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Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of its pathogenesis, highlighting the fact that there is a specific pulmonary vascular disorder. Indeed, COVID-19 may predispose patients to thrombotic disease in both venous and arterial circulation, and many cases of severe acute pulmonary embolism have been reported. The demonstrated presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the endothelial cells suggests that direct viral effects, in addition to indirect effects of perivascular inflammation and coagulopathy, may contribute to pulmonary vasculopathy in COVID-19. In this review, we discuss the pathological mechanisms leading to pulmonary vascular damage during acute infection, which appear to be mainly related to thromboembolic events, an impaired coagulation cascade, micro- and macrovascular thrombosis, endotheliitis and hypoxic pulmonary vasoconstriction. As many patients develop post-COVID symptoms, including dyspnea, we also discuss the hypothesis of pulmonary vascular damage and pulmonary hypertension as a sequela of the infection, which may be involved in the pathophysiology of long COVID.

Onobrychis montana DC. Subsp. transsilvanica (Simonk.) Jáv. (Fabaceae) is a plant taxon, endemic to the South-Eastern Carpathians, whose taxonomic status is treated inconsistently by the classic taxonomy based on morphological traits. In a previous study, by sequencing several chloroplast DNA regions and AFLP genotyping, we tried to elucidate the controversy concerning its taxonomic status in relation to the more widespread O. montana DC., and determined its phylogeographic structure within the Carpathians. The present study, based on DNA fingerprinting by seven SSR markers, brings more insights on this problematic taxon by conferring higher resolution and sub-clustering previously identified phylogeographic groups. However, the newly SSR genetic data are in agreement with molecular evidence revealed by AFLP and chloroplastic SNPs and do not support O. montana DC. Subsp. transsilvanica (Simonk.) Jáv. As a distinct species from O. montana DC.

Ma post-doctorante, Caroline Crépiat, et moi-même avons développé une base de données réunissant les traductions des textes anglais décadents parues dans 10 périodiques français entre 1885 et 1914 (decabase.u-bourgogne.fr). Cette base de données montre la présence importante de la poésie et de la prose traduites, tant en tant que telles que dans les critiques de livres, en tant que traductions fragmentaires. Ces traductions – et les commentaires qu’elles suscitent au sein des périodiques qui les publient ou dans d’autres revues – constituent la première importation de textes en langue étrangère dans les lettres françaises. L’intérêt qu’elles ont suscité a souvent conduit à entreprendre des traductions d’ouvrages plus complets et de recueils. Cet article présente la « Décabase », montre l’importance de la traduction dans le corpus de périodiques sélectionnés et trace des pistes de recherche dans un domaine qui commence à susciter l’intérêt des chercheurs en traduction et en études consacrées aux périodiques. Ce dernier nécessite l’adoption d’une approche interdisciplinaire à l’intersection des études consacrées aux périodiques, des études de réception et de traduction littéraire ainsi que de l’histoire de la traduction.

Abstract The Central Nervous System (CNS) tumor with BCOR internal tandem duplication (ITD) has recently been added as a novel embryonal histomolecular tumor type to the 2021 World Health Organization (WHO) Classification of CNS Tumors. In addition, other CNS tumors harboring a BCOR/BCORL1 fusion, which are defined by a distinct DNA-methylation profile, have been recently identified in the literature but clinical, radiological and histopathological data remain scarce. Herein, we present two adult cases of CNS tumors with EP300::BCOR fusion. These two cases presented radiological, histopathological, and immunohistochemical homologies with CNS tumors having BCOR ITD in children. To compare these tumors with different BCOR alterations, we performed a literature review with a meta-analysis. CNS tumors with EP300::BCOR fusion seem to be distinct from their BCOR ITD counterparts in terms of age, location, progression-free survival, tumor growth pattern, and immunopositivity for the BCOR protein. CNS tumors from the EP300::BCOR fusion methylation class in adults may be added to the future WHO classification.

