Explore the vast range of titles available.

The planktonic synthesis of reduced organophosphorus molecules, such as alkylphosphonates and aminophosphonates, represents one half of a vast global oceanic phosphorus redox cycle. Whilst alkylphosphonates tend to accumulate in recalcitrant dissolved organic matter, aminophosphonates do not. Here, we identify three bacterial 2-aminoethylphosphonate (2AEP) transporters, named AepXVW, AepP and AepSTU, whose synthesis is independent of phosphate concentrations (phosphate-insensitive). AepXVW is found in diverse marine heterotrophs and is ubiquitously distributed in mesopelagic and epipelagic waters. Unlike the archetypal phosphonate binding protein, PhnD, AepX has high affinity and high specificity for 2AEP ( Stappia stellulata AepX K d 23 ± 4 nM; methylphosphonate K d 3.4 ± 0.3 mM). In the global ocean, aepX is heavily transcribed (~100-fold> phnD ) independently of phosphate and nitrogen concentrations. Collectively, our data identifies a mechanism responsible for a major oxidation process in the marine phosphorus redox cycle and suggests 2AEP may be an important source of regenerated phosphate and ammonium, which are required for oceanic primary production. Here the authors show that 2-aminoethylphosphonate (2AEP) mineralisation is widespread in the global ocean, operating independently of exogenous inorganic phosphate concentration. They propose 2AEP may be a major route for the regeneration of phosphate required to support marine primary production.

The serotonin transporter (SERT) plays a pivotal role in regulating serotonin (5-HT) signaling and is a key target in the treatment of psychiatric disorders. SERT has a binding site (S1) for 5-HT that also serves as a high-affinity binding site for antidepressants. The antidepressant vilazodone has been shown to inhibit SERT by binding to an allosteric site. Here, we present the cryo-EM structure of SERT with vilazodone bound to the S1 site and extending towards the allosteric site. We systematically dissect the vilazodone molecule into fragments and find that the terminal indole ring is the key determinant of its high affinity to SERT. Further, unlike typical Na + -dependent SERT-selective antidepressants, vilazodone exhibits a dissociation constant ( K D ) for purified SERT in the nanomolar range both in the presence and absence of Na + . We substantiate this binding mode by exploring the conformational impact of vilazodone binding to SERT using site-specific insertion of the fluorescent non-canonical amino acid Anap. Our results offer molecular insight into the distinct pharmacological profile of a clinically used polymodal antidepressant. The serotonin transporter (SERT) is a key antidepressant target. Here, authors present a cryo-EM structure where the antidepressant vilazodone spans the main SERT binding site toward a secondary pocket and provide further insights into ligand binding.

Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development. Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but establish good ligandability of ATG8 isoforms through fragment screening and docking.

Background A previous meta-analysis reported that: (i) an acute bout of prolonged uninterrupted sitting induces a significant increase in peripheral blood pressure (BP) and (ii) the increase in BP can be offset by interrupting the sitting bout with light aerobic activities such as walking. However, the temporal association between prolonged uninterrupted sitting and BP was not determined. A better understanding of temporality, for example, how long it takes BP to increase, will assist in prescribing sitting interruption strategies. Objectives We aimed to determine: (1) the temporal association between the duration of uninterrupted sitting and BP and (2) whether regular sitting interruptions moderate the association between uninterrupted sitting and BP. Data Sources Electronic databases (PubMed, Web of Science, SPORTDiscus) were searched from inception to July 2022. Reference lists of eligible studies and relevant reviews were also screened. Study Selection Inclusion criteria for objective (1) were: (i) participants aged ≥ 18 years; (ii) a prolonged sitting bout ≥ 1 h; and (iii) peripheral BP measurements (systolic BP, diastolic BP, and/or mean arterial pressure) at more than two timepoints during the sitting bout. Additional criteria for objective (2) were: (i) the sitting interruption strategy was implemented during the sitting bout (i.e., not prior to engaging in sitting) and (ii) the study included a control (uninterrupted sitting) condition or group. Appraisal and Synthesis Methods There were 1555 articles identified, of which 33 met inclusion criteria for objective (1). Of those articles, 20 met inclusion criteria for objective (2). To investigate the effect of sitting duration on the BP response, unstandardized b coefficients (mmHg/h) and 95% confidence intervals (CIs) were calculated using a three-level mixed-effect meta-regression. Results Increased sitting duration was positively associated with systolic BP ( b  = 0.42 mmHg/h, 95% CI 0.18–0.60), diastolic BP ( b  = 0.24 mmHg/h, 95% CI 0.06–0.42), and mean arterial pressure ( b  = 0.66 mmHg/h, 95% CI 0.36–0.90). In trials where sitting was interrupted, there was a significant decrease in systolic BP ( b  = − 0.24 mmHg/h, 95% CI − 0.42 to − 0.06) and diastolic BP ( b  = − 0.24 mmHg/h, 95% CI − 0.42 to − 0.12), and a non-significant change in mean arterial pressure ( p  = 0.69). Conclusions Increased uninterrupted sitting duration results in greater increases in BP; however, regularly interrupting sitting may offset negative effects.

This article seeks to develop new insight from into what it means to be a trinitarian person by diagramming the interchange of cognition and love that Augustine traces in the mental trinity. It begins with some important groundwork by Augustinian scholars that enriches the formula that persons are relations. Then, we review how Augustine used ‘Eastern’ themes of interpenetration and interchange to describe the life of the divine persons, themes later to be termed perichoretic. This leads to consideration of the interesting subject of movement or logical priority in God. Finally, we move into original research by diagramming the mental trinity, that is, tracing the trinitarian movements inherent in the nature of knowing and loving and considering how this might apply to each divine person if God is indeed and . We will consider that Augustine may have conceived of the interchange of the life of the triune persons extending even to the enjoyment of a shared cognition. If this is plausible, then the mental trinity provides much more insight into what it means to be a divine person than is commonly attributed to him – insight which could be productively deployed in contemporary trinitarian theology.

The first deep field images from the James Webb Space Telescope (JWST) of the galaxy cluster SMACS J0723.3-7327 reveal a wealth of new lensed images at uncharted infrared wavelengths, with unprecedented depth and resolution. Here we securely identify 14 new sets of multiply imaged galaxies totaling 42 images, adding to the five sets of bright and multiply imaged galaxies already known from Hubble Space Telescope data. We find examples of arcs crossing critical curves, allowing detailed community follow-up, such as JWST spectroscopy for precise redshift determinations, and measurements of the chemical abundances and of the detailed internal gas dynamics of very distant, young galaxies. One such arc contains a pair of compact knots that are magnified by a factor of hundreds, and features a microlensed transient. We also detect an Einstein cross candidate only visible thanks to JWST’s superb resolution. Our parametric lens model is available through the following link (https://www.dropbox.com/sh/gwup2lvks0jsqe5/AAC2RRSKce0aX-lIFCc9vhBXa?dl=0) and will be regularly updated using additional spectroscopic redshifts. The model is constrained by 16 of these sets of multiply imaged galaxies, three of which have spectroscopic redshifts, and reproduces the multiple images to better than an rms of 0.″5, allowing for accurate magnification estimates of high-redshift galaxies. The intracluster light extends beyond the cluster members, exhibiting large-scale features that suggest a significant past dynamical disturbance. This work represents a first taste of the enhanced power JWST will have for lensing-related science.

Inorganic phosphate is the major bioavailable form of the essential nutrient phosphorus. However, the concentration of phosphate in most natural habitats is low enough to limit microbial growth. Under phosphate-depleted conditions some bacteria utilise phosphite and hypophosphite as alternative sources of phosphorus, but the molecular basis of reduced phosphorus acquisition from the environment is not fully understood. Here, we present crystal structures and ligand binding affinities of periplasmic binding proteins from bacterial phosphite and hypophosphite ATP-binding cassette transporters. We reveal that phosphite and hypophosphite specificity results from a combination of steric selection and the presence of a P-H…π interaction between the ligand and a conserved aromatic residue in the ligand-binding pocket. The characterisation of high affinity and specific transporters has implications for the marine phosphorus redox cycle, and might aid the use of phosphite as an alternative phosphorus source in biotechnological, industrial and agricultural applications. Some bacteria can use inorganic phosphite and hypophosphite as sources of inorganic phosphorus. Here, the authors report crystal structures of the periplasmic proteins that bind these reduced phosphorus species and show that a P-H…π interaction between the ligand and binding site determines their specificity.

