Quantified Metrics of Gastric Emptying Delay by GLP-1 Agonists: A Systematic Review and Meta-Analysis with Insights for Periprocedural Management.

INTRODUCTION: Divergent recommendations for periprocedural management of GLP-1 receptor agonist (GLP-1 RA) medications rely on limited evidence. We performed a systematic review and meta-analysis to provide quantitative measures of gastric emptying relevant to mechanisms of weight loss and to periprocedural management of GLP-1 RA. We hypothesized that the magnitude of gastric emptying delay would be low and of limited clinical significance to procedural sedation risks. METHODS: A protocolized search identified studies on GLP-1 RA that quantified gastric emptying measures. Pooled estimates using random effects were presented as weighted mean difference with 95% confidence intervals (CI). Univariate meta-regression was performed to assess the influence of GLP-1 RA type, short- vs long-acting mechanism of action, and duration of treatment on gastric emptying. RESULTS: Fifteen studies met inclusion criteria. Five studies (n=247) utilized scintigraphy (GES). Mean T1/2 was 138.4 minutes (CI:74.5-202.3) for GLP-1 RA versus 95.0 minutes (CI:54.9-135.0) for placebo, with pooled mean difference of 36.0 minutes (CI:17.0-55.0, p<0.01, I2=79.4%). Ten studies (n=411) utilized the acetaminophen absorption test (AAT), with no significant delay in gastric emptying measured by Tmax, AUC4hr, and AUC5hr with GLP-1 RA (p>0.05). On meta-regression, type of GLP-1 RA, mechanism of action, and treatment duration did not impact gastric emptying (p>0.05). CONCLUSIONS: While a gastric emptying delay of ∼36 minutes is quantifiable on GLP-1 RA medications, it is of limited magnitude relative to standard periprocedural fasting periods. There were no substantial differences in gastric emptying on modalities reflective of liquid emptying (AAT), particularly at time points relevant to periprocedural care.

Unveiling Hidden Shake-Up Features in the Uranyl M4-Edge Spectrum.

The M4,5-edge high energy resolution X-ray absorption near-edge structure (HR-XANES) spectra of actinyls offer valuable insights into the electronic structure and bonding properties of heavy-element complexes. To conduct a comprehensive spectral analysis, it is essential to employ computational methods that accurately account for relativistic effects and electron correlation. In this work, we utilize variational relativistic multireference configurational interaction methods to compute and analyze the X-ray M4-edge absorption spectrum of uranyl. By employing these advanced computational techniques, we achieve excellent agreement between the calculated spectral features and experimental observations. Moreover, the calculations unveil significant shake-up features, which arise from the intricate interplay between strongly correlated 3d core-electron and ligand excitations. This research provides important theoretical insights into the spectral characteristics of heavy-element complexes. Furthermore, it establishes the foundation for utilizing M4,5-edge spectroscopy as a means to investigate the chemical activities of such complexes. By leveraging this technique, we can gain a deeper understanding of the bonding behavior and reactivity of heavy-element compounds.

Overdestabilization vs Overstabilization in the Theoretical Analysis of f-Orbital Covalency.

The complex nature of the f-orbital electronic structures and their interaction with the chemical environment pose significant computational challenges. Advanced computational techniques that variationally include scalar relativities and spin-orbit coupling directly at the molecular orbital level have been developed to address this complexity. Among these, variational relativistic multiconfigurational multireference methods stand out for their high accuracy and systematic improvement in studies of f-block complexes. Additionally, these advanced methods offer the potential for calibrating low-scaling electronic structure methods such as density functional theory. However, studies on the Cl K-edge X-ray absorption spectra of the [Ce(III)Cl6]3- and [Ce(IV)Cl6]2- complexes show that time-dependent density functional theory with approximate exchange-correlation kernels can lead to inaccuracies, resulting in an overstabilization of 4f orbitals and incorrect assessments of covalency. In contrast, approaches utilizing small active space wave function methods may understate the stability of these orbitals. The results herein demonstrate the need for large active space, multireference, and variational relativistic methods in studying f-block complexes.

Comparison of Variational and Perturbative Spin-Orbit Coupling within Two-Component CASSCF.

The modeling of spin-orbit coupling (SOC) remains a challenge in computational chemistry due to the high computational cost. With the rising popularity of spin-driven processes and f-block metals in chemistry and materials science, it is incumbent on the community to develop accurate multiconfigurational SOC methods that scale to large systems and understand the limits of different treatments of SOC. Herein, we introduce an implementation of perturbative SOC in scalar-relativistic two-component CASSCF (srX2C-CASSCF-SO). Perspectives on the limitations and accuracy of srX2C-CASSCF-SO are presented via benchmark calculations.