Abstract Background Gliomas with FGFR3::TACC3 fusion mainly occur in adults, display pathological features of glioblastomas (GB) and are usually classified as glioblastoma, IDH-wildtype. However, cases demonstrating pathological features of low-grade glioma (LGG) lead to difficulties in classification and clinical management. We report a series of 8 GB and 14 LGG with FGFR3:TACC3 fusion in order to better characterize them. Methods Centralized pathological examination, search for TERT promoter mutation and DNA-methylation profiling were performed in all cases. Search for prognostic factors was done by the Kaplan–Meir method. Results TERT promoter mutation was recorded in all GB and 6/14 LGG. Among the 7 cases with a methylation score > 0.9 in the classifier (v12.5), 2 were classified as glioblastoma, 4 as ganglioglioma (GG) and 1 as dysembryoplastic neuroepithelial tumor (DNET). t-SNE analysis showed that the 22 cases clustered into three groups: one included 12 cases close to glioblastoma, IDH-wildtype methylation class (MC), 5 cases each clustered with GG or DNET MC but none with PLNTY MC. Unsupervised clustering analysis revealed four groups, two of them being clearly distinct: 5 cases shared age ( 40), pathological features of glioblastoma, and were TERT-mutated. Relevant factors associated with a better prognosis were age

Abstract The 2019 global coronavirus (COVID-19) pandemic has brought the world to a grinding halt, highlighting the urgent need for therapeutic and preventive solutions to slow the spread of emerging viruses. The objective of this study was to assess the anti-SARS-CoV-2 effectiveness of 8 FDA-approved cationic amphiphilic drugs (CADs). SARS-CoV-2-infected Vero cells, Calu-3 cells and primary Human Nasal Epithelial Cells (HNEC) were used to investigate the effects of CADs and revealed their antiviral mode of action. Among the CADs tested, desloratadine, a commonly used antiallergic, well-tolerated with no major side effects, potently reduced the production of SARS-CoV-2 RNA in Vero-E6 cells. Interestingly, desloratadine was also effective against HCoV-229E and HCoV-OC43 showing that it possessed broad-spectrum anti-coronavirus activity. Investigation of its mode of action revealed that it targeted an early step of virus lifecycle and blocked SARS-CoV-2 entry through the endosomal pathway. Finally, the ex vivo kinetic of the antiviral effect of desloratadine was evaluated on primary Human Nasal Epithelial Cells (HNEC), showing a significant delay of viral RNA production with a maximal reduction reached after 72 h of treatment. Thus, this treatment could provide a substantial contribution to prophylaxis and systemic therapy of COVID-19 or other coronaviruses infections and requires further studies.

El artículo sostiene que, desde su creación en 1990 hasta 2018, la Comisión Nacional de los Derechos Humanos se fortaleció gradualmente como institución encargada de la protección no jurisdiccional de los derechos fundamentales en México. Este fortalecimiento institucional se produjo por dos vías: una externa —reformas legales que le otorgaron mayor autonomía o facultades— y una interna, en la que enfoca este texto. El argumento central es que, cuando la Comisión hace pleno uso de sus facultades y autonomía, se dibuja un círculo virtuoso: una actuación en esa línea le brinda la posibilidad de utilizar la legitimidad social, la reserva reputacional y el posicionamiento sólido frente a otras instituciones en futuros casos de violaciones a derechos humanos. También se arguye que la coyuntura de los casos ante los que se pronuncia lo Comisión y los destinatarios de sus recomendaciones son de especial importancia. El proceso de fortalecimiento institucional desde adentro se potencia cuando la CNDH hace pleno uso de sus facultades en escenarios políticos espinosos y dirige sus exhortos a actores políticos que tienen un papel protagónico en el proyecto político del presidente mexicano en turno. Para sostener estos argumentos, se presentan cinco casos de estudio especialmente representativos. Al final, se exponen algunas reflexiones sobre la situación actual de la CNDH y la posibilidad de que la institución se debilite a sí misma desde adentro y por sus propios medios.

Abstract Individuals with complete cervical spinal cord injury suffer from a permanent paralysis of upper limbs which prevents them from achieving most of the activities of daily living. We developed a neuroprosthetic solution to restore hand motor function. Electrical stimulation of the radial and median nerves by means of two epineural electrodes enabled functional movements of paralyzed hands. We demonstrated in two participants with complete tetraplegia that selective stimulation of nerve fascicles by means of optimized spreading of the current over the active contacts of the multicontact epineural electrodes induced functional and powerful grasping movements which remained stable over the 28 days of implantation. We also showed that participants were able to trigger the activation of movements of their paralyzed limb using an intuitive interface controlled by voluntary actions and that they were able to perform useful functional movements such as holding a can and drinking through a straw.

The impact of fungal infections on human health has been exacerbated by the rise of antifungal drug resistance. In this Review, the authors outline the problem of antifungal resistance and suggest how this growing threat might be mitigated.

INTRODUCTION: Deep brain stimulation (DBS) is widely used to alleviate symptoms of movement disorders. During intraoperative stimulation the influence of active or passive movements on the neuronal activity is often evaluated but the evaluation remains mostly subjective. The objective of this paper is to investigate the potential of a previously developed Weighted-frequency Fourier Linear combiner and Kalman filter-based recursive algorithm to identify tremor phases and types. METHODS: Ten accelerometer recordings from eight patients were acquired during DBS from which 186 phases were manually annotated into: rest, postural and kinetic phase without tremor, and rest, postural and kinetic phase with tremor. The method first estimates the instantaneous tremor frequency and then decomposes the motion signal into voluntary and tremorous parts. The tremorous part is used to quantify tremor and the voluntary part to differentiate rest, postural and kinetic phases. RESULTS: Instantaneous tremor frequency and amplitude are successfully tracked online. The overall accuracy for tremorous phases only is 89.1% and 76.3% when also non-tremorous phases are considered. Two main misclassification cases are identified and further discussed. CONCLUSION: The results demonstrate the potential of the developed algorithm as an online tremorous movement classifier. It would benefit from a more advanced tremor detector but nevertheless the obtained digital biomarkers offer an evidence-based analysis and could optimize the efficacy of DBS treatment.

Abstract The modalities of induction of labor in the event of premature rupture of membranes are controversial. The main purpose of this study was to compare the modalities of delivery after the use of dinoprostone or misoprostol for labor induction in the preterm rupture of membranes after 35 weeks in women with an unfavorable cervix. We then studied maternal and fetal morbidity for the two drugs. Retrospective, single-center, comparative cohort study in a level 3 maternity unit in France from 2009 to 2018 comparing vaginal administration of misoprostol 50 µg every six hours (maximum 150 µg) and administration of dinoprostone 10 mg, a slow-release vaginal insert, for 24 h (maximum 20 mg), for labor induction in the preterm rupture of membranes after 35 weeks in women with an unfavorable cervix (Bishop score

Numerous computational methods based on sequences or structures have been developed for the characterization of protein function, but they are still unsatisfactory to deal with the multiple functions of multi-domain protein families. Here we propose an original approach based on 1) the detection of conserved sequence modules using partial local multiple alignment, 2) the phylogenetic inference of species/genes/modules/functions evolutionary histories, and 3) the identification of co-appearances of modules and functions. Applying our framework to the multidomain ADAMTS-TSL family including ADAMTS (A Disintegrin-like and Metalloproteinase with ThromboSpondin motif) and ADAMTS-like proteins over nine species including human, we identify 45 sequence module signatures that are associated with the occurrence of 278 Protein-Protein Interactions in ancestral genes. Some of these signatures are supported by published experimental data and the others provide new insights (e.g. ADAMTS-5). The module signatures of ADAMTS ancestors notably highlight the dual variability of the propeptide and ancillary regions suggesting the importance of these two regions in the specialization of ADAMTS during evolution. Our analyses further indicate convergent interactions of ADAMTS with COMP and CCN2 proteins. Overall, our study provides 186 sequence module signatures that discriminate distinct subgroups of ADAMTS and ADAMTSL and that may result from selective pressures on novel functions and phenotypes.

BackgroundPatients with inflammatory bowel disease (IBD) may have a modified immune response to SARS-CoV-2. The objectives were to evaluate the prevalence of COVID-19 in patients treated with infliximab or vedolizumab, to analyze the factors associated with the infection, the impact of treatments and trough levels.MethodsPatients with IBD treated with intravenous biologics in 14 French centers were included between March and June 2020 and followed-up for 6 months. Blood samples were collected for serologies and trough levels. The analysis of factors associated with COVID-19 was conducted in a matched 1:1 case-control sub-study with positive patients.ResultsIn total, 1026 patients were included (74.9% infliximab). Over the follow-up period, 420 patients reported the occurrence of COVID-19 symptoms; 342 had been tested of whom 18 were positive. At the end of follow-up, 38 patients had a positive serology. Considering both nasal tests and serologies together, 46 patients (4.5%) had been infected. The risk of COVID-19 was related neither to the use of treatments (whatever the trough levels) nor to disease activity. Infections were more frequent when using public transport or living in flats in urban areas.ConclusionsThe prevalence rate of COVID-19 in this IBD population treated with intravenous infliximab or vedolizumab was the same as the one in the French population before the start of the vaccination campaign. The risk was increased by urban living and was not influenced by disease activity or biologics. Sanitary barrier measures remain the best way to protect against SARS-CoV-2 in patients with IBD in biological therapy.

Background Ovarian adenocarcinoma (OVAD) frequently metastasizes to the peritoneal cavity and manifests by the formation of ascites, which constitutes a tumor-promoting microenvironment. In the peritoneal cavity, two developmentally, phenotypically and functionally distinct macrophage subsets, immunocompetent large peritoneal macrophages (LPM) and immunosuppressive small peritoneal macrophages (SPM), coexist. Because peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor participating in macrophage differentiation and cooperates with CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor essential for SPM-to-LPM differentiation, PPARγ could be also involved in the regulation of SPM/LPM balance and could be a promising therapeutic target.Methods To evaluate the 15(S)-hydroxyeicosatetraenoic acid (HETE), a PPARγ endogenous ligand, impact on ovarian tumor growth, we intraperitoneally injected 15(S)-HETE into a murine ovarian cancer model. This experimental model consists in the intraperitoneally injection of ID8 cells expressing luciferase into syngeneic C57BL/6 female mice. This ID8 orthotopic mouse model is a well-established experimental model of end-stage epithelial OVAD. Tumor progression was monitored using an in vivo imaging system. Peritoneal immune cells in ascites were analyzed by flow cytometry and cell sorting. To determine whether the impact of 15(S)-HETE in tumor development is mediated through the macrophages, these cells were depleted by injection of liposomal clodronate. To further dissect how 15(S)-HETE mediated its antitumor effect, we assessed the tumor burden in tumor-bearing mice in which the PPARγ gene was selectively disrupted in myeloid-derived cells and in mice deficient of the recombination-activating gene Rag2. Finally, to validate our data in humans, we isolated and treated macrophages from ascites of individuals with OVAD.Results Here we show, in the murine experimental model of OVAD, that 15(S)-HETE treatment significantly suppresses the tumor growth, which is associated with the differentiation of SPM into LPM and the LPM residency in the peritoneal cavity. We demonstrate that C/EBPβ and GATA6 play a central role in SPM-to-LPM differentiation and in LPM peritoneal residence through PPARγ activation during OVAD. Moreover, this SPM-to-LPM switch is associated with the increase of the effector/regulatory T-cell ratio. Finally, we report that 15(S)-HETE attenuates immunosuppressive properties of human ovarian tumor-associated macrophages from ascites.Conclusion Altogether, these results promote PPARγ as a potential therapeutic target to restrain OVAD development and strengthen the use of PPARγ agonists in anticancer therapy.

One of the most challenging categories of threats circulating in the online world is social engineering, with malicious web links, fake news, clickbait, and other tactics. Malware URLs are extremely dangerous because they represent the main propagating vector for web malware. Malicious web links detection is a challenging task because the detection mechanism should not influence the consumers’ online experience. The proposed solutions must be sensitive enough, and fast enough to perform the detection mechanism before the user accesses the link and downloads its content. Our paper proposes three goals. The main purpose of this paper is to refine a methodology for malicious web links detection that may be used to experiment with machine learning algorithms. Moreover, we propose to use this methodology for training and comparing several machine learning algorithms such as Random Forest, Decision Tree, K-Nearest Neighbor. The results are compared, justified, and placed in the malicious web links literature. In addition, we propose to identify the most relevant features and draw some observations about them.

