidence of sub-Alfvénic interactions and/or auroral emission at optical and radio wavelengths. LHS 1610 has a flare rate (0.28 ± 0.07 flares per day) on the higher end for its rotation period (84 ± 8 days), similar to other mid-M dwarf systems such as Proxima Cen and YZ Ceti that have recent radio detections compatible with star–planet interactions. While available Transiting Exoplanet Survey Satellite photometry is insufficient to determine an orbital phase dependence of the flares, our complete orbital characterization of this system makes it attractive to probe star–companion interactions with additional photometric and radio observations.

We present a new analysis of the KELT-24 system, comprising a well-aligned hot Jupiter, KELT-24 b, and a bright ( V = 8.3), nearby ( d = 96.9 pc) F-type host star. KELT-24 b was independently discovered by two groups in 2019, with each reporting best-fit stellar parameters that were notably inconsistent. Here, we present three independent analyses of the KELT-24 system, each incorporating a broad range of photometric and spectroscopic data, including eight sectors of Transiting Exoplanet Survey Satellite (TESS) photometry and more than 200 new radial velocities (RVs) from the MINiature Exoplanet Radial Velocity Array. Two of these analyses use KELT-24's observed spectral energy distribution (SED) through a direct comparison to stellar evolutionary models, while our third analysis assumes an unknown additional body contributing to the observed broadband photometry and excludes the SED. Ultimately, we find that the models that include the SED are a poor fit to the available data, so we adopt the system parameters derived without it. We also highlight a single transit-like event observed by TESS, deemed likely to be an eclipsing binary bound to KELT-24, that will require follow-up observations to confirm. We discuss the potential of these additional bodies in the KELT-24 system as a possible explanation for the discrepancies between the results of the different modeling approaches, and explore the system for longer-period planets that may be weakly evident in the RV observations. The comprehensive investigations that we present not only increase the fidelity of our understanding of the KELT-24 system but also serve as a blueprint for future stellar modeling in global analyses of exoplanet systems.

TOI-6255 b (GJ 4256) is an Earth-sized planet (1.079 ± 0.065 R _⊕ ) with an orbital period of only 5.7 hr. With the newly commissioned Keck Planet Finder and CARMENES spectrographs, we determine the planet’s mass to be 1.44 ± 0.14 M _⊕ . The planet is just outside the Roche limit, with P _orb / P _Roche = 1.13 ± 0.10. The strong tidal force likely deforms the planet into a triaxial ellipsoid with a long axis that is ∼10% longer than the short axis. Assuming a reduced stellar tidal quality factor ${Q}_{\star }^{{\prime} }\approx {10}^{7}$ , we predict that tidal orbital decay will cause TOI-6255 to reach the Roche limit in roughly 400 Myr. Such tidal disruptions may produce the possible signatures of planet engulfment that have been seen on stars with anomalously high refractory elemental abundances compared to their conatal binary companions. TOI-6255 b is also a favorable target for searching for star–planet magnetic interactions, which might cause interior melting and hasten orbital decay. TOI-6255 b is a top target (with an Emission Spectroscopy Metric of about 24) for phase-curve observations with the James Webb Space Telescope.

We present an updated version of the GRanulation And Spectrum Simulator (GRASS) which now uses an expanded library of 22 solar lines to empirically model time-resolved spectral variations arising from solar granulation. We show that our synthesis model accurately reproduces disk-integrated solar line profiles and bisectors, and we quantify the intrinsic granulation-driven radial-velocity (RV) variability for each of the 22 lines studied. We show that summary statistics of bisector shape (e.g., bisector inverse slope) are strongly correlated with the measured anomalous, variability-driven RV at high pixel signal-to-noise ratio SNR and spectral resolution. Further, the strength of the correlations varies both line by line and with the summary statistic used. These correlations disappear for individual lines at the typical spectral resolutions and SNRs achieved by current extremely precise radial velocity spectrographs; so we use simulations from GRASS to demonstrate that they can, in principle, be recovered by selectively binning lines that are similarly affected by granulation. In the best-case scenario (high SNR and large number of binned lines), we find that a ≲30% reduction in the granulation-induced root mean square RV can be achieved, but that the achievable reduction in variability is most strongly limited by the spectral resolution of the observing instrument. Based on our simulations, we predict that existing ultra-high-resolution spectrographs, namely, ESPRESSO and PEPSI, should be able to resolve convective variability in other, bright stars.

