Search

Accurate motion estimation at high acceleration factors enables rapid motion-compensated reconstruction in Magnetic Resonance Imaging (MRI) without compromising the diagnostic image quality. In this work, we introduce an attention-aware deep learning-based framework that can perform non-rigid pairwise registration for fully sampled and accelerated MRI. We extract local visual representations to build similarity maps between the registered image pairs at multiple resolution levels and additionally leverage long-range contextual information using a transformer-based module to alleviate ambiguities in the presence of artifacts caused by undersampling. We combine local and global dependencies to perform simultaneous coarse and fine motion estimation. The proposed method was evaluated on in-house acquired fully sampled and accelerated data of 101 patients and 62 healthy subjects undergoing cardiac and thoracic MRI. The impact of motion estimation accuracy on the downstream task of motion-compensated reconstruction was analyzed. We demonstrate that our model derives reliable and consistent motion fields across different sampling trajectories (Cartesian and radial) and acceleration factors of up to 16x for cardiac motion and 30x for respiratory motion and achieves superior image quality in motion-compensated reconstruction qualitatively and quantitatively compared to conventional and recent deep learning-based approaches. The code is publicly available at https://github.com/lab-midas/GMARAFT.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors1. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants2–6, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with Ggust(also known as gustducin) and Gi1. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of Ggustand Gi1. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.

In research on authoritarianism in Turkey and beyond, there is a growing interest in Ernst Fraenkel’s concept of the dual state from the Nazi era. However, upon closer inspection, these articles lack a systematic application and implementation of Fraenkel’s concept. Mostly, there is no discussion of the strengths and weaknesses of such a ‘diachronic’ conceptual transfer. This case study therefore puts particular emphasis on the methodological issues and on the possibilities and limitations of an ‘updated’ application. As a result, it turns out that Fraenkel’s categories are useful tools to trace how the Turkish administration and judiciary are reorganized along a logic of prerogative power. Fraenkel’s state-centred approach can thus contribute to close a gap left by alternative approaches. However, among the weaknesses even of Dreier and Meierhenrich’s supplement is that the time dimension was, respectively is, not sufficiently taken into account. Dual state structures can be more sustainable than originally assumed by Fraenkel.

Abstract.Although the vast majority of validation studies rely on correlational validity evidence, there is an increased recognition that validity should also focus on whether variations in the focal psychological attribute lead to variations in the measurement outcomes. Therefore, calls have been made that validity evidence should also be gathered through experiments. Existing experimental validation strategies focus on manipulating psychological attributes and their effects on measurement outcomes. In the current manuscript, we present an additional and complementary approach that focuses on manipulating test elements (instead of psychological attributes) that are considered indispensable for test functioning. Examples from personality, situational judgment, emotional intelligence, and reading comprehension domains are presented to illustrate our approach. The presented approach is integrated into existing validation strategies.

The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2–5. MRGPRX2 couples to both Giand Gqin mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1and Gqin ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

The Fraud Watch piece 'Couple Jailed for Fleecing Medicare' [Your Money] says the couple improperly billed Medicare for millions of dollars, including claims for dead people and prison inmates. Why [...]

The cubane cage system is characteristic and well known for its high strain energy, qualifying it as a promising precursor for energetic materials. 1,4-Disubstituted cubanes are the easiest accessible derivatives. A further developed laboratory-scale procedure for cubane-1,4-dicarboxylic acid dimethyl ester is presented. From this central precursor, the bis-trinitroethyl and bis-nitromethyl esters as well as the bis-methylcarbamate and bis-methylnitrocarbamate were synthesized and characterized by multinuclear NMR spectroscopy and X-ray crystallography. In addition, their physical and energetic properties were determined and studied.

Location data from mobile devices is a sensitive yet valuable commodity for location-based services and advertising. We investigate the intrinsic value of location data in the context of strong privacy, where location information is only available from end users via purchase. We present an algorithm to compute the expected value of location data from a user, without access to the specific coordinates of the location data point. We use decision-theoretic techniques to provide a principled way for a potential buyer to make purchasing decisions about private user location data. We illustrate our approach in three scenarios: the delivery of targeted ads specific to a user's home location, the estimation of traffic speed, and the prediction of location. In all three cases, the methodology leads to quantifiably better purchasing decisions than competing approaches. [ABSTRACT FROM AUTHOR]