Validated Clinical Score to Predict Gastroesophageal Reflux in Patients With Chronic Laryngeal Symptoms: COuGH RefluX.

BACKGROUND & AIMS: Discerning whether laryngeal symptoms result from gastroesophageal reflux is clinically challenging and a reliable tool to stratify patients is needed. We aimed to develop and validate a model to predict the likelihood of gastroesophageal reflux disease (GERD) among patients with chronic laryngeal symptoms. METHODS: This multicenter international study collected data from adults with chronic laryngeal symptoms who underwent objective testing (upper gastrointestinal endoscopy and/or ambulatory reflux monitoring) between March 2018 and May 2023. The training phase identified a model with optimal receiver operating characteristic curves, and ß coefficients informed a weighted model. The validation phase assessed performance characteristics of the weighted model. RESULTS: A total of 856 adults, 304 in the training cohort and 552 in the validation cohort, were included. In the training phase, the optimal predictive model (area under the curve, 0.68; 95% CI, 0.62-0.74), was the Cough, Overweight/obesity, Globus, Hiatal Hernia, Regurgitation, and male seX (COuGH RefluX) score, with a lower threshold of 2.5 and an upper threshold of 5.0 to predict proven GERD. In the validation phase, the COuGH RefluX score had an area under the curve of 0.67 (95% CI, 0.62-0.71), with 79% sensitivity and 81% specificity for proven GERD. CONCLUSIONS: The externally validated COuGH RefluX score is a clinically practical model to predict the likelihood of proven GERD. The score classifies most patients with chronic laryngeal symptoms as low/high likelihood of proven GERD, with only 38% remaining as indeterminate. Thus, the COuGH RefluX score can guide diagnostic strategies and reduce inappropriate proton pump inhibitor use or testing for patients referred for evaluation of chronic laryngeal symptoms.

New insights into the systematics of the afrotropical Amblyomma marmoreum complex (Acari: Ixodidae) and the genome of a novel Rickettsia africae strain using morphological and metagenomic approaches.

The Amblyomma marmoreum complex includes afrotropical species, such as Amblyomma sparsum, a three-host tick that parasitizes reptiles, birds, and mammals, and is a recognized vector of Ehrlichia ruminantium. However, the lack of morphological, genetic and ecological data on A. sparsum has caused considerable confusion in its identification. In this study, we used microscopy and metagenomic approaches to analyze A. sparsum ticks collected from a puff adder snake (Bitis arietans) in southwest Senegal (an endemic rickettsioses area) in order to supplement previous morphological descriptions, provide novel genomic data for the A. marmoreum complex, and describe the genome of a novel spotted fever group Rickettsia strain. Based on stereoscope and scanning electron microscopy (SEM) morphological evaluations, we provide high-quality images and new insights about punctation and enameling in the adult male of A. sparsum to facilitate identification for future studies. The metagenomic approach allowed us assembly the complete mitochondrial genome of A. sparsum, as well as the nearly entire chromosome and complete plasmid sequences of a novel Rickettsia africae strain. Phylogenomic analyses demonstrated a close relationship between A. sparsum and Amblyomma nuttalli for the first time and confirmed the position of A. sparsum within the A. marmoreum complex. Our results provide new insights into the systematics of A. sparsum and A. marmoreum complex, as well as the genetic diversity of R. africae in the Afrotropical region. Future studies should consider the possibility that A. sparsum may be a vector for R. africae.

Allergic phenotype identified on allergen testing is associated with proton pump inhibitor nonresponse in eosinophilic esophagitis.

