Deep Learning Based Reconstruction of 3D-T1-SPACE Vessel Wall Imaging Provides Improved Image Quality with Reduced Scan Times: A Preliminary Study.

BACKGROUND AND PURPOSE: Intra-cranial vessel wall imaging (IC-VWI) is technically challenging to implement, given the simultaneous requirements of high spatial resolution, excellent blood and CSF signal suppression and clinically acceptable gradient times. Herein, we present our preliminary findings on the evaluation of a deep learning optimized sequence using T1 weighted imaging. MATERIALS AND METHODS: Clinical and optimized Deep learning-based image reconstruction (DLBIR) T1 SPACE sequences were evaluated, comparing non-contrast sequences in ten healthy controls and post-contrast sequences in five consecutive patients. Images were reviewed on a Likert-like scale by four fellowship-trained neuroradiologists. Scores (range 1-4) were separately assigned for eleven vessel segments in terms of vessel wall and lumen delineation. Additionally, images were evaluated in terms of overall background noise, image sharpness and homogenous CSF signal. Segment-wise scores were compared using paired samples t-tests. RESULTS: The scan time for the clinical and DLBIR sequences were 7:26 minutes and 5:23 minutes respectively. DLBIR images showed consistently higher wall signal and lumen visualization scores, with the differences being statistically significant in the majority of vessel segments on both pre and post contrast images. DLBIR images had lower background noise, higher image sharpness and uniform CSF signal. Depiction of intracranial pathologies was better or similar on the DLBIR images. CONCLUSIONS: Our preliminary findings suggest that DLBIR optimized IC-VWI sequences may be helpful in achieving shorter gradient times with improved vessel wall visualization and overall image quality. These improvements may help with wider adoption of ICVWI in clinical practice and should be further validated on a larger cohort. ABBREVIATIONS: DL deep learning; VWI = vessel wall imaging.

Molecular mechanism of trehalose 6-phosphate inhibition of the plant metabolic sensor kinase SnRK1.

SUCROSE-NON-FERMENTING1-RELATED PROTEIN KINASE1 (SnRK1), a central plant metabolic sensor kinase, phosphorylates its target proteins, triggering a global shift from anabolism to catabolism. Molecular modeling revealed that upon binding of KIN10 to GEMINIVIRUS REP-INTERACTING KINASE1 (GRIK1), KIN10's activation T-loop reorients into GRIK1's active site, enabling its phosphorylation and activation. Trehalose 6-phosphate (T6P) is a proxy for cellular sugar status and a potent inhibitor of SnRK1. T6P binds to KIN10, a SnRK1 catalytic subunit, weakening its affinity for GRIK1. Here, we investigate the molecular details of T6P inhibition of KIN10. Molecular dynamics simulations and in vitro phosphorylation assays identified and validated the T6P binding site on KIN10. Under high-sugar conditions, T6P binds to KIN10, blocking the reorientation of its activation loop and preventing its phosphorylation and activation by GRIK1. Under these conditions, SnRK1 maintains only basal activity levels, minimizing phosphorylation of its target proteins, thereby facilitating a general shift from catabolism to anabolism.

Effect of the Relationship between Respiratory Interval and Temporal Resolution on Image Quality in Free-breathing Abdominal MR Imaging.

PURPOSE: To evaluate how the relationship between respiratory interval (RI) and temporal resolution (TR) impacts image quality in free-breathing abdominal MRI (FB-aMRI) using golden-angle radial sparse parallel (GRASP). METHODS: Ten healthy volunteers (25.9 ± 2.5 years, four women) underwent 2 mins free-breathing fat-suppression T1-weighted imaging using GRASP at RIs of 3 and 5s (RI3 and RI5, respectively) and retrospectively reconstructed at TR of 1.8, 2.9, 4.8, and 7.7s (TR1.8, TR2.9, TR4.8, and TR7.7, respectively) in each patient. The standard deviation (SD) under the diaphragm was measured using SD maps showing the discrepancy for each horizontal section at all TRs. Two radiologists evaluated image quality (visualization of the right hepatic vein at the confluence of the inferior vena cava, posterior segment branch of portal vein, pancreas, left kidney, and artifacts) at all TRs using a 5-point scale. RESULTS: The SD was significantly higher at TR1.8 compared to TR4.8 (P < 0.01) and TR7.7 (P < 0.001), as well as at TR2.9 compared to TR7.7 (P < 0.01) for both RIs. The SD between TR4.8 and TR7.7 did not differ for both RIs. For all visual assessment metrics, the TR1.8 scores were significantly lower than the TR4.8 and TR7.7 scores for both RIs. The pancreas and left kidney scores at TR2.9 were significantly lower than those at TR7.7 (P < 0.05) for RI5. Additionally, the left kidney score at TR1.8 was lower than that at TR2.9 (P < 0.05) for RI3. All scores at TR2.9, TR4.8, and TR7.7 were similar for RI3, while those at TR4.8 and TR7.7 were similar for RI5. CONCLUSION: Prolonging the TRs compared to RIs enhances image quality in FB-aMRI using GRASP.

