The bacterial Type III toxin-antitoxin system, ToxIN, is a dynamic protein-RNA complex with stability-dependent antiviral abortive infection activity.

Bacteria have evolved numerous defense systems to protect themselves from viral (bacteriophage) infection. The ToxIN system of Pectobacterium atrosepticum is a Type III toxin-antitoxin complex and "altruistic suicide" anti-phage system, which kills phage-infected cells through the release of a ribonuclease toxin, ToxN. ToxN is counteracted by a co-transcribed antitoxic RNA pseudoknot, ToxI, which self-assembles with ToxN into an inactive 3 ToxI:3 ToxN complex in vitro. However it is not known whether this complex is predominant in vivo, or how the complex is disassembled following infection to trigger a lethal, "altruistic" response. In this study, we characterise ToxI turnover and folding, and explore the link between complex stability and anti-phage activity, with a view to understanding events that lead to ToxN-mediated suicide following phage infection. We present evidence that ToxN constantly cleaves fresh ToxI in vivo rather than staying associated with pre-processed antitoxin, and that the ToxI antitoxin can partially fold spontaneously using conserved nucleotides. We also show that reducing the stability of the ToxIN complex can increase the strength of the antiviral response in a phage-dependent manner. Based on this information, we propose a revised model for ToxN inhibition, complex assembly and activation by infecting bacteriophage

Discovery of Two Distant Type Ia Supernovae in the Hubble Deep Field North with the Advanced Camera for Surveys

We present observations of the first two supernovae discovered with the recently installed Advanced Camera for Surveys (ACS) on the Hubble Space Telescope. The supernovae were found in Wide Field Camera images of the Hubble Deep Field North taken with the F775W, F850LP, and G800L optical elements as part of the ACS guaranteed time observation program. Spectra extracted from the ACS G800L grism exposures confirm that the objects are Type Ia supernovae (SNe Ia) at redshifts z=0.47 and z=0.95. Follow-up HST observations have been conducted with ACS in F775W and F850LP and with NICMOS in the near-infrared F110W bandpass, yielding a total of 9 flux measurements in the 3 bandpasses over a period of 50 days in the observed frame. We discuss many of the important issues in doing accurate photometry with the ACS. We analyze the multi-band light curves using two different fitting methods to calibrate the supernovae luminosities and place them on the SNe Ia Hubble diagram. The resulting distances are consistent with the redshift-distance relation of the accelerating universe model, although evolving intergalactic grey dust remains as a less likely possibility. The relative ease with which these SNe Ia were found, confirmed, and monitored demonstrates the potential ACS holds for revolutionizing the field of high-redshift SNe Ia, and therefore of testing the accelerating universe cosmology and constraining the "epoch of deceleration".Comment: 11 pages, 8 embedded figures. Accepted for publication in Ap

Cis–trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel

5-Hydroxytryptamine type 3 (5-HT_3) receptors are members of the Cys-loop receptor superfamily. Neurotransmitter binding in these proteins triggers the opening (gating) of an ion channel by means of an as-yet-uncharacterized conformational change. Here we show that a specific proline (Pro 8*), located at the apex of the loop between the second and third transmembrane helices (M2–M3), can link binding to gating through a cis–trans isomerization of the protein backbone. Using unnatural amino acid mutagenesis, a series of proline analogues with varying preference for the cis conformer was incorporated at the 8* position. Proline analogues that strongly favour the trans conformer produced non-functional channels. Among the functional mutants there was a strong correlation between the intrinsic cis–trans energy gap of the proline analogue and the activation of the channel, suggesting that cis–trans isomerization of this single proline provides the switch that interconverts the open and closed states of the channel. Consistent with this proposal, nuclear magnetic resonance studies on an M2–M3 loop peptide reveal two distinct, structured forms. Our results thus confirm the structure of the M2–M3 loop and the critical role of Pro 8* in the 5-HT_3 receptor. In addition, they suggest that a molecular rearrangement at Pro 8* is the structural mechanism that opens the receptor pore

Galaxy clusters and groups in the ALHAMBRA Survey

We present a catalogue of 348 galaxy clusters and groups with $0.2<z<1.2$ selected in the 2.78 $deg^2$ ALHAMBRA Survey. The high precision of our photometric redshifts, close to $1\%$, and the wide spread of the seven ALHAMBRA pointings ensure that this catalogue has better mass sensitivity and is less affected by cosmic variance than comparable samples. The detection has been carried out with the Bayesian Cluster Finder (BCF), whose performance has been checked in ALHAMBRA-like light-cone mock catalogues. Great care has been taken to ensure that the observable properties of the mocks photometry accurately correspond to those of real catalogues. From our simulations, we expect to detect galaxy clusters and groups with both $70\%$ completeness and purity down to dark matter halo masses of $M_h\sim3\times10^{13}\rm M_{\odot}$ for $z<0.85$. Cluster redshifts are expected to be recovered with $\sim0.6\%$ precision for $z<1$. We also expect to measure cluster masses with $\sigma_{M_h|M^*_{CL}}\sim0.25-0.35\, dex$ precision down to $\sim3\times10^{13}\rm M_{\odot}$, masses which are $50\%$ smaller than those reached by similar work. We have compared these detections with previous optical, spectroscopic and X-rays work, finding an excellent agreement with the rates reported from the simulations. We have also explored the overall properties of these detections such as the presence of a colour-magnitude relation, the evolution of the photometric blue fraction and the clustering of these sources in the different ALHAMBRA fields. Despite the small numbers, we observe tentative evidence that, for a fixed stellar mass, the environment is playing a crucial role at lower redshifts (z$<$0.5).Comment: Accepted for publication in MNRAS. Catalogues and figures available online and under the following link: http://bascaso.net46.net/ALHAMBRA_clusters.htm

JWST's PEARLS: dust attenuation and gravitational lensing in the backlit-galaxy system VV 191

We derive the spatial and wavelength behavior of dust attenuation in the multiple-armed spiral galaxy VV191b using backlighting by the superimposed elliptical system VV191a in a pair with an exceptionally favorable geometry for this measurement. Imaging using JWST and HST spans the wavelength range 0.3-4.5 microns with high angular resolution, tracing the dust in detail from 0.6 to 1.5 microns. Distinct dust lanes continue well beyond the bright spiral arms, and trace a complex web, with a very sharp radial cutoff near 1.7 Petrosian radii. We present attenuation profiles and coverage statistics in each band at radii 14-21 kpc. We derive the attenuation law with wavelength; the data both within and between the dust lanes clearly favor a stronger reddening behavior (R ~ 2.0 between 0.6 and 0.9 microns, approaching unity by 1.5 microns) than found for starbursts and star-forming regions of galaxies. Power-law extinction behavior lambda^(-beta) gives beta=2.1 from 0.6-0.9 microns. R decreases at increasing wavelengths (R~1.1 between 0.9 and 1.5 microns), while beta steepens to 2.5. Mixing regions of different column density flattens the wavelength behavior, so these results suggest a different grain population than in our vicinity. The NIRCam images reveal a lens arc and counterimage from a background galaxy at z~1, spanning 90 degrees azimuthally at 2.8" from the foreground elliptical galaxy nucleus, and an additional weakly-lensed galaxy. The lens model and imaging data give a mass/light ratio 7.6 in solar units within the Einstein radius 2.0 kpc.Comment: Accepted by Astron. J. Analysis redone since submission, using updated JWST calibrations. Dust reddening behavior is steeper with wavelength and lensed galaxy redshift lower than we first derive

Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity

IMPORTANCE: Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES: To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN SETTING AND PARTICIPANTS: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log CONCLUSIONS AND RELEVANCE: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes