Search

Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure–activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L1. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) are susceptible to complement-mediated intravascular hemolysis and thrombosis. Factor H (FH) is the main regulator of the complement alternative pathway, which protects cells from unwanted complement-mediated damage. Although FH is not a glycosylphosphatidylinositol-linked molecule, it may play a role in PNH. We sought to determine if rare germline variants in complement factor H (CFH) affect the PNH course, screening 84 patients with PNH treated with eculizumab for rare variants in CFH, CFI, and C3 genes. We compared the allelic frequencies with populational data and a geographically-matched control group, looking for an association between presence of the variants and treatment response (transfusion independence by 6 months). Sixteen patients presented rare variants, 9 in CFH (10.7%). Germline CFH variants were more frequent among patients with PNH than among controls (P = .02) or public data (P < .001) and were more likely to be transfusion-dependent at 6 months after eculizumab initiation (P = .015). With a median follow-up of 5.8 years, 8 of 9 patients with the CFH variant received transfusions, and 2 developed thromboses. None of the patients with the CFH variant had severe aplastic anemia from eculizumab initiation until 6 months. We demonstrated for the first time that rare CFH variants are over-represented among patients with PNH and that germline genetic background may affect the response to eculizumab.

This study highlights the indoor thermal comfort in a classroom building mostly built with locally available construction materials combined with some passive techniques in the hot semi-arid climate of Marrakech, Morocco. The thermal assessment of this so-called Baterre building was analysed against a typical building (TB), which represents the structure most widely used in Moroccan rural classrooms and is constructed with conventional materials. A TRNSYS-based dynamic model was developed and validated using onsite monitoring measurements according to American Society of Heating, Refrigerating and Air-Conditioning Engineers (Ashrae) guideline 14. Simulation results show that the Baterre structure has a noticeable positive effect on indoor thermal comfort since its indoor air temperature remains stable while that of the TB classroom has higher oscillations. The hourly calculated indoor air temperature in Baterre is greater by 3.6°C during winter and lower by 9.54°C during summer than that in the TB. Moreover, indoor thermal comfort analysis based on the Ashrae Standard 55-2013 shows that Baterre provides good indoor thermal comfort 63% of the time all year round, while the corresponding indoor thermal comfort time value in the TB is 32%. Furthermore, the annual thermal load of Baterre is lower by 53% than that of the TB.

The present work aims to optimize the thermal behavior of a building envelope by combining sensitivity analysis (SA) and multi-objective optimization (MOO). An existing classroom located in Marrakech city was considered a case study building. The building model was analyzed under six Moroccan climate zones. The SA was applied on 16 design variables and performed using the Morris method implemented in the tool Simlab to rank each design variable based on its influence on the objective function (overall energy demand). The SA results showed that the solar absorptance of the internal roof, wall, and ground floor and the ground hollow core slab thickness impacted less the overall energy demand. Therefore, the only remaining variables showing the most relevant effect will be optimized afterward. The optimization phase was conducted by coupling the generic optimization tool GenOpt with TRNSYS. The optimum solution was selected based on the Pareto front approach. The obtained results assessed the effectiveness of the adopted methodological approach in significant minimization of the required thermal loads. Furthermore, the values of each optimum design variables set differ from one climate zone to another; leading to energy demand reduction varying from 30 to 42%, in comparison with the original design building.

Introduction: in recent years, scientists have looked into the subject of love addiction given the neurobiological, psychological and behavioral similarities of people who have experienced this feeling, which is described by some as a mystery and by others as a disease in its own right. What about the psychiatric and scientific point of view? Does an addiction to a person or an emotion exist? Is love addictogenic? Objectives: Evaluate the notion of love addiction and its prevalence, assess the severity of addiction and dependence on the “loved” person and finally determine if this entity really exists? Material and methods: descriptive study including 507 people who were able to answer our online survey (Google forms) and patients consulting or hospitalized in the addictology department at Arrazi Hospital in Salé Morroco, this survey was inspired by the diagnostic criteria of substance use disorders of the DSM 5, and the statistical analysis will be done through the same tool. Results: Female gender was the most to participate (79.9%) as well as young age between 21 and 40 years (80.5%), all with a university school level. 80.5% had no psychiatric history and 80.9% had no history of addictive behaviors. The questions that were asked to the participants correspond to the DSM 5 criteria of substance use disorders applied in the context of love addiction, and they were asked to answer each of them with yes or no: The 2 criteria out of 11 essential to make the diagnosis of an addictive behaviour were found in: 70% of the participants! Of which 44.4% had 6 or more criteria and therefore the intensity was severe. Conclusion: love addiction is a disorder that can cause suffering as intense as substance use, therefore, it needs to be treated with as much interest as drug use.

