DeepARV: ensemble deep learning to predict drug-drug interaction of clinical relevance with antiretroviral therapy.

Drug-drug interaction (DDI) may result in clinical toxicity or treatment failure of antiretroviral therapy (ARV) or comedications. Despite the high number of possible drug combinations, only a limited number of clinical DDI studies are conducted. Computational prediction of DDIs could provide key evidence for the rational management of complex therapies. Our study aimed to assess the potential of deep learning approaches to predict DDIs of clinical relevance between ARVs and comedications. DDI severity grading between 30,142 drug pairs was extracted from the Liverpool HIV Drug Interaction database. Two feature construction techniques were employed: 1) drug similarity profiles by comparing Morgan fingerprints, and 2) embeddings from SMILES of each drug via ChemBERTa, a transformer-based model. We developed DeepARV-Sim and DeepARV-ChemBERTa to predict four categories of DDI: i) Red: drugs should not be co-administered, ii) Amber: interaction of potential clinical relevance manageable by monitoring/dose adjustment, iii) Yellow: interaction of weak relevance and iv) Green: no expected interaction. The imbalance in the distribution of DDI severity grades was addressed by undersampling and applying ensemble learning. DeepARV-Sim and DeepARV-ChemBERTa predicted clinically relevant DDI between ARVs and comedications with a weighted mean balanced accuracy of 0.729 ± 0.012 and 0.776 ± 0.011, respectively. DeepARV-Sim and DeepARV-ChemBERTa have the potential to leverage molecular structures associated with DDI risks and reduce DDI class imbalance, effectively increasing the predictive ability on clinically relevant DDIs. This approach could be developed for identifying high-risk pairing of drugs, enhancing the screening process, and targeting DDIs to study in clinical drug development.

p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response.

Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.

Physiologically-based pharmacokinetic modelling of long-acting injectable cabotegravir and rilpivirine in pregnancy.

AIMS: Long-acting cabotegravir and rilpivirine have been approved to manage HIV in adults, but data regarding safe use in pregnancy are limited. Physiologically-based pharmacokinetic (PBPK) modelling was used to simulate the approved dosing regimens in pregnancy and explore if Ctrough was maintained above cabotegravir and rilpivirine target concentrations (664 and 50 ng/mL, respectively). METHODS: An adult PBPK model was validated using clinical data of cabotegravir and rilpivirine in nonpregnant adults. This was modified by incorporating pregnancy-induced metabolic and physiological changes. The pregnancy PBPK model was validated with data on oral rilpivirine and raltegravir (UGT1A1 probe substrate) in pregnancy. Twelve weeks' disposition of monthly and bimonthly dosing of long-acting cabotegravir and rilpivirine was simulated at different trimesters and foetal exposure was also estimated. RESULTS: Predicted Ctrough at week 12 for monthly long-acting cabotegravir was above 664 ng/mL throughout pregnancy, but below the target in 0.5% of the pregnant population in the third trimester with bimonthly long-acting cabotegravir. Predicted Ctrough at week 12 for monthly and bimonthly long-acting rilpivirine was below 50 ng/mL in at least 40% and over 90% of the pregnant population, respectively, throughout pregnancy. Predicted medians (range) of cord-to-maternal blood ratios were 1.71 (range, 1.55-1.79) for cabotegravir and 0.88 (0.78-0.93) for rilpivirine between weeks 38 and 40. CONCLUSIONS: Model predictions suggest that monthly long-acting cabotegravir could maintain antiviral efficacy throughout pregnancy, but that bimonthly administration may require careful clinical evaluation. Both monthly and bimonthly long-acting rilpivirine may not adequately maintain antiviral efficacy in pregnancy.

New genetic drivers in hemorrhagic hereditary telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in around 90% of the patients; also 2% of patients harbor pathogenic variants at SMAD4 and GDF2. Importantly, the genetic cause of 8% of patients with clinical HHT remains unknown. Here, we present new putative genetic drivers of HHT. METHODS: To identify new HHT genetic drivers, we performed exome sequencing of 19 HHT patients and relatives with unknown HHT genetic etiology. We applied a multistep filtration strategy to catalog deleterious variants and prioritize gene candidates based on their known relevance in endothelial cell biology. Additionally, we performed in vitro validation of one of the identified variants. RESULTS: We identified variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1 and SMAD6 genes as putative drivers in HHT. We have identified the SMAD6 p.(Glu407Lys) variant in one of the families; this is a loss-of-function variant leading to the activation of the BMP/TGFß signaling in endothelial cells. CONCLUSIONS: Variants in these genes should be considered for genetic testing in patients with HHT phenotype and negative for ACVRL1/ENG mutations.