We revisit the long-studied radial velocity (RV) target HD 26965 using recent observations from the NASA-NSF “NEID” precision Doppler facility. Leveraging a suite of classical activity indicators, combined with line-by-line RV analyses, we demonstrate that the claimed 45-day signal previously identified as a planet candidate is most likely an activity-induced signal. Correlating the bulk (spectrally averaged) RV with canonical line activity indicators confirms a multiday “lag” between the observed activity indicator time series and the measured RV. When accounting for this lag, we show that much of the observed RV signal can be removed by a linear detrending of the data. Investigating activity at the line-by-line level, we find a depth-dependent correlation between individual line RVs and the bulk RVs, further indicative of periodic suppression of convective blueshift causing the observed RV variability, rather than an orbiting planet. We conclude that the combined evidence of the activity correlations and depth dependence is consistent with an RV signature dominated by a rotationally modulated activity signal at a period of ∼42 days. We hypothesize that this activity signature is due to a combination of spots and convective blueshift suppression. The tools applied in our analysis are broadly applicable to other stars and could help paint a more comprehensive picture of the manifestations of stellar activity in future Doppler RV surveys.

The following hypothesis proposes non-diffusive, environmental bacteriophage (phage) motion. (1) Some phage-hosting, motile bacteria undergo chemotaxis down ATP concentration gradients to escape lysis-inducing conditions, such as phage infection. (2) Some phages respond by non-infective binding to the motile bacteria. (3) When the bacteria reach a lower ATP concentration, which is a condition that signals increased density of phage-susceptible bacteria, the phage converts, Trojan-horse-like, to productive binding and infection. This hypothesis was previously proposed for Bacillus thuringiensis siphophage 0105phi7-2. It is tested here and confirmed with the following observations. (1) B. thuringiensis is found, macroscopically, preferentially located at low ATP concentrations when propagated in-gel after inoculation in the center of an artificially generated ATP concentration gradient. (2) Inoculating phage 0105phi7-2 at the bacteria inoculation site, 2–3 h after inoculation of bacteria, results in cell lysing activity that moves with the bacteria, without a visible trail of lysis. Trojan-horse-like behavior is consistent with only biofilm-inhabiting phages because environmental selection for this behavior requires limited fluid flows. We propose using artificial ATP concentration gradients to instigate Trojan-horse-like phage behavior during phage therapy of bacterial biofilms.

(1) Pulmonary hypertension (PH)-associated right ventricular (RV) failure is linked to a reduction in pulmonary vasodilators. Treprostinil has shown effectiveness in PAH patients with cardiac decompensation, hinting at potential cardiac benefits. We investigated treprostinil’s synergy with isoprenaline in RV and LV cardiomyocytes. We hypothesised that disease-related RV structural changes in cardiomyocytes would reduce contractile responses and cAMP/PKA signalling activity. (2) We induced PH in male Sprague Dawley rats using monocrotaline and isolated their ventricular cardiomyocytes. The effect of in vitro treprostinil and isoprenaline stimulation on contraction was assessed. FRET microscopy was used to study PKA activity associated with treprostinil stimulation in AKAR3-NES FRET-based biosensor-expressing cells. (3) RV cells exhibited maladaptive remodelling with hypertrophy, impaired contractility, and calcium transients compared to control and LV cardiomyocytes. Combining treprostinil and isoprenaline failed to enhance inotropy in PH RV cardiomyocytes. PH RV cardiomyocytes displayed an aberrant contractile behaviour, which the combination treatment could not rectify. Finally, we observed decreased PKA activity in treprostinil-treated PH RV cardiomyocytes. (4) PH-associated RV cardiomyocyte remodelling reduced treprostinil sensitivity, inotropic support, and impaired relaxation. Overall, this study highlights the complexity of RV dysfunction in advanced PH and suggests the need for alternative therapeutic strategies.