Accelerated free-breathing liver fat and R 2 * quantification using multi-echo stack-of-radial MRI with motion-resolved multidimensional regularized reconstruction: Initial retrospective evaluation.

PURPOSE: To improve image quality, mitigate quantification biases and variations for free-breathing liver proton density fat fraction (PDFF) and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ quantification accelerated by radial k-space undersampling. METHODS: A free-breathing multi-echo stack-of-radial MRI method was developed with compressed sensing with multidimensional regularization. It was validated in motion phantoms with reference acquisitions without motion and in 11 subjects (6 patients with nonalcoholic fatty liver disease) with reference breath-hold Cartesian acquisitions. Images, PDFF, and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps were reconstructed using different radial view k-space sampling factors and reconstruction settings. Results were compared with reference-standard results using Bland-Altman analysis. Using linear mixed-effects model fitting (p < 0.05 considered significant), mean and SD were evaluated for biases and variations of PDFF and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ , respectively, and coefficient of variation on the first echo image was evaluated as a surrogate for image quality. RESULTS: Using the empirically determined optimal sampling factor of 0.25 in the accelerated in vivo protocols, mean differences and limits of agreement for the proposed method were [-0.5; -33.6, 32.7] s-1 for R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and [-1.0%; -5.8%, 3.8%] for PDFF, close to those of a previous self-gating method using fully sampled radial views: [-0.1; -27.1, 27.0] s-1 for R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and [-0.4%; -4.5%, 3.7%] for PDFF. The proposed method had significantly lower coefficient of variation than other methods (p < 0.001). Effective acquisition time of 64 s or 59 s was achieved, compared with 171 s or 153 s for two baseline protocols with different radial views corresponding to sampling factor of 1.0. CONCLUSION: This proposed method may allow accelerated free-breathing liver PDFF and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ mapping with reduced biases and variations.

A practical model of faculty development in medical education: make it accessible, versatile, and easy to use!

Faculty development programs should offer transformative resources and prioritize the needs of the faculty. If faculty face difficulty in accessing such programs, the potential impact of the resources may be limited. To alleviate such issues, we designed a faculty development program that is available to anyone at any time in any configuration. By allowing faculty to choose from a diverse range of medical education topics based on their interests and needs, they may promptly apply crucial concepts in their teaching and education leadership roles. Faculty members can engage in personalized professional development, enhance their teaching practices, and ultimately foster their professional growth. Also, program coordinators and administrators can seamlessly integrate our resources into any existing faculty development program, serving as self-study materials, resources for existing programs, or a stand-alone curriculum with high accessibility, versatility, and ease of use.

Les programmes de développement du corps professoral doivent offrir des ressources transformatrices et donner la priorité aux besoins des enseignants. Si ces derniers ont des difficultés à accéder à ces programmes, l'impact potentiel des ressources peut être limité. Pour y remédier, nous avons conçu un programme de développement du corps professoral accessible à tous, à tout moment et dans n'importe quelle configuration. En permettant aux enseignants de choisir parmi une gamme variée de sujets relatifs à l'enseignement médical en fonction de leurs intérêts et de leurs besoins, ils peuvent rapidement mettre en pratique des concepts cruciaux dans leur rôle d'enseignant et de responsable de l'enseignement. Les membres du corps enseignant peuvent s'engager dans un développement professionnel personnalisé, améliorer leurs pratiques d'enseignement et, en fin de compte, favoriser leur croissance professionnelle. En outre, les coordonnateurs et administrateurs de programmes peuvent aisément intégrer nos ressources dans n'importe quel programme existant de formation du corps enseignant, en tant qu'outil d'auto-apprentissage, de ressources pour les programmes existants, ou de programme autonome avec une grande accessibilité, polyvalence et facilité d'utilisation.

