Search Results (32)

Background/Objectives: Individuals with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) in pregnancy are two distinct cardiometabolic populations, each potentially necessitating alternative clinical management. However, our understanding of the unique physiological effects of uncomplicated MHO on fetoplacental growth and metabolism remains limited. In this study, we aimed to identify changes in placental morphology and metabolites associated with maternal obesity, independent of pregnancy-related cardiometabolic complications. Methods: Placentae from women with a prepregnancy body mass index (BMI) < 25 kg/m² (control; n = 15) and women with MHO (prepregnancy BMI > 30 kg/m² with no cardiometabolic diseases; n = 15) were analyzed for indices of placental growth and untargeted metabolomics. Complementary assessments were conducted on proinflammatory genes and antioxidant defense system genes, proteins, and enzymes, along with lipid peroxidation markers. Results: Clear placentomegaly without histopathological changes was observed in uncomplicated MHO pregnancies. The metabolite 3-aminoisobutanoic acid emerged as the top-ranked feature distinguishing placentae from MHO individuals from control placentae, and changes in the cysteine, methionine, and vitamin B6 metabolism pathways were among the most distinct differences identified. Conclusions: These findings illustrate an altered placental morphology and metabolomic profile specific to uncomplicated MHO, offering new insights into how obesity, without cardiometabolic complications, may influence fetoplacental growth and metabolism. They may also represent a crucial first step towards marker identification for MHO pregnancy and underscore the importance of alternative care pathways when obesity is present but metabolic comorbidities are absent. Full article

Medical researchers are increasingly utilizing advanced LLMs like ChatGPT-4 and Gemini to enhance diagnostic processes in the medical field. This research focuses on their ability to comprehend and apply complex medical classification systems for breast conditions, which can significantly aid plastic surgeons in making informed decisions for diagnosis and treatment, ultimately leading to improved patient outcomes. Fifty clinical scenarios were created to evaluate the classification accuracy of each LLM across five established breast-related classification systems. Scores from 0 to 2 were assigned to LLM responses to denote incorrect, partially correct, or completely correct classifications. Descriptive statistics were employed to compare the performances of ChatGPT-4 and Gemini. Gemini exhibited superior overall performance, achieving 98% accuracy compared to ChatGPT-4’s 71%. While both models performed well in the Baker classification for capsular contracture and UTSW classification for gynecomastia, Gemini consistently outperformed ChatGPT-4 in other systems, such as the Fischer Grade Classification for gender-affirming mastectomy, Kajava Classification for ectopic breast tissue, and Regnault Classification for breast ptosis. With further development, integrating LLMs into plastic surgery practice will likely enhance diagnostic support and decision making. Full article

In marine ecology, the most studied interactions are trophic and are in networks called food webs. Trophic modeling is mainly based on weighted networks, where each weighted edge corresponds to a flow of organic matter between two trophic compartments, containing individuals of similar feeding behaviors and metabolisms and with the same predators. To take into account the unknown flow values within food webs, a class of methods called Linear Inverse Modeling was developed. The total linear constraints, equations and inequations defines a multidimensional convex-bounded polyhedron, called a polytope, within which lie all realistic solutions to the problem. To describe this polytope, a possible method is to calculate a representative sample of solutions by using the Monte Carlo Markov Chain approach. In order to extract a unique solution from the simulated sample, several goal (cost) functions—also called Ecological Network Analysis indices—have been introduced in the literature as criteria of fitness to the ecosystems. These tools are all related to information theory. Here we introduce new functions that potentially provide a better fit of the estimated model to the ecosystem. Full article

The choice of the factorization rank of a matrix is critical, e.g., in dimensionality reduction, filtering, clustering, deconvolution, etc., because selecting a rank that is too high amounts to adjusting the noise, while selecting a rank that is too low results in the oversimplification of the signal. Numerous methods for selecting the factorization rank of a non-negative matrix have been proposed. One of them is the cophenetic correlation coefficient ($ccc$), widely used in data science to evaluate the number of clusters in a hierarchical clustering. In previous work, it was shown that $ccc$ performs better than other methods for rank selection in non-negative matrix factorization (NMF) when the underlying structure of the matrix consists of orthogonal clusters. In this article, we show that using the ratio of $ccc$ to the approximation error significantly improves the accuracy of the rank selection. We also propose a new criterion, $concordance$, which, like $ccc$, benefits from the stochastic nature of NMF; its accuracy is also improved by using its ratio-to-error form. Using real and simulated data, we show that $concordance$, with a CUSUM-based automatic detection algorithm for its original or ratio-to-error forms, significantly outperforms $ccc$. It is important to note that the new criterion works for a broader class of matrices, where the underlying clusters are not assumed to be orthogonal. Full article

Background: Peripheral femoro-femoral veno-arterial extracorporeal membrane oxygenation is increasingly used in refractory cardiogenic shock. However, the obstruction of the femoral artery by the return cannula could lead to acute limb ischemia, a frequently encountered situation that is inconstantly prevented by the adjunction of a distal perfusion cannula (DPC). The aim of this study was to investigate the influence of three physical parameters on the perfusion of the cannulated lower limb. Methods: Using patient-specific arterial models and computational fluid dynamic simulations, we studied four diameters of arterial cannula, three diameters of DPC, and two percentages of arterial section limitation. Results: We found that adequate perfusion of the cannulated limb was achieved in only two out of the twenty-one configurations tested, specifically, when the arterial cannula had a diameter of 17 Fr, was considered to limit the section of the artery by 90%, and was associated with an 8 Fr or a 10 Fr DPC. Multivariable analysis revealed that the perfusion of the cannulated lower limb was correlated with the diameter of the DPC, but also with the diameter of the arterial cannula and the percentage of arterial section limitation. Conclusions: In most of the cases simulated here, the current system combining unsized arterial cannula and non-specific DPC was not sufficient to provide adequate perfusion of the cannulated lower limb, urging the need for innovative strategies to efficiently prevent acute limb ischemia during peripheral femoro-femoral veno-arterial extracorporeal membrane oxygenation. Full article

Bats are a major reservoir of zoonotic viruses, including coronaviruses. Since the emergence of SARS-CoV in 2002/2003 in Asia, important efforts have been made to describe the diversity of Coronaviridae circulating in bats worldwide, leading to the discovery of the precursors of epidemic and pandemic sarbecoviruses in horseshoe bats. We investigated the viral communities infecting horseshoe bats living in Northern Vietnam, and report here the first identification of sarbecoviruses in Rhinolophus thomasi and Rhinolophus siamensis bats. Phylogenetic characterization of seven strains of Vietnamese sarbecoviruses identified at least three clusters of viruses. Recombination and cross-species transmission between bats seemed to constitute major drivers of virus evolution. Vietnamese sarbecoviruses were mainly enteric, therefore constituting a risk of spillover for guano collectors or people visiting caves. To evaluate the zoonotic potential of these viruses, we analyzed in silico and in vitro the ability of their RBDs to bind to mammalian ACE2s and concluded that these viruses are likely restricted to their bat hosts. The workflow applied here to characterize the spillover potential of novel sarbecoviruses is of major interest for each time a new virus is discovered, in order to concentrate surveillance efforts on high-risk interfaces. Full article

Maternal obesity and gestational diabetes mellitus (GDM) are linked with impaired placental function and early onset of non-communicable cardiometabolic diseases in offspring. Previous studies have highlighted that the dietary non-esterified fatty acids (NEFAs) palmitate (PA) and oleate (OA), key dietary metabolites associated with maternal obesity and GDM, are potential modulators of placental lipid processing. Using the BeWo cell line model, the current study integrated transcriptomic (mRNA microarray), metabolomic, and lipidomic readouts to characterize the underlying impacts of exogenous PA and OA on placental villous trophoblast cell metabolism. Targeted gas chromatography and thin-layer chromatography highlighted that saturated and monounsaturated NEFAs differentially impact BeWo cell lipid profiles. Furthermore, cellular lipid profiles differed when exposed to single and multiple NEFA species. Additional multi-omic analyses suggested that PA exposure is associated with enrichment in β-oxidation pathways, while OA exposure is associated with enrichment in anti-inflammatory and antioxidant pathways. Overall, this study further demonstrated that dietary PA and OA are important regulators of placental lipid metabolism. Encouraging appropriate dietary advice and implementing dietary interventions to maintain appropriate placental function by limiting excessive exposure to saturated NEFAs remain crucial in managing at-risk obese and GDM pregnancies. Full article

The improvement of our knowledge of the virosphere, which includes unknown viruses, is a key area in virology. Metagenomics tools, which perform taxonomic assignation from high throughput sequencing datasets, are generally evaluated with datasets derived from biological samples or in silico spiked samples containing known viral sequences present in public databases, resulting in the inability to evaluate the capacity of these tools to detect novel or distant viruses. Simulating realistic evolutionary directions is therefore key to benchmark and improve these tools. Additionally, expanding current databases with realistic simulated sequences can improve the capacity of alignment-based searching strategies for finding distant viruses, which could lead to a better characterization of the “dark matter” of metagenomics data. Here, we present Virus Pop, a novel pipeline for simulating realistic protein sequences and adding new branches to a protein phylogenetic tree. The tool generates simulated sequences with substitution rate variations that are dependent on protein domains and inferred from the input dataset, allowing for a realistic representation of protein evolution. The pipeline also infers ancestral sequences corresponding to multiple internal nodes of the input data phylogenetic tree, enabling new sequences to be inserted at various points of interest in the group studied. We demonstrated that Virus Pop produces simulated sequences that closely match the structural and functional characteristics of real protein sequences, taking as an example the spike protein of sarbecoviruses. Virus Pop also succeeded at creating sequences that resemble real sequences not included in the databases, which facilitated the identification of a novel pathogenic human circovirus not included in the input database. In conclusion, Virus Pop is helpful for challenging taxonomic assignation tools and could help improve databases to better detect distant viruses. Full article

Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties. Full article

Conditions are highlighted for generalized entropies to allow for non-trivial time-averaged entropy rates for a large class of random sequences, including Markov chains and continued fractions. The axiomatic-free conditions arise from the behavior of the marginal entropy of the sequence. Apart from the well-known Shannon and Rényi cases, only logarithmic versions of Sharma–Taneja–Mittal entropies may fulfill these conditions. Their main properties are detailed. Full article

We present Microseek, a pipeline for virus identification and discovery based on RVDB-prot, a comprehensive, curated and regularly updated database of viral proteins. Microseek analyzes metagenomic Next Generation Sequencing (mNGS) raw data by performing quality steps, de novo assembly, and by scoring the Lowest Common Ancestor (LCA) from translated reads and contigs. Microseek runs on a local computer. The outcome of the pipeline is displayed through a user-friendly and dynamic graphical interface. Based on two representative mNGS datasets derived from human tissue and plasma specimens, we illustrate how Microseek works, and we report its performances. In silico spikes of known viral sequences, but also spikes of fake Neopneumovirus viral sequences generated with variable evolutionary distances from known members of the Pneumoviridae family, were used. Results were compared to Chan Zuckerberg ID (CZ ID), a reference cloud-based mNGS pipeline. We show that Microseek reliably identifies known viral sequences and performs well for the detection of distant pseudoviral sequences, especially in complex samples such as in human plasma, while minimizing non-relevant hits. Full article

Background: To evaluate the cost-effectiveness of the extended use of ablation for the treatment of hepatocellular carcinoma (HCC) with cirrhosis in an expert ablation center when compared to the non-extended use of ablation in equivalent tertiary care centers. Methods: Consecutive cirrhotic patients with non-metastatic HCC, no prior treatment, and referred to three tertiary care centers between 2012 and 2016 were retrospectively identified. The Bondy group, including all of the patients treated at Jean Verdier Hospital, where the extended use of ablation is routinely performed, was compared to the standard of care (SOC) group, including all of the patients treated at the Beaujon and Mondor Hospitals, using propensity score matching. A cost-effectiveness analysis was carried out from the perspective of French health insurance using a Markov model on a lifetime horizon. Results: 532 patients were matched. The Bondy group led to incremental discounted lifetime effects of 0.8 life-years gained (LYG) (95% confidence interval: 0.4, 1.3) and a decrease in lifetime costs of EUR 7288 (USD 8016) (95% confidence interval: EUR 5730 [USD 6303], EUR 10,620 [USD 11,682]) per patient, compared with the SOC group, resulting in a dominant mean incremental cost-effectiveness ratio (ICER). A compliance with the Barcelona Clinic Liver Classification (BCLC) guidelines for earlier stage contributed to the greater part of the ICER. Conclusion: The extended use of ablation in cirrhotic patients with HCC was more effective and less expensive than the non-extended use of the ablation strategy. Full article

Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders. Full article

Canine babesiosis is an important tick-borne disease worldwide, caused by parasites of the Babesia genus. Although the disease process primarily affects erythrocytes, it may also have multisystemic consequences. The goal of this study was to explore and characterize the serum metabolome, by identifying potential metabolites and metabolic pathways in dogs naturally infected with Babesia canis using liquid and gas chromatography coupled to mass spectrometry. The study included 12 dogs naturally infected with B. canis and 12 healthy dogs. By combining three different analytical platforms using untargeted and targeted approaches, 295 metabolites were detected. The untargeted ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) metabolomics approach identified 64 metabolites, the targeted UHPLC-MS/MS metabolomics approach identified 205 metabolites, and the GC-MS metabolomics approach identified 26 metabolites. Biological functions of differentially abundant metabolites indicate the involvement of various pathways in canine babesiosis including the following: glutathione metabolism; alanine, aspartate, and glutamate metabolism; glyoxylate and dicarboxylate metabolism; cysteine and methionine metabolism; and phenylalanine, tyrosine, and tryptophan biosynthesis. This study confirmed that host–pathogen interactions could be studied by metabolomics to assess chemical changes in the host, such that the differences in serum metabolome between dogs with B. canis infection and healthy dogs can be detected with liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) methods. Our study provides novel insight into pathophysiological mechanisms of B. canis infection. Full article

Archean greenstone belts are renowned for their Au endowment. Gold can be associated with orogenic Au style of mineralization and with diorite-hosted Au-Cu disseminated sulfides interpreted as a porphyry style of mineralization. The Regnault Au project, located in the Frotet–Evans greenstone belt (Superior craton), is a structurally-controlled and diorite-hosted mineralization with an unclear metallogenic model. The aim of this study is to evaluate the fertility of the Regnault granodiorite-diorite-gabbro intrusive. Using whole-rock chemistry and petrological observations, it is concluded that the intrusive suite derives from a differentiated and water-bearing magma extracted from the metasomatized mantle. Amphibole chemistry indicates that the magma was moderately oxidized and that it emplaced at a shallow depth. It is concluded that the Regnault intrusive suite displays several characteristics favorable to the exsolution of magmatic fluids in the upper crust and that the Regnault Au mineralization potentially corresponds to, at least in part, a magmatic-hydrothermal system. Full article