We report the measurement of the sky-projected obliquity angle λ of the warm Jovian exoplanet TOI-1670 c via the Rossiter–McLaughlin effect. We observed the transit window during UT 2023 April 20 for 7 continuous hours with NEID on the 3.5 m WIYN Telescope at Kitt Peak National Observatory. TOI-1670 hosts a sub-Neptune ( P ∼ 11 days; planet b) interior to the warm Jovian ( P ∼ 40 days; planet c), which presents an opportunity to investigate the dynamics of a warm Jupiter with an inner companion. Additionally, TOI-1670 c is now among the longest-period planets to date to have its sky-projected obliquity angle measured. We find planet c is well aligned to the host star, with λ = − 0.°3 ± 2.°2. TOI-1670 c joins a growing census of aligned warm Jupiters around single stars and aligned planets in multiplanet systems.

Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40–41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.

ABSTRACT: This work describes a new approach for synthesizing extremely fouling-resistant, zwitterionic membranes with controlled, tunable pore sizes that extend from ion separations (< 1 nm) to the ultrafiltration range (∼2 nm). These membranes are manufactured by the UV treatment of high zwitterion content amphiphilic copolymers with cross-linkable functionality to stabilize the membrane selective layers, preventing excessive swelling and dissolution of copolymers containing as high as 80 wt% zwitterionic repeat units. Zwitterion weight fraction allows the tuning of membrane performance, with effective pore size and permeance both increasing with zwitterion content. The high zwitterion content membranes were remarkably fouling-resistant and demonstrated a salt-responsive behavior not previously observed with self-assembling zwitterionic copolymer membranes.

Background: Research has established End-of-Life Dreams and Visions (ELDVs) as prevalent, meaningful valid experiences that may help patients cope with illness and approaching death. However, no inductive qualitative analysis has explored the phenomenology of ELDVs from the perspective of hospice homecare patients. Objective: The purpose of this study is to evaluate the content of ELDVs by using a rigorous qualitative approach. Design: Five hundred forty-eight ELDVs were collected from weekly interviews of hospice homecare patients and analyzed by using Consensual Qualitative Research Methodology. Settings/Subject: Participants were enrolled in a county-wide hospice homecare program between January 2013?March 2015. Results: The following domains emerged: (1) Interpersonal, (2) Affective Experience and Reflection, (3) Activities, and (4) Setting/Location. Conclusions: This study suggests that ELDV content may include a broader spectrum of experiences that reflect waking life than previously believed. Clinical implications suggest that it may be important for providers to engage with ELDVs, as they are psychologically significant experiences that may be a source of clinical insight.

Despite the importance of Jupiter and Saturn to Earth’s formation and habitability, there has not yet been a comprehensive observational study of how giant exoplanets correlate with the architectural properties of close-in, sub-Neptune-sized exoplanets. This is largely because transit surveys are particularly insensitive to planets at orbital separations ≳1 au, and so their census of Jupiter-like planets is incomplete, inhibiting our study of the relationship between Jupiter-like planets and the small planets that do transit. To investigate the relationship between close-in, small and distant, giant planets, we conducted the Kepler Giant Planet Survey (KGPS). Using the W. M. Keck Observatory High Resolution Echelle Spectrometer, we spent over a decade collecting 2844 radial velocities (RVs; 2167 of which are presented here for the first time) of 63 Sunlike stars that host 157 transiting planets. We had no prior knowledge of which systems would contain giant planets beyond 1 au, making this survey unbiased with respect to previously detected Jovians. We announce RV-detected companions to 20 stars from our sample. These include 13 Jovians ( $0.3\,{M}_{{\rm{J}}}\lt M\sin i\lt 13\,{M}_{{\rm{J}}}$ , 1 au < a < 10 au), eight nontransiting sub-Saturns, and three stellar-mass companions. We also present updated masses and densities of 84 transiting planets. The KGPS project leverages one of the longest-running and most data-rich collections of RVs of the NASA Kepler systems yet, and it will provide a basis for addressing whether giant planets help or hinder the growth of sub-Neptune-sized and terrestrial planets. Future KGPS papers will examine the relationship between small, transiting planets and their long-period companions.