Summary: Histone deacetylases enzymes (HDACs) are chromatin modifiers that regulate gene expression through deacetylation of lysine residues within specific histone and non-histone proteins. A cell-specific gene expression pattern defines the identity of insulin-producing pancreatic β cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic β-cell identity and function using the pan-HDAC inhibitor trichostatin A through chromatin immunoprecipitation assays and RNA sequencing experiments. We observed that TSA alters insulin secretion associated with β-cell specific transcriptome programming in both mouse and human β-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative β-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. Our data indicate that HDAC activity could be required to protect against loss of β-cell identity with unsuitable expression of genes associated with alternative cell fates.

We present an in-situ energy dispersive X-ray fluorescence measurement of the content of Chromium and Nickel in the fumes produced by selective laser melting on an Inconel 625 powder. Significant variations of the intensities of the Chromium and Nickel Kα fluorescence lines were evidenced as a function of the laser power, lasing velocity and chamber atmosphere. Calibration has been carried out using Monte–Carlo particle transport simulations allowed to obtain a quantitative estimate of the Chromium and Nickel mass fraction in the fumes. The experimental data has been compared to the predictions of an analytical physico-chemical model with consistent results. This approach thus also allows to provide information on the temperature of the metallic bath.

Oxford University Press’ The Complete Works of Oscar Wilde (2000-) and The Collected Works of Walter Pater (2019-), are the result of a series of personal and editorial engagements spanning two centuries.From Walter Pater's Essays from ‘The Guardian’, which appeared in a private edition in 1897, to the two volumes of his journalism announced for 2023, including the two volumes of Oscar Wilde's journalistic writings published in 2013, publishers have always been interested in the periodical writings of Pater and Wilde. While the former’s reviews were published at the turn of the century, the latter’s extensive journalistic writings were quickly published in a (near) complete edition by a trio of committed editors in 1908. This commitment contrasts with the reticence of Pater’s editors, as this article aims to show by paying attention to the various editions of their reviews since the turn of the 20th century.

Microsatellite markers previously developed for other leguminous species were tested for cross-genus transferability and evaluated for their potential usefulness in providing an improved assessment of the genetic relationships between two closely related taxa belonging to Onobrychis genus (Fabaceae). Candidate microsatellite markers were tested for polymorphism and replicability in sixteen populations of O. montana DC. subsp. transsilvanica (Simonk.) Jáv. and O. montana. Out of the 23 SSRs, there were identified seven polymorphic loci. In total 32 alleles were detected and the number of alleles per locus varied from two to six. PIC values ranged from 0.375 to 0.6454, and four SSRs displayed a PIC > 0.5. Relative uniform rates of genetic diversity were obtained. In case of O. montana DC. subsp. transsilvanica (Simonk.) Jáv. the observed and expected heterozygosity ranged from 0.100 to 0.952 and from 0.219 to 0.525, respectively, while for O. montana ranged from 0.166 to 0.750 and from 0.083 to 0.375, respectively. Seven polymorphic SSRs with clear and reproducible amplification were identified. These markers proved to be very efficient for unambiguous population discrimination based on both geographic and taxonomic criteria. Hereafter, these SSR markers can be used as tools for evolutionary studies in Onobrychis genus, as well in providing knowledge on patterns of the species phylogeography.