Confiabilidad y validez psicométrica del cuestionario sororidad aplicable a mujeres docentes en espacios universitarios / Reliability and psychometric validity of the sorority questionnaire applicable to female teachers in university settings

RESUMEN La sororidad es un concepto que posibilita la reflexión crítica y discusión constructiva de las formas en que las mujeres tejen relaciones sociales y generan interacciones. Actualmente, no existe un precedente de instrumento o escala para su medición, ya que los estudios realizados se han abordado con enfoque cualitativo, desde el nivel experiencial, fenomenológico. Es ahí la importancia de ampliar el diálogo y discusión teórica con un enfoque cuantitativo, sin reducir la experiencia humana a estándares paramétricos. El objetivo de este trabajo fue demostrar evidencia de confiabilidad y validez psicométrica de un instrumento respecto a la percepción femenina acerca del concepto de sororidad, en un contexto universitario, con la intención de que a partir de él se pueda realizar un análisis desde la perspectiva de género de las relaciones de las mujeres. El método se circunscribe a los parámetros estadísticos para su construcción y su evaluación. Se determinó la validez de contenido, mediante conversatorios, análisis teórico y la valoración de los ítems a través de expertos; la validez de constructo mediante un análisis factorial exploratorio, con las pruebas de Kaiser-Meyer-Olkin y Bertlett; y la validez de confiabilidad, utilizando alfa de Cronbach. La muestra fue no probabilística, de inclusión continua y voluntaria, utilizando la técnica de la bola de nieve, conformada por 118 profesoras universitarias, de México. El instrumento mostró una confiabilidad global excelente (0.915), por lo que permitió medir la sororidad de un modo consistente y válido. Es recomendable su futura aplicación en otros contextos, ya que cuenta con las propiedades psicométricas necesarias.

ABSTRACT Sorority is a concept that enables critical reflection and constructive discussion of the ways in which women weave relationships and generate interactions. Currently, there is no precedent of an instrument or scale for its measurement, since the studies conducted have been approached with a qualitative focus, from the experiential, phenomenological level. Hence the importance of expanding the dialogue and theoretical discussion with a quantitative approach, without reducing human experience to parametric standards. The objective of this work was to demonstrate evidence of reliability and psychometric validity of an instrument regarding the female perception of the concept of sorority, in a university context, with the intention of being able to analyze women's relationships from a gender perspective. The method is circumscribed to the statistical parameters for its construction and evaluation. Content validity was determined by means of discussions, theoretical analysis, and the evaluation of the items by experts; construct validity was determined by means of an exploratory factor analysis, with the KaiserMeyer-Olkin and Bertlett tests; and reliability validity was determined using Cronbach's alpha. The sample was non-probabilistic, of continuous and voluntary inclusion, using the snowball technique, made up of 118 female university professors from Mexico. The results show that the instrument measures sorority in a consistent and valid way and is suitable for future application in other contexts since it has the necessary psychometric properties.

PI3K-C2ß limits mTORC1 signaling and angiogenic growth.

Phosphoinositide 3-kinases (PI3Ks) phosphorylate intracellular inositol lipids to regulate signaling and intracellular vesicular trafficking. Mammals have eight PI3K isoforms, of which class I PI3Kα and class II PI3K-C2α are essential for vascular development. The class II PI3K-C2ß is also abundant in endothelial cells. Using in vivo and in vitro approaches, we found that PI3K-C2ß was a critical regulator of blood vessel growth by restricting endothelial mTORC1 signaling. Mice expressing a kinase-inactive form of PI3K-C2ß displayed enlarged blood vessels without corresponding changes in endothelial cell proliferation or migration. Instead, inactivation of PI3K-C2ß resulted in an increase in the size of endothelial cells, particularly in the sprouting zone of angiogenesis. Mechanistically, we showed that the aberrantly large size of PI3K-C2ß mutant endothelial cells was caused by mTORC1 activation, which sustained growth in these cells. Consistently, pharmacological inhibition of mTORC1 with rapamycin normalized vascular morphogenesis in PI3K-C2ß mutant mice. Together, these results identify PI3K-C2ß as a crucial determinant of endothelial signaling and illustrate the importance of mTORC1 regulation during angiogenic growth.