Abstract Background Organizational Participatory Research (OPR) seeks organizational learning and/or practice improvement. Previous systematic literature reviews described some OPR processes and outcomes, but the link between these processes and outcomes is unknown. We sought to identify and sequence the key processes of OPR taking place with and within healthcare organizations and the main outcomes to which they contribute, and to define ideal-types of OPR. Methods This article reports a participatory systematic mixed studies review with qualitative synthesis A specialized health librarian searched MEDLINE, CINAHL, Embase Classic + Embase, PsycINFO, the Cochrane Library, Social Work Abstracts and Business Source Complete, together with grey literature data bases were searched from inception to November 29, 2012. This search was updated using forward citation tracking up to June 2014. Reporting quality was appraised and unclear articles were excluded. Included studies clearly reported OPR where the main research related decisions were co-constructed among the academic and healthcare organization partners. Included studies were distilled into summaries of their OPR processes and outcomes, which were subsequently analysed using deductive and inductive thematic analysis. All summaries were analysed; that is, data analysis continued beyond saturation. Results Eighty-three studies were included from the 8873 records retrieved. Eight key OPR processes were identified. Four follow the phases of research: 1) form a work group and hold meetings, 2) collectively determine research objectives, 3) collectively analyse data, and 4) collectively interpret results and decide how to use them. Four are present throughout OPR: 1) communication, 2) relationships; 3) commitment; 4) collective reflection. These processes contribute to extra benefits at the individual and organizational levels. Four ideal-types of OPR were defined. Basic OPR consists of OPR processes leading to achieving the study objectives. This ideal-type and may be combined with any of the following three ideal-types: OPR resulting in random additional benefits for the individuals or organization involved, OPR spreading to other sectors of the organization and beyond, or OPR leading to subsequent initiatives. These results are illustrated with a novel conceptual model. Conclusion The model provides operational guidance to help OPR stakeholders collaboratively address organizational issues and achieve desired outcomes and more. Review registration As per PROSPERO inclusion criteria, this review is not registered.

The measurement of the contractile behavior of single cardiomyocytes has made a significant contribution to our understanding of the physiology and pathophysiology of the myocardium. However, the isolation of cardiomyocytes introduces various technical and statistical issues. Traditional video and fluorescence microscopy techniques based around conventional microscopy systems result in low-throughput experimental studies, in which single cells are studied over the course of a pharmacological or physiological intervention. We describe a new approach to these experiments made possible with a new piece of instrumentation, the CytoCypher High-Throughput System (CC-HTS). We can assess the shortening of sarcomeres, cell length, Ca2+ handling, and cellular morphology of almost 4 cells per minute. This increase in productivity means that batch-to-batch variation can be identified as a major source of variability. The speed of acquisition means that sufficient numbers of cells in each preparation can be assessed for multiple conditions reducing these batch effects. We demonstrate the different temporal scales over which the CC-HTS can acquire data. We use statistical analysis methods that compensate for the hierarchical effects of clustering within heart preparations and demonstrate a significant false-positive rate, which is potentially present in conventional studies. We demonstrate a more stringent way to perform these tests. The baseline morphological and functional characteristics of rat, mouse, guinea pig, and human cells are explored. Finally, we show data from concentration response experiments revealing the usefulness of the CC-HTS in such studies. We specifically focus on the effects of agents that directly or indirectly affect the activity of the motor proteins involved in the production of cardiomyocyte contraction. A variety of myocardial preparations with differing levels of complexity are in use (e.g., isolated muscle bundles, thin slices, perfused dual innervated isolated heart, and perfused ventricular wedge). All suffer from low throughput but can be regarded as providing independent data points in contrast to the clustering problems associated with isolated cell studies. The greater productivity and sampling power provided by CC-HTS may help to reestablish the utility of isolated cell studies, while preserving the unique insights provided by studying the contribution of the fundamental, cellular unit of myocardial contractility.

Cardiomyocyte β3-adrenoceptors (β3-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3’,5’-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of β3-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β3-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase two dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the β3-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.