Influence of Peptoid Sequence on the Mechanisms and Kinetics of 2D Assembly.

Two-dimensional (2D) materials have attracted intense interest due to their potential for applications in fields ranging from chemical sensing to catalysis, energy storage, and biomedicine. Recently, peptoids, a class of biomimetic sequence-defined polymers, have been found to self-assemble into 2D crystalline sheets that exhibit unusual properties, such as high chemical stability and the ability to self-repair. The structure of a peptoid is close to that of a peptide except that the side chains are appended to the amide nitrogen rather than the α carbon. In this study, we investigated the effect of peptoid sequence on the mechanism and kinetics of 2D assembly on mica surfaces using in situ AFM and time-resolved X-ray scattering. We explored three distinct peptoid sequences that are amphiphilic in nature with hydrophobic and hydrophilic blocks and are known to self-assemble into 2D sheets. The results show that their assembly on mica starts with deposition of aggregates that spread to establish 2D islands, which then grow by attachment of peptoids, either monomers or unresolvable small oligomers, following well-known laws of crystal step advancement. Extraction of the solubility and kinetic coefficient from the dependence of the growth rate on peptoid concentration reveals striking differences between the sequences. The sequence with the slowest growth rate in bulk and with the highest solubility shows almost no detachment; i.e., once a growth unit attaches to the island edge, there is almost no probability of detaching. Furthermore, a peptoid sequence with a hydrophobic tail conjugated to the final carboxyl residue in the hydrophilic block has enhanced hydrophobic interactions and exhibits rapid assembly both in the bulk and on mica. These assembly outcomes suggest that, while the π-π interactions between adjacent hydrophobic blocks play a major role in peptoid assembly, sequence details, particularly the location of charged groups, as well as interaction with the underlying substrate can significantly alter the thermodynamic stability and assembly kinetics.

Development of a Systematic and Extensible Force Field for Peptoids (STEPs).

Peptoids (N-substituted glycines) are a class of biomimetic polymers that have attracted significant attention due to their accessible synthesis and enzymatic and thermal stability relative to their naturally occurring counterparts (polypeptides). While these polymers provide the promise of more robust functional materials via hierarchical approaches, they present a new challenge for computational structure prediction for material design. The reliability of calculations hinges on the accuracy of interactions represented in the force field used to model peptoids. For proteins, structure prediction based on sequence and de novo design has made dramatic progress in recent years; however, these models are not readily transferable for peptoids. Current efforts to develop and implement peptoid-specific force fields are spread out, leading to replicated efforts and a fragmented collection of parameterized sidechains. Here, we developed a peptoid-specific force field containing 70 different side chains, using GAFF2 as starting point. The new model is validated based on the generation of Ramachandran-like plots from DFT optimization compared against force field reproduced potential energy and free energy surfaces as well as the reproduction of equilibrium cis/trans values for some residues experimentally known to form helical structures. Equilibrium cis/trans distributions (Kct) are estimated for all parameterized residues to identify which residues have an intrinsic propensity for cis or trans states in the monomeric state.

The Southern Ocean mixed layer and its boundary fluxes: fine-scale observational progress and future research priorities.

Interactions between the upper ocean and air-ice-ocean fluxes in the Southern Ocean play a critical role in global climate by impacting the overturning circulation and oceanic heat and carbon uptake. Remote and challenging conditions have led to sparse observational coverage, while ongoing field programmes often fail to collect sufficient information in the right place or at the time-space scales required to constrain the variability occurring in the coupled ocean-atmosphere system. Only within the last 10 years have we been able to directly observe and assess the role of the fine-scale ocean and rapidly evolving atmospheric marine boundary layer on the upper limb of the Southern Ocean's overturning circulation. This review summarizes advances in mechanistic understanding, arising in part from observational programmes using autonomous platforms, of the fine-scale processes (1-100 km, hours-seasons) influencing the Southern Ocean mixed layer and its variability. We also review progress in observing the ocean interior connections and the coupled interactions between the ocean, atmosphere and cryosphere that moderate air-sea fluxes of heat and carbon. Most examples provided are for the ice-free Southern Ocean, while major challenges remain for observing the ice-covered ocean. We attempt to elucidate contemporary research gaps and ongoing/future efforts needed to address them. This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.