Ghrelin is a potential therapy for cachexia due to its orexigenic properties and anabolic effects on muscle and fat. However, its clinical use is limited by the short half‐life of active (acylated) ghrelin (~11 min in humans). EXT418 is a novel long‐acting, constitutively active ghrelin analog created by covalently linking it to a vitamin D derivative. Here, we evaluated the effects and mechanisms of action of EXT418 on Lewis lung carcinoma (LLC)‐induced cachexia in mice. Male C57BL/6J mice (5‐ to 7‐month‐old) were implanted with 1 × 106heat‐killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T + V) or EXT418daily (T + 418 Daily, 0.25 mg/kg/day) or every other day (T + 418 EOD, 0.5 mg/kg/EOD) for up to 14 days, whereas HK‐treated mice were given vehicle (HK + V). Subsets of T + 418 Daily or EOD‐treated mice were pair‐fed to the T + V group. Body composition and grip strength were evaluated before tumour implantation and at the end of the experiment. Molecular markers were probed in muscles upon termination. In tumour‐bearing mice, administration of EXT418daily or EOD partially prevented weight loss (T + V vs. T + 418 Daily, P= 0.030; and vs. T + 418 EOD, P= 0.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour‐bearing mice was improved by EXT418daily (P= 0.010) or EOD (P= 0.008) administration compared with vehicle‐treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. EXT418daily administration also improved type IIA (P= 0.015), IIB (P= 0.037) and IIX (P= 0.050) fibre cross‐sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; P =0.005). In skeletal muscles, tumour‐induced increases in atrogenes Fbxo32and Trim63were ameliorated by EXT418 treatments (TA and GAS/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker Bnip3(GAS/PL; P≤ 0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; P= 0.039). In addition, EXT418 treatments ameliorated the tumour‐induced elevation in muscle Il6transcript levels (TA and GAS/PL), independently of food intake. Il‐6transcript levels in adipose tissue and circulating IL‐10 were elevated in response to the tumour but these increases were not significant with EXT418 administration. Tumour mass was not altered by EXT418. EXT418 mitigates LLC‐induced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake.

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders1. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects2. The initiation of KOR signalling requires the Gi/o-family proteins including the conventional (Gi1, Gi2, Gi3, GoAand GoB) and nonconventional (Gzand Gg) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers—Gi1, GoA, Gzand Gg—using cryo-electron microscopy. The KOR–G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing Gi/o-family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.

IMPORTANCE: Understanding how to translate workplace-based assessment (WBA) ratings into metrics that communicate the ability of a surgeon to perform a procedure would represent a critical advancement in graduate medical education. OBJECTIVE: To evaluate the association between past and future performance in a comprehensive assessment system for the purpose of assessing point-in-time competence among general surgery trainees. DESIGN, SETTING, AND PARTICIPANTS: This case series included WBA ratings from September 2015 to September 2021 from the WBA system of the Society for Improving Medical Professional Learning (SIMPL) for all general surgery residents who were provided a rating following an operative performance across 70 programs in the US. The study included ratings for 2605 trainees from 1884 attending surgeon raters. Analyses were conducted between September 2021 and December 2021 using bayesian generalized linear mixed-effects models and marginal predicted probabilities. EXPOSURES: Longitudinal SIMPL ratings. MAIN OUTCOMES AND MEASURES: Performance expectations for 193 unique general surgery procedures based on an individual trainee’s prior successful ratings for a procedure, clinical year of training, and month of the academic year. RESULTS: Using 63 248 SIMPL ratings, the association between prior and future performance was positive (β, 0.13; 95% credible interval [CrI], 0.12-0.15). The largest source of variation was postgraduate year (α, 3.15; 95% CrI, 1.66-6.03), with rater (α, 1.69; 95% CrI, 1.60-1.78), procedure (α, 1.35; 95% CrI, 1.22-1.51), case complexity (α, 1.30; 95% CrI, 0.42-3.66), and trainee (α, 0.99; 95% CrI, 0.94-1.04) accounting for significant variation in practice ready ratings. After marginalizing overcomplexity and trainee and holding rater constant, mean predicted probabilities had strong overall discrimination (area under the receiver operating characteristic curve, 0.81) and were well calibrated. CONCLUSIONS AND RELEVANCE: In this study, prior performance was associated with future performance. This association, combined with an overall modeling strategy that accounted for various facets of an assessment task, may offer a strategy for quantifying competence as performance expectations.

The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for β-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1.

The human MAS-related G protein–coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1–Gαq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs.