BACKGROUND AND AIM: Food/environmental allergens have been associated with eosinophilic esophagitis (EoE); however, the correlation between allergy profiles and disease responsiveness to proton pump inhibitor (PPI) therapy remains unclear. We aimed to assess the association between food/environmental allergies identified on allergen testing and histologic response to PPI in patients with treatment-naive EoE. METHODS: Adults with newly diagnosed EoE who underwent formal testing for food/environmental allergies at a tertiary center were included. All patients underwent twice-daily PPI for 8 weeks with subsequent repeat endoscopy and biopsy to assess histologic response. Patients with <15 eosinophils/hpf on post-PPI mucosal biopsies were classified as responders (PPI-r-EoE), while those with ≥15 eosinophils/hpf were nonresponders (PPI-nr-EoE). RESULTS: Sixty-one patients met inclusion criteria (21 PPI-r-EoE vs 40 PPI-nr-EoE). Demographic, clinical, and endoscopic finding variables were similar between groups. Positive food allergen test was more prevalent among PPI-nr-EoE patients (82.5% vs 42.9%, P = 0.003). On multivariable analysis, positive food allergen testing remained an independent predictor for PPI nonresponse (aOR 0.15, CI: 0.04-0.58, P = 0.0006). Positive environmental allergen testing was highly prevalent, with no significant differences between groups (77.5% vs 95.2%, P = 0.14). However, higher number of positive environmental allergens (23.3% [≥5 allergens] vs 73.3% [<5 allergens], P = 0.003) and specific aeroallergens correlated with PPI-nr-EoE. CONCLUSION: Positive food allergy testing and increased environmental allergens predicted lower likelihood of histologic response to PPI in EoE. Our findings support an allergic phenotype of EoE that may less likely respond to PPI therapy. Formal allergen testing may play a role in therapy selection and tailored management in EoE.

Higher obesity class is associated with more severe esophageal symptoms and reflux burden but not altered motor function or contractile reserve.

BACKGROUND: Patients with obesity often report esophageal symptoms, with abnormal reflux and esophageal motility suggested as potential mechanisms. However, prior studies showed varying results, often limited by study design/size and esophageal function/symptom measures utilized. We aimed to examine the relationship between obesity and objective esophageal function testing and patient-reported outcomes, utilizing prospective symptom, manometric and reflux monitoring data with impedance. METHODS: Adults referred for high-resolution impedance-manometry (HRiM) and multichannel intraluminal impedance-pH monitoring (MII-pH) to evaluate esophageal symptoms were enrolled. Validated symptom and health-related quality of life (HR-QOL) instruments were prospectively collected: GERDQ, reflux symptoms index (RSI), dominant symptom intensity (DSI, multiplied 5-point Likert scales for symptom frequency/severity), global symptom severity (GSS, 100-point visual analog scale), and Short Form-12 (SF-12) for HR-QOL. Esophageal function testing measures were compared across body mass index (BMI) categories and correlated with patient-reported outcomes. KEY RESULTS: Seven hundred and fifty four patients were included (Normal:281/Overweight:253/Class I obesity:137/Class II/III obesity:83). Reflux burden measures on MII-pH (acid exposure time, total reflux episodes, bolus exposure time), conclusive pathologic reflux (Lyon), and hiatal hernia were increased in higher obesity classes compared to normal BMI. Class II/III obesity was associated with more normal/hypercontractile swallows, less ineffective swallows, and better bolus transit on HRiM. BMI correlated positively with GERDQ/RSI/DSI/GSS, and negatively with physical component score (SF-12). Esophageal symptom severity and HR-QOL correlated strongly with MII-pH findings, but not HRiM measures. CONCLUSIONS/INFERENCES: Obesity is associated with increased esophageal symptom burden and worse physical HR-QOL, which correlate with higher acid/bolus reflux burden but not altered esophageal motility/transit/contractile reserve.

Dietary counselling plus omega-3 supplementation in the treatment of generalized anxiety disorder: protocol for a randomized wait-list controlled pilot trial (the "EASe-GAD Trial").

BACKGROUND: Anxiety disorders are prevalent and disabling conditions involving excessive worry and tension. Generalized anxiety disorder (GAD), the most common anxiety disorder, affects 5% of individuals from high-income countries and many individuals report that treatment options are not accessible, effective, or tolerable. Clinical evidence suggests that nutrition interventions, based on the Mediterranean diet and supplementation of omega-3 fatty acids, can significantly improve symptoms of depression; however, the effect of nutrition interventions on anxiety symptoms has not been studied in a clinical population. The primary objective of the present study is to assess the feasibility and acceptability of a dietary counselling and omega-3 fatty acid supplementation intervention delivered to adult women with GAD. The secondary objectives include assessing changes in anxiety symptom severity, assessing changes in quality of life, assessing changes in biomarkers, and evaluating the components of the program. METHODS: This study is a randomized, wait-list controlled pilot trial delivering a 12-week, dietary counselling intervention and omega-3 supplementation to 50 adult women with GAD. Participants will complete seven individual counselling sessions which include education, personalized recommendations, mindful eating techniques, motivational interviewing, and goal setting. They will be provided with recipes, instructional videos, and food items. The intervention is designed based on the Social Cognitive Theory and previous research that has been done by the author team to identify dietary constituents with the most evidence to support their use in the treatment of anxiety disorders. Questionnaires and blood work will be completed at baseline, after the waiting period (for those in the waitlist group), and after the intervention. DISCUSSION: Results from this study will lay the foundation for future large-scale studies in this area and may provide preliminary evidence of the role of diet counselling and omega-3 supplementation in the management of GAD. Research on the role of nutrition in psychiatric care has been identified as a priority by a number of international organizations. The present trial directly addresses the call for the research that is most needed to advance the field. TRIAL REGISTRATION: This protocol was registered at ClinicalTrials.gov on October 10, 2022; NCT05573672 . Trial sponsor: The Canadian College of Naturopathic Medicine, 1255 Sheppard Ave E, Toronto, ON M2K 1E2, 416-498-1255. Steering committee: Composed of MA, LL, KC, IvdW, SM, UN, AJ. The committee meets monthly to oversee the trial. Protocol identifier: CCNM_EASe-GADCT_2201v4.