Optimal Temporal Resolution to Achieve Good Image Quality and Perform Pharmacokinetic Analysis in Free-breathing Dynamic Contrast-enhanced MR Imaging of the Pancreas.

PURPOSE: The optimal temporal resolution for free-breathing dynamic contrast-enhanced MRI (FBDCE-MRI) of the pancreas has not been determined. This study aimed to evaluate the appropriate temporal resolution to achieve good image quality and to perform pharmacokinetic analysis in FBDCE-MRI of the pancreas using golden-angle radial sparse parallel (GRASP). METHODS: Sixteen participants (53 ± 15 years, eight females) undergoing FBDCE-MRI were included in this prospective study. Images were retrospectively reconstructed at four temporal resolutions (1.8, 3.0, 4.8, and 7.8s). Two radiologists (5 years of experience) evaluated the image quality of each reconstructed image by assessing the visualization of the celiac artery (CEA), the common hepatic artery, the splenic artery, each area of the pancreas, and artifacts using a 5-point scale. Using Tissue-4D, pharmacokinetic parameters were calculated for each area in the reconstructed images at each temporal resolution for 16 examinations, excluding two with errors in the pharmacokinetic modeling analysis. Friedman and Bonferroni tests were used for analysis. A P value < 0.05 was considered statistically significant. RESULTS: During vascular assessment, only scores for the CEA at 7.8s were significantly lower than the other temporal resolutions. Scores of all pancreatic regions and artifacts were significantly lower at 1.8s than at 4.8s and 7.8s. In the pharmacokinetic analysis, all volume transfer coefficients (Ktrans), rate constants (Kep), and the initial area under the concentration curve (iAUC) in the pancreatic head and tail were significantly lower at 4.8s and 7.8s than at 1.8s. iAUC in the pancreatic body and extracellular extravascular volume fraction (Ve) in the pancreatic head were significantly lower at 7.8s than at 1.8s. CONCLUSION: A temporal resolution of 3.0s is appropriate to achieve image quality and perform pharmacokinetic analysis in FBDCE-MRI of the pancreas using GRASP.

Analysis of the nutritional composition and organization of school meals in the province of Kadiogo in Burkina Faso: challenges and prospects.

Background: In the face of food shortages and precariousness, school meals are an effective means of encouraging pupils to attend and stay in school, and of combating nutritional deficiencies. Unfortunately, there are bottlenecks to be identified and resolved. Objective: Analyzing the composition of meals served to school-age children in primary schools in the province of Kadiogo, while assessing the opinion of school staff on these meals (Burkina Faso). Methods: A descriptive cross-sectional survey about school meals was carried out during the period from April to May 2019 among school stakeholders in primary schools in five (05) municipalities of the province of Kadiogo. Results: Insufficient quantity and quality of rations served were recorded in primary schools. The endogenous initiative canteens represented 46.4% of the registered canteens. The promotion of Health-Hygiene-Nutrition (H-H-N) activities in schools encountered difficulties in covering the sanitary needs of school-aged children because unavailability of socio-sanitary infrastructures. School meals consisted of starchy foods and legumes in rural schools and more diversified meals consisting of fruits and vegetables as well as meat and fish in urban schools. In rural municipalities, school meals were insufficient in quantity and quality, while in the urban municipality, macronutrient intakes were in excess with micronutrient intakes largely deficient. Conclusion: Despite the shortcomings, school officials specified that school meals cover lunch rations, increase school enrolment, and improve school-aged children' learning capacity.

Current use and future potential of (physiologically based) pharmacokinetic modelling of radiopharmaceuticals: a review.