Genome-scale metabolic models reveal determinants of phenotypic differences in non-Saccharomyces yeasts.

BACKGROUND: Use of alternative non-Saccharomyces yeasts in wine and beer brewing has gained more attention the recent years. This is both due to the desire to obtain a wider variety of flavours in the product and to reduce the final alcohol content. Given the metabolic differences between the yeast species, we wanted to account for some of the differences by using in silico models. RESULTS: We created and studied genome-scale metabolic models of five different non-Saccharomyces species using an automated processes. These were: Metschnikowia pulcherrima, Lachancea thermotolerans, Hanseniaspora osmophila, Torulaspora delbrueckii and Kluyveromyces lactis. Using the models, we predicted that M. pulcherrima, when compared to the other species, conducts more respiration and thus produces less fermentation products, a finding which agrees with experimental data. Complex I of the electron transport chain was to be present in M. pulcherrima, but absent in the others. The predicted importance of Complex I was diminished when we incorporated constraints on the amount of enzymatic protein, as this shifts the metabolism towards fermentation. CONCLUSIONS: Our results suggest that Complex I in the electron transport chain is a key differentiator between Metschnikowia pulcherrima and the other yeasts considered. Yet, more annotations and experimental data have the potential to improve model quality in order to increase fidelity and confidence in these results. Further experiments should be conducted to confirm the in vivo effect of Complex I in M. pulcherrima and its respiratory metabolism.

General Framework to Quantitatively Predict Pharmacokinetic Induction Drug-Drug Interactions Using In Vitro Data.

INTRODUCTION: Metabolic inducers can expose people with polypharmacy to adverse health outcomes. A limited fraction of potential drug-drug interactions (DDIs) have been or can ethically be studied in clinical trials, leaving the vast majority unexplored. In the present study, an algorithm has been developed to predict the induction DDI magnitude, integrating data related to drug-metabolising enzymes. METHODS: The area under the curve ratio (AUCratio) resulting from the DDI with a victim drug in the presence and absence of an inducer (rifampicin, rifabutin, efavirenz, or carbamazepine) was predicted from various in vitro parameters and then correlated with the clinical AUCratio (N = 319). In vitro data including fraction unbound in plasma, substrate specificity and induction potential for cytochrome P450s, phase II enzymes and uptake, and efflux transporters were integrated. To represent the interaction potential, the in vitro metabolic metric (IVMM) was generated by combining the fraction of substrate metabolised by each hepatic enzyme of interest with the corresponding in vitro fold increase in enzyme activity (E) value for the inducer. RESULTS: Two independent variables were deemed significant and included in the algorithm: IVMM and fraction unbound in plasma. The observed and predicted magnitudes of the DDIs were categorised accordingly: no induction, mild, moderate, and strong induction. DDIs were assumed to be well classified if the predictions were in the same category as the observations, or if the ratio between these two was < 1.5-fold. This algorithm correctly classified 70.5% of the DDIs. CONCLUSION: This research presents a rapid screening tool to identify the magnitude of potential DDIs utilising in vitro data which can be highly advantageous in early drug development.

Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non-Small-Cell Lung Cancer.

PURPOSE: In many cancers, the expression of immunomodulatory ligands leads to immunoevasion, as exemplified by the interaction of PD-L1 with PD-1 on tumor-infiltrating lymphocytes. Profound advances in cancer treatments have come with the advent of immunotherapies directed at blocking these immuno-suppressive ligand-receptor interactions. However, although there has been success in the use of these immune checkpoint interventions, correct patient stratification for these therapies has been challenging. MATERIALS AND METHODS: To address this issue of patient stratification, we have quantified the intercellular PD-1/PD-L1 interaction in formalin-fixed paraffin-embedded tumor samples from patients with non-small cell lung carcinoma, using a high-throughput automated quantitative imaging platform (quantitative functional proteomics [QF-Pro]). RESULTS: The multisite blinded analysis across a cohort of 188 immune checkpoint inhibitor-treated patients demonstrated the intra- and intertumoral heterogeneity of PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression. Importantly, PD-L1 expression scores used clinically to stratify patients correlated poorly with overall survival; by contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti-PD-1/PD-L1 treatments, as evidenced by increased overall survival. This relationship was particularly strong in the setting of first-line treatments. CONCLUSION: The functional readout of PD-1/PD-L1 interaction as a predictive biomarker for the stratification of patients with non-small-cell lung carcinoma, combined with PD-L1 expression, should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients) and additionally avoid treating patients who despite their high PD-L1 expression do not respond and suffer from side effects.

Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation.

Oncogenic mutations in PIK3CA, encoding p110α-PI3K, are a common cause of venous and lymphatic malformations. Vessel type-specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C-producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.

Prevalence of Potentially Clinically Significant Drug-Drug Interactions With Antiretrovirals Against HIV Over Three Decades: A Systematic Review of the Literature.

BACKGROUND: Contemporary first-line antiretrovirals have considerably reduced liability for clinically significant drug-drug interactions (DDI). This systematic review evaluates the prevalence of DDI among people receiving antiretrovirals across 3 decades. METHODS: We searched 3 databases for studies reporting the prevalence of clinically significant DDIs in patients receiving antiretrovirals published between January 1987 and July 2022. Clinically significant DDIs were graded by severity. All data extractions were undertaken by 2 independent reviewers, adjudicated by a third. RESULTS: Of 21,665 records returned, 13,474 were duplicates. After screening the remaining 13,596 abstracts against inclusion criteria, 122 articles were included for full-text analysis, from which a final list of 34 articles were included for data synthesis. The proportion of patients experiencing a clinically significant DDI did not change over time (P = 0.072). The most frequently reported classes of antiretrovirals involved in DDIs were protease inhibitors and non-nucleoside reverse transcriptase inhibitors; of note, integrase use in the most recent studies was highly variable and ranged between 0% and 89%. CONCLUSIONS: The absolute risk of DDIs has not decreased over the period covered. This is likely related to continued use of older regimens and an ageing cohort of patients. A greater reduction in DDI prevalence can be anticipated with broader uptake of regimens containing unboosted integrase inhibitors or non-nucleoside reverse transcriptase inhibitors.

Movimientos sociales, narrativas y emociones. El caso de lideresas comunitarias afrodescendientes en el departamento del Chocó (Colombia) / Social Movements, Narratives, and Emotions. The Case of Afro-Descendant Community Leaders in the Department of Chocó, Colombia

Resumen Las emociones favorecen las movilizaciones, pero también las dificultan y que la narración constituye un enfoque privilegiado para entender las dinámicas de los movimientos sociales y sus integrantes. Desde un enfoque narrativo, se describe el entorno sociocultural que da lugar al nacimiento y participación de mujeres en movimientos de reivindicaciones de género y acciones de emprendimiento colaborativo e identifica y se analiza emociones negativas y positivas, aisladas y secuenciales, que movilizan la acción y generan solidaridades, como la ira, la impotencia y la tristeza o el orgullo y la alegría en lideresas comunitarias afro- descendientes en el departamento del Chocó (Colombia).

Abstract Emotions favor mobilizations, but they also hinder them, and that narrative constitutes a privileged approach to understand the dynamics of social move ments and their members. From a narrative approach, we describe the sociocul tural environment, which gives rise to the birth and participation of women in movements of gender claims and collaborative entrepreneurship actions and to identify and to analyze negative and positive emotions, isolated and sequential, which mobilize action and generate solidarity, such as anger, helplessness, and sadness or pride and joy in Afro-descendant community leaders in the depart ment of Chocó, Colombia.

Predictive evolution of metabolic phenotypes using model-designed environments.

Adaptive evolution under controlled laboratory conditions has been highly effective in selecting organisms with beneficial phenotypes such as stress tolerance. The evolution route is particularly attractive when the organisms are either difficult to engineer or the genetic basis of the phenotype is complex. However, many desired traits, like metabolite secretion, have been inaccessible to adaptive selection due to their trade-off with cell growth. Here, we utilize genome-scale metabolic models to design nutrient environments for selecting lineages with enhanced metabolite secretion. To overcome the growth-secretion trade-off, we identify environments wherein growth becomes correlated with a secondary trait termed tacking trait. The latter is selected to be coupled with the desired trait in the application environment where the trait manifestation is required. Thus, adaptive evolution in the model-designed selection environment and subsequent return to the application environment is predicted to enhance the desired trait. We experimentally validate this strategy by evolving Saccharomyces cerevisiae for increased secretion of aroma compounds, and confirm the predicted flux-rerouting using genomic, transcriptomic, and proteomic analyses. Overall, model-designed selection environments open new opportunities for predictive evolution.