Abstract Background Autologous chondrocyte implantation (ACI) has a failure rate of approximately 20%, but it is yet to be fully understood why. Biomarkers are needed that can pre-operatively predict in which patients it is likely to fail, so that alternative or individualised therapies can be offered. We previously used label-free quantitation (LF) with a dynamic range compression proteomic approach to assess the synovial fluid (SF) of ACI responders and non-responders. However, we were able to identify only a few differentially abundant proteins at baseline. In the present study, we built upon these previous findings by assessing higher-abundance proteins within this SF, providing a more global proteomic analysis on the basis of which more of the biology underlying ACI success or failure can be understood. Methods Isobaric tagging for relative and absolute quantitation (iTRAQ) proteomic analysis was used to assess SF from ACI responders (mean Lysholm improvement of 33; n = 14) and non-responders (mean Lysholm decrease of 14; n = 13) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Differentially abundant proteins in iTRAQ and combined iTRAQ and LF datasets were investigated using pathway and network analyses. Results iTRAQ proteomic analysis confirmed our previous finding that there is a marked proteomic shift in response to cartilage harvest (70 and 54 proteins demonstrating ≥ 2.0-fold change and p

Abstract: Classical Hodgkin lymphoma (cHL) is characterized by nearly universal genetic alterations in 9p24.1, resulting in constitutive expression of PD-1 ligands. This likely underlies the unique sensitivity of cHL to PD-1 blockade, with response rates of ∼70% in relapsed/refractory disease. There are now numerous clinical trials testing PD-1 inhibitors in earlier stages of treatment and in combination with many other therapies. In general, non-Hodgkin lymphomas (NHLs) do not display a high frequency of 9p24.1 alterations and do not share cHL's vulnerability to PD-1 blockade. However, a few entities have genetic or immunologic features that may predict sensitivity to immune checkpoint blockade. These include primary mediastinal B cell lymphoma, primary central nervous system lymphoma, and primary testicular lymphoma, which harbor frequent alterations in 9p24.1, as well as Epstein Barr virus (EBV)–infected lymphomas, where EBV infection leads to increased PD-L1 expression. Although these subtypes may be specifically vulnerable to PD-1 blockade, the majority of NHLs appear to be minimally sensitive to PD-1 blockade monotherapy. Current investigations in NHL are therefore focusing on targeting other checkpoints or studying PD-1–based combination therapy. Looking forward, additional insight into the most common mechanisms of resistance to immune checkpoint inhibitors will be important to guide rational clinical trial design. In this review, we describe the biological basis for checkpoint blockade in cHL and NHL and summarize the clinical data generated to date. Guided by our rapidly evolving understanding of the pathobiology of various lymphoma subtypes, we are hopeful that the role of checkpoint inhibitors in lymphoma treatment will continue to grow.

Abstract Background Epidemiology has contributed in many ways to identifying various risk factors for disease and to promoting population health. However, there is a continuing debate about the ability of epidemiology not only to describe, but also to provide results which can be better translated into public health practice. It has been proposed that participatory research approaches be applied to epidemiology as a way to bridge this gap between description and action. A systematic account of what constitutes participatory epidemiology practice has, however, been lacking. Methods A scoping review was carried out focused on the question of what constitutes participatory approaches to epidemiology for the purpose of demonstrating their potential for advancing epidemiologic research. Relevant databases were searched, including both the published and non-published (grey) literature. The 102 identified sources were analyzed in terms of comparing common epidemiologic approaches to participatory counterparts regarding central aspects of the research process. Exemplary studies applying participatory approaches were examined more closely. Results A highly diverse, interdisciplinary body of literature was synthesized, resulting in a framework comprised of seven aspects of the research process: research goal, research question, population, context, data synthesis, research management, and dissemination of findings. The framework specifies how participatory approaches not only differ from, but also how they can enhance common approaches in epidemiology. Finally, recommendations for the further development of participatory approaches are given. These include: enhancing data collection, data analysis, and data validation; advancing capacity building for research at the local level; and developing data synthesis. Conclusion The proposed framework provides a basis for systematically developing the emergent science of participatory epidemiology.