Rationale: Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PK) modelling approaches are widely accepted in non-radiopharmaceutical drug development and research, while there is no major role for these approaches in radiopharmaceutical development yet. In this review, a literature search was performed to specify different research purposes and questions that have previously been answered using both PBPK and population PK modelling for radiopharmaceuticals. Methods: The literature search was performed using the databases PubMed and Embase. Wide search terms included radiopharmaceutical, tracer, radioactivity, physiologically based pharmacokinetic model, PBPK, population pharmacokinetic model and nonlinear mixed-effects model. Results: Eight articles and twenty articles were included for this review based on this literature search for population PK modelling and PBPK modelling, respectively. Included population PK analyses showed to have an added value to develop predictive models for a population and to describe individual variability sources. Main purposes of PBPK models appeared related to optimizing treatment (planning), or more specifically: to find the optimal combination of peptide amount and radioactivity, to optimize treatment planning by reducing the number of measurements, to individualize treatment, to get insights in differences between pre-therapeutic and therapeutic scans or to understand inter-patient differences. Other main research subjects were regarding radiopharmaceutical comparisons, selecting ligands based on their peptide characteristics and gaining a better understanding of drug-drug interactions. Conclusions: The use of PK modelling approaches in radiopharmaceutical research remains scarce, but can be expanded to obtain a better understanding of PK and whole-body distribution of radiopharmaceuticals in general. PK modelling of radiopharmaceuticals has great potential for the nearby future and could contribute to the evolving research of radiopharmaceuticals.

Alostasis y carga alostática de las enfermedades

Introducción: La homeostasis es la propiedad fundamental de los sistemas biológicos de preservar el medio interno. La presión arterial, el pH, las concentraciones plasmáticas de sodio y glucosa son ejemplos de variables homeostáticos, donde el propósito de la regulación fisiológica es fijar cada parámetro interno en un punto de ajuste, detecta errores y los corrige con realimentación negativa. Los fisiólogos han evidenciado que muchos errores no son constantes sino adaptativos. Objetivo: Exponer los conceptos novedosos acerca de la influencia de un ambiente de estrés sobre nuestra fisiología y sus efectos deletéreos a largo plazo. Métodos: Se realizó una revisión bibliográfica, en el motor de búsqueda Google académico, los descriptores: homeostasis, alostasis y carga alostática. Conclusiones: Se expuso los conceptos novedosos acerca de la influencia de un ambiente de estrés sobre nuestra fisiología y sus efectos deletéreos a largo plazo. La alostasis es el precio que el cuerpo paga por verse obligado a adaptarse a situaciones psicosociales o físicas adversas. La obesidad, la diabetes, la insulinoresistencia, la hipertensión arterial, son variables alostáticas, no homeostáticas, no son parámetros constantes, sino adaptativos, el organismo cambiará su medio interno para enfrentar el desafío o perturbación que le llega desde el exterior. Pensar en muchas de estas patologías bajo un modelo alostático puede enriquecer los recursos conceptuales del médico y modificar el abordaje de enfermedades prevalentes.

Introduction: Homeostasis is the fundamental property of biological systems to preserve the internal environment. Blood pressure, pH, plasma sodium and glucose concentrations are examples of homeostatic variables, where the purpose of physiological regulation is to fix each internal parameter at a set point, detect errors and correct them with negative feedback. Physiologists have shown that many errors are not constant but adaptive. Objective: To expose novel concepts about the influence of a stressful environment on our physiology and its deleterious long-term effects. Methods: A literature review was performed, in the academic Google search engine, the descriptors: homeostasis, allostasis and allostatic load. Conclusions: Novel concepts about the influence of a stressful environment on our physiology and its deleterious long-term effects were exposed. Allostasis is the price the body pays for being forced to adapt to adverse psychosocial or physical situations. Obesity, diabetes, insulin resistance, arterial hypertension, are allostatic variables, not homeostatic, they are not constant parameters, but adaptive, the organism will change its internal environment to face the challenge or perturbation that comes from the outside. Thinking about many of these pathologies under an allostatic model can enrich the conceptual resources of the physician and modify the approach to prevalent diseases.

Surgical margins after partial nephrectomy as prognostic factor for the risk of local recurrence in pT1 RCC: a systematic review and narrative synthesis.