Reply to Paterson, R.R.M. Comment on "Castillo et al. Ganoderma zonatum Is the Causal Agent of Basal Stem Rot in Oil Palm in Colombia. J. Fungi 2022, 8, 230".

Reader Q: There was no morphological information provided for the isolated specimens, and so it is not known if they are even Ganoderma [...].

Comparison of Chemical Composition, Physicochemical Parameters, and Antioxidant and Antibacterial Activity of the Essential Oil of Cultivated and Wild Mexican Oregano Poliomintha longiflora Gray.

Mexican oregano Poliomintha longiflora Gray located in the municipality of Higueras, Nuevo Leon, Mexico was collected during the autumn (September, OCO), winter (January, OCI) and summer (June, OCV) seasons, under cultivation conditions. It was also collected in wild conditions during the autumn (OSO). Essential oil (EO) was extracted from leaves and the color, refractive index and density were reported. The EO yield, antioxidant activity by ORAC assay, thymol and carvacrol concentration and antibacterial activity were statistically compared (p-value = 0.05). Among the various harvests, the highest EO yield, antioxidant activity, thymol and carvacrol content and antibacterial activity against Salmonella Typhi were observed in leaves harvested in autumn. In order to compare wild oregano with cultivated oregano, analyses were performed in the season with the highest essential oil yield and antioxidant activity, recorded in autumn. The main difference found was the ratio of thymol:carvacrol in wild oregano oil, which was 1:8.6, while in cultivated oregano, it was approximately 1:2, which was maintained in all three seasons. The EO on wild conditions showed the best antibacterial activity in Salmonella Typhi. On the other hand, wild and cultivated oregano showed similar antioxidant activity. One advantage of the use of cultivated oregano is that its supply is guaranteed, in contrast to that of wild oregano.

The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib.

Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3caH1047R activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K-driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low-flow vascular malformations.

Ganoderma zonatum Is the Causal Agent of Basal Stem Rot in Oil Palm in Colombia.

Basal stem rot (BSR), caused by Ganoderma spp., is one of the most important emerging oil palm diseases in Colombia, and is restricted to two oil palm production areas in the country. To identify the causal agent of the disease, basidiocarp of oil palms affected by BSR were used to prepare isolates, and their pathogenicity was then assessed in pre-nursery plants. Four-month-old oil palm seedlings were inoculated with rubber wood (Hevea brasiliensis) blocks colonized with dikaryotic mycelia of Ganoderma. The incidence, severity, and symptoms of the pathogen were assessed. A multiregional analysis (ITS, rpb2, and tef1-α) was carried out to identify the isolates; all isolates were determined to be Ganoderma zonatum. Phylogenetic analyses with the three regions yielded concordant phylogenetic information and supported the distinction of the isolates with high bootstrap support. Seven isolates (CPBsZN-01-29, CPBsZN-02-30, CPBsZN-03-31, CPBsZN-04-34, CPBsZN-05-35, CPBsZN-06-36, and CPBsZN-07-38) were pathogenic in oil palm, with incidences greater than 90% and a maximum severity of 34%, and the highest severity index was found in isolates CPBsZN-03-31, CPBsZN-04-34, and CPBsZN-06-36. The pathogen was recovered from inoculated oil palms in all cases. This study reveals the pathogenic association of Ganoderma zonatum with BSR in Colombia.

Angiocrine polyamine production regulates adiposity.

Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid ß-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism.

PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease.

The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18-60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35%-60%) and the plasma concentrations increased (170%-400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

Behavioural immune landscapes of inflammation.

Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream 'behavioural' outputs3-5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte identities in the inflamed skin and trachea, and uncovered a continuum of neutrophil states inside blood vessels, including a large, sessile state that was embraced by the underlying endothelium and associated with pathogenic inflammation. Behavioural screening in 24 mouse mutants identified the kinase Fgr as a driver of this pathogenic state, and interference with Fgr protected mice from inflammatory injury. Thus, behavioural landscapes report distinct properties of dynamic environments at high cellular resolution.