Diagnostic Yield of Ambulatory Reflux Monitoring Systems for Evaluation of Chronic Laryngeal Symptoms.

INTRODUCTION: Among patients with chronic laryngeal symptoms, ambulatory reflux monitoring off acid suppression is recommended to evaluate for laryngopharyngeal reflux (LPR). However, reflux monitoring systems are diverse in configuration and monitoring capabilities, which present a challenge in creating a diagnostic reference standard in these patients. This study aimed to compare diagnostic yield and performance between reflux monitoring systems in patients with chronic laryngeal symptoms. METHODS: This multicenter, international study of adult patients referred for evaluation of LPR over a 5-year period (March 2018-May 2023) assessed and compared diagnostic yield of pathologic gastroesophageal reflux (GER+) on ambulatory reflux monitoring off acid suppression. RESULTS: Of 813 patients, 296 (36%) underwent prolonged wireless pH, 532 (65%) underwent 24-hour pH-impedance monitoring, and 15 (2%) underwent both tests. Overall diagnostic yield for GER+ was 36% and greater for prolonged wireless pH compared with that for 24-hour pH-impedance monitoring (50% vs 27%; P < 0.01). Among 15 patients who underwent both prolonged wireless pH and 24-h pH-impedance monitoring, concordance between systems for GER+ was 40%. The most common source of discordance was strong evidence of GER+ across multiple days on prolonged wireless pH compared with no evidence of GER+ on pH-impedance. DISCUSSION: In this multicenter international study of patients with chronic laryngeal symptoms referred for LPR evaluation, diagnostic yield of ambulatory reflux monitoring off acid suppression was 36% and rose to 50% when using wireless pH monitoring. In patients referred for chronic laryngeal symptoms, 24-hour pH-impedance monitoring may risk a low negative predictive value in patients with unproven GER+ disease.

Improving One-Electron Exact-Two-Component Relativistic Methods with the Dirac-Coulomb-Breit-Parameterized Effective Spin-Orbit Coupling.

In photochemical processes, spin-orbit coupling plays a crucial role in determining the outcome of the reaction. However, the exact treatment of the Dirac-Coulomb-Breit two-electron operator required for rigorous inclusion of spin-orbit coupling is computationally prohibitive. To address this challenge, we present a Dirac-Coulomb-Breit-parameterized screened-nuclear spin-orbit factor to approximate two-electron spin-orbit couplings in the effective one-electron spin-orbit Hamiltonian. We propose two schemes, the universal and row-dependent parameterizations, to further improve the accuracy of the method. Benchmark calculations on both atomic and molecular systems are performed and compared to results from the computationally expensive four-component Dirac-Coulomb-Breit method. The Dirac-Coulomb-Breit-parameterized approach offers a more computationally feasible method for accurate spin-orbit coupling calculations.

De novo CLPTM1 variants with reduced GABAA R current response in patients with epilepsy.