PURPOSE: To systematically review the published literature on surgical margins as a risk factor for local recurrence (LR) in patients undergoing partial nephrectomy (PN) for pT1 renal cell carcinomas (RCC). EVIDENCE ACQUISITION: A systematic literature search of relevant databases (MEDLINE, Embase and the Cochrane Library) was performed according to the PRISMA criteria up to February 2022. The hypothesis was developed using the PPO method (Patients = patients with pT1 RCC undergoing PN, Prognostic factor = positive surgical margins (PSM) detected on final pathology versus negative surgical margins (NSM) and Outcome = LR diagnosed on follow-up imaging). The primary outcome was the rate of PSM and LR. The risk of bias was assessed by the QUIPS tool. EVIDENCE SYNTHESIS: After assessing 1525 abstracts and 409 full-text articles, eight studies met the inclusion criteria. The percentage of PSM ranged between 0 and 34.3%. In these patients with PSM, LR varied between 0 and 9.1%, whereas only 0-1.5% of LR were found in the NSM-group. The calculated odds ratio (95% confident intervals) varied between 0.04 [0.00-0.79] and 0.27 [0.01-4.76] and was statistically significant in two studies (0.14 [0.02-0.80] and 0.04 [0.00-0.79]). The quality analysis of the included studies resulted in an overall intermediate to high risk of bias and the level of evidence was overall very low. A meta-analysis was considered unsuitable due to the high heterogeneity between the included studies. CONCLUSION: PSM after PN in patients with pT1 RCC is associated with a higher risk of LR. However, the evidence has significant limitations and caution should be taken with the interpretation of this data.

Angiopoietin-2/-1 ratios and MMP-3 levels as an early warning sign for the presence of giant cell arteritis in patients with polymyalgia rheumatica.

BACKGROUND: Diagnosing patients with giant cell arteritis (GCA) remains difficult. Due to its non-specific symptoms, it is challenging to identify GCA in patients presenting with symptoms of polymyalgia rheumatica (PMR), which is a more common disease. Also, commonly used acute-phase markers CRP and ESR fail to discriminate GCA patients from PMR and (infectious) mimicry patients. Therefore, we investigated biomarkers reflecting vessel wall inflammation for their utility in the accurate diagnosis of GCA in two international cohorts. METHODS: Treatment-naïve GCA patients participated in the Aarhus AGP cohort (N = 52) and the Groningen GPS cohort (N = 48). The AGP and GPS biomarker levels and symptoms were compared to patients presenting phenotypically as isolated PMR, infectious mimicry controls and healthy controls (HCs). Serum/plasma levels of 12 biomarkers were measured by ELISA or Luminex. RESULTS: In both the AGP and the GPS cohort, we found that weight loss, elevated erythrocyte sedimentation rate (ESR) and higher angiopoietin-2/-1 ratios but lower matrix metalloproteinase (MMP)-3 levels identify concomitant GCA in PMR patients. In addition, we confirmed that elevated platelet counts are characteristic of GCA but not of GCA mimicry controls and that low MMP-3 and proteinase 3 (PR3) levels may help to discriminate GCA from infections. CONCLUSION: This study, performed in two independent international cohorts, consistently shows the potential of angiopoietin-2/-1 ratios and MMP-3 levels to identify GCA in patients presenting with PMR. These biomarkers may be used to select which PMR patients require further diagnostic workup. Platelet counts may be used to discriminate GCA from GCA look-alike patients.

Linear Weak Scalability of Density Functional Theory Calculations without Imposing Electron Localization.

Linear scaling density functional theory (DFT) approaches to the electronic structure of materials are often based on the tendency of electrons to localize in large atomic and molecular systems. However, in many cases of actual interest, such as semiconductor nanocrystals, system sizes can reach a substantial extension before significant electron localization sets in, causing a considerable deviation from linear scaling. Herein, we address this class of systems by developing a massively parallel DFT approach which does not rely on electron localization and is formally quadratic scaling yet enables highly efficient linear wall-time complexity in the weak scalability regime. The method extends from the stochastic DFT approach described in Fabian et al. ( WIRES: Comp. Mol. Sci. 2019, e1412) but is entirely deterministic. It uses standard quantum chemical atom-centered Gaussian basis sets to represent the electronic wave functions combined with Cartesian real-space grids for some operators and enables a fast solver for the Poisson equation. Our main conclusion is that when a processor-abundant high-performance computing (HPC) infrastructure is available, this type of approach has the potential to allow the study of large systems in regimes where quantum confinement or electron delocalization prevents linear scaling.