With 1,3,5-trinitrocyclohexane-1,3,5-triyl trimethanol as a precursor, available from 1,3,5-trinitrobenzene, two further nitro-containing molecules were synthesized. Via modification of the hydroxyl groups, new oxygen-rich compounds were obtained, the corresponding trinitrate and trinitrocarbamate. From the latter, various salts were obtained by treatment with bases. All compounds were fully characterized by NMR and IR spectroscopy, X-ray diffraction, and elemental and differential thermal analyses. Moreover, the sensitivity toward friction and impact was determined according to BAM standard techniques and the energetic properties were calculated by using the EXPLO5 computer code.

illus bibliog

tab illus bibliog

The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders, including Parkinson’s Disease (PD) and schizophrenia. Here, we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist, rotigotine, which is used to treat PD and restless legs syndrome. The structures reveal the basis of rotigotine recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system.

The Co-Worker Observation System (CORS) is a tool and a process to address disrespectful behavior through feedback from trained peer messengers. First used by physicians and advanced practice providers (APPs), CORS has been shown to decrease instances of unprofessional behaviors among physicians and APPs. The research team assessed the feasibility and fidelity of implementing CORS for staff nurses.

Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling1–4. The muscarinic receptor-based DREADDs are the most widely used chemogenetic tools in neuroscience research. The Gq-coupled DREADD (hM3Dq) is used to enhance neuronal activity, whereas the Gi/o-coupled DREADD (hM4Di) is utilized to inhibit neuronal activity5. Here we report four DREADD-related cryogenic electron microscopy high-resolution structures: a hM3Dq–miniGqcomplex and a hM4Di–miniGocomplex bound to deschloroclozapine; a hM3Dq–miniGqcomplex bound to clozapine-N-oxide; and a hM3R–miniGqcomplex bound to iperoxo. Complemented with mutagenesis, functional and computational simulation data, our structures reveal key details of the recognition of DREADD chemogenetic actuators and the molecular basis for activation. These findings should accelerate the structure-guided discovery of next-generation chemogenetic tools.

•Faculty plays the largest role in deciding whether to give residents feedback•Examination of over 67,000 resident evaluations from across 70 general surgery programs•Formative feedback can be captured in workplace-based assessments and can be used to understand how feedback is given

In studying electoral reforms, the democratic context is often a neglected variable. Israel and Turkey, at different times with different levels of democracy, have implemented a similar reform, the direct election of the chief executive. While there were similar justifications at the time of the introduction, the reforms then took on different dynamics. In Israel the reform was reversed, while in Turkey it became the centrepiece of further autocratisation. Adapting a framework of policy-analysis, the article explores similarities and differences in both cases. It argues that the democratic environment turns out as an important factor to explain the different trajectories of seemingly similar policy reforms in both cases. While the reverse reform in the Israeli case is linked to advantages in processing expert and civil society information, the trajectory in the Turkish case is based on the different power structure in the course of presidentialisation. Applying a comparative policy analysis to these cases of electoral reform, the article concludes that the democratic environment, that is, the degree of freely available information, helps explaining the different trajectories in both cases.

The study of electoral system reform is often focused on consolidated democracies. This special issue on electoral reforms in the Mediterranean region selects both consolidated democracies and moderate authoritarian systems. It analyses reforms under the aspects of how they deal with the dilemma between improving ‘governability’ by majoritarian instruments versus increasing proportionality of representation. While governability also depends on other factors, public debates are frequently structured along this dichotomy, which also affects the outcome of the reform process. The Mediterranean focus reflects the higher degree of reform activities in this policy area (for instance compared to the Nordic countries), which helps to focus on drivers, scope, direction, and vested interests of electoral reforms.

One solution to reduce CO2emissions and advance climate protection in the heat sector is the utilization of thermochemical energy storages (TCES) based on the material Ca(OH)2to store waste heat or surplus electricity. In contrast to powdered materials, the material in granular form has a lower tendency to be affected by agglomeration effects and provides higher energy density and thermal conductivity. This results in enhanced durability, stability, and efficiency of the storage, making the storage material Ca(OH)2in granular form more suitable for TCES applications. This work investigates the performance of a chemically unmodified granular sample over 15 storage cycles in a test fixed bed reactor and evaluates whether its performance and durability are already sufficient for potential applications without further modification. In addition, different granule samples with different diameters were also cycled to determine whether the selection of certain diameter sizes can improve the stability of the granules. Furthermore, different methods were used in the pre- and post-analyses to assess the stability of the samples. The comparison of three tested granular samples with different diameters reveals that the sample with a diameter of 2–4 mm has the highest durability and reactor performance. Despite a decrease in mechanical strength, this configuration could be suitable for applications with a small number of storage cycles, such as seasonal storages.

Among all the dynamical modular curves associated to quadratic polynomial maps, we determine which curves have infinitely many quadratic points. This yields a classification statement on preperiodic points for quadratic polynomials over quadratic fields, extending previous work of Poonen, Faber, and the authors.