Background Blood pressure (BP) varies over time within individual patients and across different BP measurement techniques. The effect of different BP targets on concordance between BP measurements is unknown. The goals of this analysis are to evaluate concordance between (1) clinic and ambulatory BP, (2) clinic visit‐to‐visit variability and ambulatory BP variability, and (3) first and second ambulatory BP and to evaluate whether different clinic targets affect these relationships. Methods and Results The SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP monitoring ancillary study obtained ambulatory BP readings in 897 participants at the 27‐month follow‐up visit and obtained a second reading in 203 participants 293±84 days afterward. There was considerable lack of agreement between clinic and daytime ambulatory systolic BP with wide limits of agreement in Bland‐Altman plots of −21 to 34 mm Hg in the intensive‐treatment group and −26 to 32 mm Hg in the standard‐treatment group. Overall, there was poor agreement between clinic visit‐to‐visit variability and ambulatory BP variability with correlation coefficients for systolic and diastolic BP all

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infection, responsible for millions of infections each year. Despite this high prevalence, the elucidation of the molecular mechanisms of Chlamydia pathogenesis has been difficult due to limitations in genetic tools and its intracellular developmental cycle. Within a host epithelial cell, chlamydiae replicate within a vacuole called the inclusion. Many Chlamydia-host interactions are thought to be mediated by the Inc family of type III secreted proteins that are anchored in the inclusion membrane, but their array of host targets are largely unknown. To investigate how the inclusion membrane proteome changes over the course of an infected cell, we have adapted the APEX2 system of proximity-dependent biotinylation. APEX2 is capable of specifically labeling proteins within a 20 nm radius in living cells. We transformed C. trachomatis to express the enzyme APEX2 fused to known inclusion membrane proteins, allowing biotinylation and purification of inclusion-associated proteins. Using quantitative mass spectrometry against APEX2 labeled samples, we identified over 400 proteins associated with the inclusion membrane at early, middle, and late stages of epithelial cell infection. This system was sensitive enough to detect inclusion interacting proteins early in the developmental cycle, at 8 hours post infection, a previously intractable time point. Mass spectrometry analysis revealed a novel, early association between C. trachomatis inclusions and endoplasmic reticulum exit sites (ERES), functional regions of the ER where COPII-coated vesicles originate. Pharmacological and genetic disruption of ERES function severely restricted early chlamydial growth and the development of infectious progeny. APEX2 is therefore a powerful in situ approach for identifying critical protein interactions on the membranes of pathogen-containing vacuoles. Furthermore, the data derived from proteomic mapping of Chlamydia inclusions has illuminated an important functional role for ERES in promoting chlamydial developmental growth.

BackgroundThe clinical implications of ankle‐brachial index (ABI) cutpoints are not well defined in patients with chronic kidney disease (CKD) despite increased prevalence of high ABI attributed to arterial stiffness. We examined the relationship of ABI with cardiovascular disease (CVD) and all‐cause mortality among CKD patients. Methods and ResultsThree thousand six hundred twenty‐seven participants without clinical peripheral artery disease (PAD) at baseline from the Chronic Renal Insufficiency Cohort Study were included. ABI was obtained per standard protocol and CVD events were confirmed by medical record adjudication. A U‐shaped association of ABI with PAD, myocardial infarction (MI), composite CVD, and all‐cause mortality was observed. Individuals with an ABI between 1.0 and

Autologous chondrocyte implantation (ACI) is a cell-based therapy that has been used clinically for over 20 years to treat cartilage injuries more efficiently in order to negate or delay the need for joint replacement surgery. In this time, very little has changed in the ACI procedure, but now many centres are considering or using alternative cell sources for cartilage repair, in particular mesenchymal stem cells (MSCs). In this study, we have tested the chondrogenic potential of donor-matched MSCs derived from bone marrow (BM), infrapatellar fat pad (FP), and subcutaneous fat (SCF), compared to chondrocytes. We have confirmed that there is a chondrogenic potency hierarchy ranging across these cell types, with the most potent being chondrocytes, followed by FP-MSCs, BM-MSCs, and lastly SCF-MSCs. We have also examined gene expression and surface marker profiles in a predictive model to identify cells with enhanced chondrogenic potential. In doing so, we have shown that Sox-9, Alk-1, and Coll X expressions, as well as immunopositivity for CD49c and CD39, have predictive value for all of the cell types tested in indicating chondrogenic potency. The findings from this study have significant clinical implications for the refinement and development of novel cell-based cartilage repair strategies.