Effect of Pulsed Low-Intensity Ultrasonography on Symptom Relief and Tibiofemoral Articular Cartilage Thickness Among Veterans Affairs Enrollees With Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Osteoarthritis (OA) is a major cause of disability in the US, with no approved treatments to slow progression, but animal models suggest that pulsed low-intensity ultrasonography (PLIUS) may promote cartilage growth. Objective: To evaluate the efficacy of PLIUS in providing symptom reduction and decreased loss of tibiofemoral cartilage thickness in patients with knee OA. Design, Setting, and Participants: A phase 2A, sham-controlled, parallel, double-blind randomized clinical trial was conducted at 2 Veterans Affairs hospitals in Salt Lake City, Utah, and San Diego, California, from May 22, 2015, to January 31, 2019. Data were analyzed from June 27, 2020, to October 20, 2020. Participants recruited through the US Department of Veterans Affairs (N = 132) with clinical and radiographic evidence of early knee OA were randomly assigned to receive PLIUS or a sham device, self-administered for 20 minutes daily over the medial compartment of the knee. All enrollees participated in a 4-week prerandomization sham run-in period, followed by a 48-week treatment period. Randomization was stratified by study site and Kellgren-Lawrence grades 1 (n = 15), 2 (n = 51), and 3 (n = 66). Intervention: Participants either received 48 weeks of PLIUS or sham ultrasonography. Main Outcomes and Measures: The trial incorporated 2 coprimary outcomes: symptomatic improvement assessed by Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International Responder Criteria (ie, met if either >50% improvement in pain and function with at least a 20% absolute improvement of at least 2 of the following 3 factors: improvement by at least 20% [pain, function, and patient global assessment] with at least a 10-mm absolute improvement), and cartilage preservation assessed as change in central medial femoral condyle cartilage thickness by magnetic resonance imaging. Intention-to-treat analysis was used. Results: The mean (SD) participant age was 63.6 (10.7) years and 119 were men (90.2%). The mean (SD) duration of OA symptoms was 13.4 (12.3) years. In the PLIUS group, 70.4% (95% CI, 58.2%-82.6%) of the participants experienced symptomatic improvement, compared with 67.3% (95% CI, 54.9%-79.7%) of participants in the sham group (P = .84); there was no statistically significant difference in response rates between the treatment groups, and the between-group rate difference of 3.1% (95% CI, -14.3% to 20.5%) did not meet the predefined 10% threshold for clinically significant symptomatic improvement from application of PLIUS. At 48 weeks of treatment, central medial femoral condyle cartilage thickness decreased by a mean (SD) of 73.8 (168.1) µm in the PLIUS group and by 42.2 (297.0) µm in the sham group. This 48-week mean change between the 2 groups did not reach statistical significance (P = .44), and the between-group 48-week difference of -31.7 µm (95% CI, -129.0 µm to 65.7 µm) did not meet the predefined threshold. There were 99 nonserious adverse events in the PLIUS group and 89 in the sham group during the trial. No serious adverse events were deemed related to the study device. Conclusions and Relevance: PLIUS, as implemented in this study, demonstrated neither symptomatic benefit nor a decrease in loss of tibiofemoral cartilage thickness in knee OA. Trial Registration: ClinicalTrials.gov Identifier: NCT02034409.

Storms drive outgassing of CO2 in the subpolar Southern Ocean.

The subpolar Southern Ocean is a critical region where CO2 outgassing influences the global mean air-sea CO2 flux (FCO2). However, the processes controlling the outgassing remain elusive. We show, using a multi-glider dataset combining FCO2 and ocean turbulence, that the air-sea gradient of CO2 (∆pCO2) is modulated by synoptic storm-driven ocean variability (20 µatm, 1-10 days) through two processes. Ekman transport explains 60% of the variability, and entrainment drives strong episodic CO2 outgassing events of 2-4 mol m-2 yr-1. Extrapolation across the subpolar Southern Ocean using a process model shows how ocean fronts spatially modulate synoptic variability in ∆pCO2 (6 µatm2 average) and how spatial variations in stratification influence synoptic entrainment of deeper carbon into the mixed layer (3.5 mol m-2 yr-1 average). These results not only constrain aliased-driven uncertainties in FCO2 but also the effects of synoptic variability on slower seasonal or longer ocean physics-carbon dynamics.

Accelerated k-space shift calibration for free-breathing stack-of-radial MRI quantification of liver fat and R2∗.