We present results on the morphological and structural evolution of a total of 3956 galaxies observed with JWST at 1.5 < z < 6.5 in the JWST CEERS observations that overlap with the CANDELS EGS field. This is the biggest visually classified sample observed with JWST yet, ∼20 times larger than previous studies, and allows us to examine in detail how galaxy structure has changed over this critical epoch. All sources were classified by six individual classifiers using a simple classification scheme aimed at producing disk/spheroid/peculiar classifications, whereby we determine how the relative number of these morphologies has evolved since the Universe’s first billion years. Additionally, we explore structural and quantitative morphology measurements using Morfometryka, and show that galaxies with M * > 109 M ⊙ at z > 3 are not dominated by irregular and peculiar structures, either visually or quantitatively, as previously thought. We find a strong dominance of morphologically selected disk galaxies up to z = 6 in this mass range. We also find that the stellar mass and star formation rate densities are dominated by disk galaxies up to z ∼ 6, demonstrating that most stars in the Universe were likely formed in a disk galaxy. We compare our results to theory to show that the fraction of types we find is predicted by cosmological simulations, and that the Hubble Sequence was already in place as early as one billion years after the Big Bang. Additionally, we make our visual classifications public for the community.

We present an early analysis on the search for high-redshift galaxies using the deepest public JWST imaging to date, the NGDEEP field. These data consist of six-band NIRCam imaging on the Hubble Ultra Deep Field Parallel 2 (HUDF-Par2), covering a total area of 6.3 arcmin2. Based on our initial reduction of the first half of this survey, we reach 5σ depths up to mag = 29.5–29.9 between 1 and 5 μm. Such depths present an unprecedented opportunity to begin exploring the very early universe with JWST. As such, we find high-redshift galaxies by examining the spectral energy distribution of all F444W detections and present 16 new z > 8.5 galaxies identified using two different photometric redshift codes: LePhare and EAZY combined with other significance criteria. The highest-redshift object in our sample is at z=15.6−0.3+0.4 , which has a blue β=−3.02−0.46+0.42 and a very low inferred stellar mass of M * = 107.4 M ⊙. We also discover a series of faint, low-mass dwarf galaxies with M * < 108.5 M ⊙ at z ∼ 9 that have blue colors, flat surface brightness profiles, and small sizes <1 kpc. Comparing to previous work in the HUDF-Par2, we find 21 6 < z < 9 candidates including two z = 8 major mergers. One of these merger candidates has an additional two z = 8 sources within 30″, indicating that it may form part of an overdensity. We also compare our results to theory, finding no significant disagreement with a few cold-dark-matter-based models. The discovery of these objects demonstrates the critical need for deeper, or similar depth but wider-area, JWST surveys to explore the early universe.

The insertion of magnesium into protoporphyrin initiates the biosynthesis of chlorophyll, the pigment that underpins photosynthesis. This reaction, catalysed by the magnesium chelatase complex, couples ATP hydrolysis by a ChlID motor complex to chelation within the ChlH subunit. We probed the structure and catalytic function of ChlH using a combination of X-ray crystallography, computational modelling, mutagenesis and enzymology. Two linked domains of ChlH in an initially open conformation of ChlH bind protoporphyrin IX, and the rearrangement of several loops envelops this substrate, forming an active site cavity. This induced fit brings an essential glutamate (E660), proposed to be the key catalytic residue for magnesium insertion, into proximity with the porphyrin. A buried solvent channel adjacent to E660 connects the exterior bulk solvent to the active site, forming a possible conduit for the delivery of magnesium or abstraction of protons. The insertion of magnesium into protoporphyrin starts the biosynthesis of chlorophyll. X-ray crystallography, computational modelling, mutagenesis and enzymology combined probe the magnesium chelatase complex’s structure and catalytic function.