Torrefaction tests on miscanthus and white oak sawdust were conducted in a bubbling sand bed reactor to see the effect of temperature and residence time on the chemical composition. Process conditions for miscanthus and white oak sawdust were 250–350 °C for 30–120 min and 220–270 °C for 30 min, respectively. Torrefaction of miscanthus at 250 °C and a residence time of 30 min resulted in a significant decrease in moisture—about 82.68%—but the other components—hydrogen, nitrogen, sulfur, and volatiles—changed only marginally. Increasing torrefaction temperatures to 350 °C with a residence time of 120 min further reduced the moisture content to 0.54%, with a significant decrease in the hydrogen, nitrogen, and volatiles by 58.29%, 14.28%, and 70.45%, respectively. Regression equations developed for the moisture, hydrogen, nitrogen, and volatile content of the samples with respect to torrefaction temperature and time have adequately described the changes in chemical composition based on R2 values of >0.82. Surface plots based on the regression equation indicate that torrefaction temperatures of 280–350 °C with residence times of 30–120 min can help reduce moisture, nitrogen, and volatile content from 1.13% to 0.6%, 0.27% to 0.23%, and 79% to 23%, with respect to initial values. Trends of chemical compositional changes in white oak sawdust are similar to miscanthus. Torrefaction temperatures of 270 °C and a 30 min residence time reduced the moisture, volatiles, hydrogen, and nitrogen content by about 79%, 17.88%, 20%, and 5.88%, respectively, whereas the carbon content increased by about 3.5%.

Signal transduction via G-protein coupled receptors (GPCRs) relies upon the production of cAMP and other signaling cascades. A given receptor and agonist pair, produce multiple effects upon cellular physiology which can be opposite in different cell types. The production of variable cellular effects via the signaling of the same GPCR in different cell types is a result of signal organization in space and time (compartmentation). This organization is usually based upon the physical and chemical properties of the membranes in which the GPCRs reside and the repertoire of downstream effectors and co-factors that are available at that location. In this review we explore mechanisms of GPCR signal compartmentation and broadly review the state-of-the-art methodologies which can be utilized to study them. We provide a clear rationale for a ‘localized’ approach to the study of the pharmacology and physiology of GPCRs and particularly the secondary messenger cAMP.

We recently demonstrated that human C-reactive protein (CRP), expressed hepatically in transgenic mice (CRPtg), improved the outcome of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). The liver is the primary site of CRP synthesis in humans and in CRPtg mice but is also expressed by both at low levels in the CNS. To determine if CNS expression of human CRP is sufficient to impact EAE, we generated neuronal CRP transgenic mice (nCRPtg) wherein human CRP expression is driven by the neuron-specific Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) gene promoter. We found that hepatically expressed/blood-borne CRP, but not CNS expressed CRP, lessened EAE severity. These outcomes indicate that the protective actions of human CRP in EAE are manifested in the periphery and not in the CNS and reveal a previously unappreciated site specificity for the beneficial actions of CRP in CNS disease.

Protein redox chemistry constitutes a major void in knowledge pertaining to photoautotrophic system regulation and signaling processes. We have employed a chemical biology approach to analyze redox sensitive proteins in live Synechococcus sp. PCC 7002 cells in both light and dark periods, and to understand how cellular redox balance is disrupted during nutrient perturbation. The present work identified 300 putative redox-sensitive proteins that are involved in the generation of reductant, macromolecule synthesis, and carbon flux through central metabolic pathways, and may be involved in cell signaling and response mechanisms. Furthermore, our research suggests that dynamic redox changes in response to specific nutrient limitations, including carbon and nitrogen limitations, contribute to the regulatory changes driven by a shift from light to dark. Taken together, these results contribute to a high-level understanding of post-translational mechanisms regulating flux distributions and suggest potential metabolic engineering targets for redirecting carbon towards biofuel precursors.