PURPOSE: To develop an accelerated k-space shift calibration method for free-breathing 3D stack-of-radial MRI quantification of liver proton-density fat fraction (PDFF) and R2∗ . METHODS: Accelerated k-space shift calibration was developed to partially skip acquisition of k-space shift data in the through-plane direction then interpolate in processing, as well as to reduce the in-plane averages. A multi-echo stack-of-radial sequence with the baseline calibration was evaluated on a phantom versus vendor-provided reference-standard PDFF and R2∗ values at 1.5T, and in 13 healthy subjects and 5 clinical subjects at 3T with respect to reference-standard breath-hold Cartesian acquisitions. PDFF and R2∗ maps were calculated with different calibration acceleration factors offline and compared to reference-standard values using Bland-Altman analysis. Bias and uncertainty were evaluated using normal distribution and Bayesian probability of difference (P < .05 considered significant). RESULTS: Bland-Altman plots of phantom and in vivo data showed that substantial acceleration was highly feasible in both through-plane and in-plane directions. Compared to the baseline calibration without acceleration, Bayesian analysis revealed no significant differences on biases and uncertainties of PDFF and R2∗ measurements with all acceleration methods in this study, except the method with through-plane acceleration equaling slices and averages equaling 20 for PDFF and R2∗ (both P < .001) for the phantom. A six-fold reduction in equivalent calibration acquisition time (time saving ≥25 s and ≥80.7%) was achieved using recommended acceleration factors for the in vivo protocols in this study. CONCLUSION: This proposed method may allow accelerated calibration for free-breathing stack-of-radial MRI PDFF and R2∗ mapping.

Regioselectivity mechanism of the Thunbergia alata Δ6-16:0-acyl carrier protein desaturase.

Plant plastidial acyl-acyl carrier protein (ACP) desaturases are a soluble class of diiron-containing enzymes that are distinct from the diiron-containing integral membrane desaturases found in plants and other organisms. The archetype of this class is the stearoyl-ACP desaturase which converts stearoyl-ACP into oleoyl (18:1Δ9cis)-ACP. Several variants expressing distinct regioselectivity have been described including a Δ6-16:0-ACP desaturase from black-eyed Susan vine (Thunbergia alata). We solved a crystal structure of the T. alata desaturase at 2.05 Å resolution. Using molecular dynamics (MD) simulations, we identified a low-energy complex between 16:0-ACP and the desaturase that would position C6 and C7 of the acyl chain adjacent to the diiron active site. The model complex was used to identify mutant variants that could convert the T. alata Δ6 desaturase to Δ9 regioselectivity. Additional modeling between ACP and the mutant variants confirmed the predicted regioselectivity. To validate the in-silico predictions, we synthesized two variants of the T. alata desaturase and analyzed their reaction products using gas chromatography-coupled mass spectrometry. Assay results confirmed that mutants designed to convert T. alata Δ6 to Δ9 selectivity exhibited the predicted changes. In complementary experiments, variants of the castor desaturase designed to convert Δ9 to Δ6 selectivity lost some of their Δ9 desaturation ability and gained the ability to desaturate at the Δ6 position. The computational workflow for revealing the mechanistic understanding of regioselectivity presented herein lays a foundation for designing acyl-ACP desaturases with novel selectivities to increase the diversity of monoenes available for bioproduct applications.

Protonation of Serine in Gas and Condensed and Microsolvated States in Aqueous Solution.

Identification of molecules and elucidation of their chemical structure are ubiquitous problems in chemistry. Mass spectrometry (MS) can be used due to its sensitivity and versatility. For detection to occur, analytes must be ionized and transferred to the gas phase. Soft ionization processes such as electrospray ionization are popular; however, resulting microsolvated phases can alter the chemistry of analytes and therefore detection and identification. To understand these processes, we use computational methods to probe the ionization propensity of serine in the gas phase, aqueous microsolvated clusters, and aqueous solution. We show that the tautomeric form of serine is altered by the presence of water, as five water molecules can stabilize the zwitterionic tautomer. Inclusion of cosolutes such as ions can stabilize the zwitterion with as few as one or two water molecules present. We demonstrate that ionization propensity, as measured by gas phase bacisity, can increase by over 100 kJ/mol when placed in a small water-serine cluster, showing the sensitivity of the chemistry of microsolvated analytes. Finally, detailed analysis reveals that small droplets (less than seven water molecules) are extremely sensitive to addition of further water molecules. Beyond this limit, structural and electronic properties change little with droplet size.