OBJECTIVE: To investigate the clinical features and potential pathogenesis mechanism of de novo CLPTM1 variants associated with epilepsy. METHODS: Identify de novo genetic variants associated with epilepsy by reanalyzing trio-based whole-exome sequencing data. We analyzed the clinical characteristics of patients with these variants and performed functional in vitro studies in cells expressing mutant complementary DNA for these variants using whole-cell voltage-clamp current recordings and outside-out patch-clamp recordings from transiently transfected human embryonic kidney (HEK) cells. RESULTS: Two de novo missense variants related to epilepsy were identified in the CLPTM1 gene. Functional studies indicated that CLPTM1-p.R454H and CLPTM1-p.R568Q variants reduced the γ-aminobutyric acid A receptor (GABAA R) current response amplitude recorded under voltage clamp compared to the wild-type receptors. These variants also reduced the charge transfer and altered the time course of desensitization and deactivation following rapid removal of GABA. The surface expression of the GABAA R γ2 subunit from the CLPTM1-p.R568Q group was significantly reduced compared to CLPTM1-WT. SIGNIFICANCE: This is the first report of functionally relevant variants within the CLPTM1 gene. Patch-clamp recordings showed that these de novo CLPTM1 variants reduce GABAA R currents and charge transfer, which should promote excitation and hypersynchronous activity. This study may provide insights into the molecular mechanisms of the CLPTM1 variants underlying the patients' phenotypes, as well as for exploring potential therapeutic targets for epilepsy.

Small Molecule Activation of NAPE-PLD Enhances Efferocytosis by Macrophages.

N-Acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to form N-acyl-ethanolamines (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance, NAPEPLD expression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators (VU534 and VU533) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced in Napepld-/- BMDM or after Nape-pld inhibition. Together, these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.

Screening Ion Channels in Cancer Cells.

Ion channels are critical for cell development and maintaining cell homeostasis. The perturbation of ion channel function contributes to the development of a broad range of disorders or channelopathies. Cancer cells utilize ion channels to drive their own development, as well as to improve as a tumor and to assimilate in a microenvironment that includes various non-cancerous cells. Furthermore, increases in levels of growth factors and hormones within the tumor microenvironment can result in enhanced ion channel expression, which contributes to cancer cell proliferation and survival. Thus, the pharmacological targeting of ion channels is potentially a promising approach to treating solid malignancies, including primary and metastatic brain cancers. Herein, protocols to characterize the function of ion channels in cancerous cells and approaches to analyze modulators of ion channels to determine their impact on cancer viability are described. These include staining a cell(s) for an ion channel(s), testing the polarized state of mitochondria, establishing ion channel function using electrophysiology, and performing viability assays to assess drug potency.

Risk Factors for Death or Cardiovascular Events after Acute Coronary Syndrome in Patients with Myeloproliferative Neoplasms.

Patients with myeloproliferative neoplasms (MPNs) are at increased risk of cardiovascular disease (CVD), including acute coronary syndrome (ACS). However, data on long-term outcomes of patients with MPN who have had ACS and risk factors for all-cause death or CV events post-ACS hospitalization are lacking. We conducted a single-center study of 41 consecutive patients with MPN with ACS hospitalization after MPN diagnosis. After a median follow-up of 80 months after ACS hospitalization, 31 (76%) experienced death or a CV event (myocardial infarction, ischemic stroke, or heart failure hospitalization). After multivariable Cox proportional hazards regression, index ACS within 12 months of MPN diagnosis (HR 3.84, 95% CI 1.44-10.19), WBC ≥ 20 K/µL (HR 9.10, 95% CI 2.71-30.52), JAK2 mutation (HR 3.71, 95% CI 1.22-11.22), and prior CVD (HR 2.60, 95% CI 1.12-6.08) were associated with increased death or CV events. Further studies are warranted to improve cardiovascular outcomes in this patient population.

Coherent Mixing of Singlet and Triplet States in Acrolein and Ketene: A Computational Strategy for Simulating the Electron-Nuclear Dynamics of Intersystem Crossing.

We present a theoretical study of intersystem crossing (ISC) in acrolein and ketene with the Ehrenfest method that can describe a superposition of singlet and triplet states. Our simulations illustrate a new mechanistic effect of ISC, namely, that a superposition of singlets and triplets yields nonadiabatic dynamics characteristic of that superposition rather than the constituent state potential energy surfaces. This effect is particularly significant in ketene, where mixing of singlet and triplet states along the approach to a singlet/singlet conical intersection occurs, with the spin-orbit coupling (SOC) remaining small throughout. In both cases, the effects require many recrossings of the singlet/triplet state crossing seam, consistent with the textbook treatment of ISC.

Prevalence of tick-borne encephalitis virus in questing Ixodes ricinus nymphs in southern Scandinavia and the possible influence of meteorological factors.