Background: Among all studies describing COVID-19 clinical features during the first wave of the pandemic, only a few retrospective studies have assessed the correlation between olfac-tory dysfunction (OD) and the evolution of disease severity. The main aim was to assess whether OD is a predictive factor of COVID-19 severity based on the patient’s medical management (outpa-tient care, standard hospital admission, and ICU admission). Methods: A national, prospective, mul-ticenter cohort study was conducted in 20 public hospitals and a public center for COVID-19 screen-ing. During the first wave of the pandemic, from 6 April to 11 May 2020, all patients tested positive for COVID-19 confirmed by RT-PCR underwent two follow-up ENT consultations within 10 days of symptom onset. The main outcome measures were the evolution of medical management (out-patient care, standard hospital admission, and ICU admission) at diagnosis and along the clinical course of COVID-19 disease. Results: Among 481 patients included, the prevalence of OD was 60.7%, and it affected mostly female patients (74.3%) under 65 years old (92.5%), with fewer comor-bidities than patients with normal olfactory function. Here, 99.3% (290/292) of patients with OD presented with non-severe COVID-19 disease. Patients reporting OD were significantly less hospi-talized than the ones managed as outpatients, in either a standard medical unit or an ICU. Conclu-sions: As regards the clinical course of COVID-19 disease, OD could predict a decreased risk of hospitalization during the first wave of the pandemic.

This paper gives an overview of the processing methods available for now in GALILÉE-1 [1], the verification and processing system for evaluated data, developed at CEA. This paper shows also results illustrating the main processing steps. GALILÉE-1 consists of various components respectively dedicated to read/write the evaluated data independently of the format, to diagnose inconsistencies in the evaluated data and to provide continuous-energy and multigroup data as well as probability tables for particle transport and depletion codes. All these components are written in C++ language and share the same objects.

This paper describes the current status of GALILÉE-1 [1], the verification and processing system for evaluated data, developed at CEA. It consists of various components respectively dedicated to read/write the evaluated data independently of the format, to diagnose inconsistencies in the evaluated data and to provide continuous-energy and multigroup data as well as probability tables for particle transport and depletion codes. All these components are written in C++ language and share the same objects. In this paper, we detail the main advances made in GALILÉE-1: Unresolved Resonance Range (URR) treatment and anisotropy data production.

This study aimed to investigate the biotransformation capabilities of a hydroquinone-tolerant Digitalis purpurea cell line (DpHQ) for bioconverting hydroquinone (HQ) into arbutin, a compound with significant therapeutic and cosmetic applications. The research evaluated the influence of various HQ concentrations, feeding protocols, and carbon sources on arbutin bioconversion yield. By using HPLC-MS for the quantification of arbutin in biomass and medium, the study revealed that higher precursor (HQ) concentration led to a more pronounced growth inhibition under single dosing than sequential dosing. At lower sugar (3%) and precursor (4 mM HQ) levels, arbutin predominantly remained within the cells, whereas higher sugar (6%) and HQ (5–6 mM) levels promoted its release into the medium. Arbutin production ranged from 591 mg/L under single dosing to 3049 mg/L with sequential dosing, with the highest yield being achieved with 5 mM HQ in divided doses and 6% glucose. This study holds novelty for being the first to demonstrate the DpHQ’s tolerance to high concentrations of HQ and its efficient capabilities to bioconvert HQ to arbutin, indicating that D. purpurea is equipped with the enzymes required for this process. These aspects highlight its potential as a biotechnological source for arbutin synthesis.

Neurons exhibit a limited ability of repair. Given that mechanical forces affect neuronal outgrowth, it is important to investigate whether mechanosensitive ion channels may regulate axon regeneration. Here, we show that DmPiezo, a Ca2+-permeable non-selective cation channel, functions as an intrinsic inhibitor for axon regeneration in Drosophila. DmPiezo activation during axon regeneration induces local Ca2+ transients at the growth cone, leading to activation of nitric oxide synthase and the downstream cGMP kinase Foraging or PKG to restrict axon regrowth. Loss of DmPiezo enhances axon regeneration of sensory neurons in the peripheral and CNS. Conditional knockout of its mammalian homolog Piezo1 in vivo accelerates regeneration, while its pharmacological activation in vitro modestly reduces regeneration, suggesting the role of Piezo in inhibiting regeneration may be evolutionarily conserved. These findings provide a precedent for the involvement of mechanosensitive channels in axon regeneration and add a potential target for modulating nervous system repair.

Background & aimsIncreased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH.MethodsIn an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis.ResultsThe contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF.ConclusionIn an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555.