Ixodes ricinus ticks are Scandinavia's main vector for tick-borne encephalitis virus (TBEV), which infects many people annually. The aims of the present study were (i) to obtain information on the TBEV prevalence in host-seeking I. ricinus collected within the Øresund-Kattegat-Skagerrak (ØKS) region, which lies in southern Norway, southern Sweden and Denmark; (ii) to analyse whether there are potential spatial patterns in the TBEV prevalence; and (iii) to understand the relationship between TBEV prevalence and meteorological factors in southern Scandinavia. Tick nymphs were collected in 2016, in southern Scandinavia, and screened for TBEV, using pools of 10 nymphs, with RT real-time PCR, and positive samples were confirmed with pyrosequencing. Spatial autocorrelation and cluster analysis was performed with Global Moran's I and SatScan to test for spatial patterns and potential local clusters of the TBEV pool prevalence at each of the 50 sites. A climatic analysis was made to correlate parameters such as minimum, mean and maximum temperature, relative humidity and saturation deficit with TBEV pool prevalence. The climatic data were acquired from the nearest meteorological stations for 2015 and 2016. This study confirms the presence of TBEV in 12 out of 30 locations in Denmark, where six were from Jutland, three from Zealand and two from Bornholm and Falster counties. In total, five out of nine sites were positive from southern Sweden. TBEV prevalence of 0.7%, 0.5% and 0.5%, in nymphs, was found at three sites along the Oslofjord (two sites) and northern Skåne region (one site), indicating a potential concern for public health. We report an overall estimated TBEV prevalence of 0.1% in questing I. ricinus nymphs in southern Scandinavia with a region-specific prevalence of 0.1% in Denmark, 0.2% in southern Sweden and 0.1% in southeastern Norway. No evidence of a spatial pattern or local clusters was found in the study region. We found a strong correlation between TBEV prevalence in ticks and relative humidity in Sweden and Norway, which might suggest that humidity has a role in maintaining TBEV prevalence in ticks. TBEV is an emerging tick-borne pathogen in southern Scandinavia, and we recommend further studies to understand the TBEV transmission potential with changing climate in Scandinavia.

State Interaction Linear Response Time-Dependent Density Functional Theory with Perturbative Spin-Orbit Coupling: Benchmark and Perspectives.

Spin-orbit coupling (SOC) is an important driving force in photochemistry. In this work, we develop a perturbative spin-orbit coupling method within the linear response time-dependent density function theory framework (TDDFT-SO). A full state interaction scheme, including singlet-triplet and triplet-triplet coupling, is introduced to describe not only the coupling between the ground and excited states, but also between excited states with all couplings between spin microstates. In addition, expressions to compute spectral oscillator strengths are presented. Scalar relativity is included variationally using the second-order Douglas-Kroll-Hess Hamiltonian, and the TDDFT-SO method is validated against variational SOC relativistic methods for atomic, diatomic, and transition metal complexes to determine the range of applicability and potential limitations. To demonstrate the robustness of TDDFT-SO for large-scale chemical systems, the UV-Vis spectrum of Au25(SR)18 - is computed and compared to experiment. Perspectives on the limitation, accuracy, and capability of perturbative TDDFT-SO are presented via analyses of benchmark calculations. Additionally, an open-source Python software package (PyTDDFT-SO) is developed and released to interface with the Gaussian 16 quantum chemistry software package to perform this calculation.

Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABAAR Activation.

GABAA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAA receptor negative allosteric modulators (GABAARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABAARNAMs can restore the Excitation/Inhibition (E/I) balance in vitro and arousal in vivo, we chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism. We determined modulation with both conventional and microfluidic patch clamp methods. We found that receptor activation was variably modulated by all 11 compounds: Rifampicin (RIF), Metronidazole (MET), Minocycline (MIN), Erythromycin (ERY), Ofloxacin (OFX), Chloroquine (CQ), Hydroxychloroquine sulfate (HCQ), Flumazenil (FLZ), Pentylenetetrazol (PTZ), (-)-Epigallocatechin Gallate (EGCG), and clarithromycin (CLR). The computational modeling of modulator-receptor interactions predicted drug action at canonical binding sites and novel orphan sites on the receptor. Our findings suggest that multiple avenues of investigation are now open to investigate large and brain-penetrant molecules for the treatment of patients with diminished CNS E/I balance.

Small Molecule Activation of NAPE-PLD Enhances Efferocytosis by Macrophages.

N -acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes N -acyl-phosphatidylethanolamine (NAPEs) to form N -acyl-ethanolamides (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance, NAPEPLD expression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators (VU534 and VU533) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced in Napepld -/- BMDM or after Nape-pld inhibition. Together these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.