International audience; Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients.Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707).Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034).Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens.

Lignin is a promising bio-polyphenol that can be used as a catalyst in various industrial and commercial processes. Its high catalytic activity and reusability can provide a sustainable alternative to conventional catalysts.

We force the existence of a non-trivial κ \kappa -complete ultrafilter over κ \kappa which fails to satisfy the Galvin property. This answers a question asked by Benhamou and Gitik [Ann. Pure Appl. Logic 173 (2022), Paper No. 103107].

Survivors of immune-mediated thrombotic thrombocytopenic purpura (iTTP) are exposed to clinical relapses when a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13 (ADAMTS13) activity decreases during follow-up. Although preemptive rituximab usually improves ADAMTS13 activity in this context, 15% of patients experience refractoriness or intolerance to rituximab and require alternative strategies. Here, we addressed whether cyclosporine A (CSA) could improve ADAMTS13 activity and prevent clinical relapses in this context. We treated preemptively with CSA 14 iTTP patients who were unresponsive (n = 11) or intolerant (n = 3) to rituximab. All patients had a severe ADAMTS13 deficiency (activity20%) and otherwise in clinical remission. ADAMTS13 activity normalized in almost all patients (n = 13, 93%), after a median time of 2.5 months [IQR 1-6] following initiation. Median duration of CSA treatment was 17.5 months [IQR 10-34]. ADAMTS13 activity further declined to undetectable values during follow-up in five patients, but retreatment with rituximab or CSA allowed a recovery in ADAMTS13 activity in three cases. CSA could be stopped durably in two patients, while two others experienced an ADAMTS13 relapse. Severe but reversible side effects requiring cessation of the treatment occurred in two patients. CSA provides high and sustained response rates in patients who are refractory or intolerant to rituximab, with acceptable adverse events.

The current study investigates for the first time the physico-chemical performances of lignins from cactus waste seeds (CWS) and spent coffee (SC) in comparison to previously isolated lignins from sugar byproducts (bagasse (SCB) and beet pulp (SBP)). In this work, lignin-phenol formaldehyde (LPF) resins were formulated using various lignin loadings (5-30 wt%), characterized and applied in the manufacturing of plywood panels. Several characterization techniques were applied to identify the chemical and morphological properties, thermal stability, and phenolic content of the extracted lignins, as well as the bonding strength and wood failure of the formulated resins. Results showed that the CWS and SC could be considered as an important source for lignin recovery with a considerable yield of 15.46 % and 27.08 % and an important hydroxyl phenolic content of 1.26 mmol/g and 1.36 mmol/g for CWS and SC, respectively. Interestingly, 20 wt% of extracted lignins in PF adhesives were the optimal formulation showing an improved modulus of elasticity (MOE) of about 3505, 3536 and 3515 N/mm

The current COVID-19 pandemic has resulted in an urgent need for methods to decontaminate respirators masks for reuse while keeping them intact and functional. The severe shortage of professional masks such as N95 and FFP2 has necessitated their reuse over long periods. A very promising method is the pasteurization of these masks by thermoplasmonic heat generated by plasmonics nanoparticles when they are irradiated by light. Under illumination at its plasmonic resonance, a metal nanoparticle features enhanced light absorption, turning it into an ideal nano-source of heat, remotely controllable using light. In this work, we propose a numerical study based on the finite element method (FEM) of the thermoplasmonic properties of silver nanoparticles (AgNPs) decorating polypropylene (PP) fibers which is a basic material for the manufacture of these masks. The surface plasmon resonance (SPR) of these nanostructures was investigated through the computation of the complex effective dielectric permittivity and the absorption cross section in the near UV-visible (NUV-Vis) range. First, the SPR characteristics of AgNPs for different morphologies are determined from the absorption spectra, including the SPR-peak position λ

Local anesthetics have anti-inflammatory effects. Because most previous experiments were performed with supra-therapeutic concentrations, we measured the effects of clinically relevant concentrations of bupivacaine on the Toll like receptor 4 (TLR4)- and TLR2-myeloid differentiation primary response 88 (MyD88)-nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathways. We measured tumor necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2) release, p38 mitogen-activated protein kinase (MAP-kinase) phosphorylation and translocation of NF-κB in human peripheral blood mononuclear cells (hPBMCs) and human monocytes challenged with lipopolysaccharide (LPS) or tripalmitoylated lipopeptide Pam3CysSerLys4 (Pam3CSK4) in the presence or absence of bupivacaine. Similarly, we measured the effect of bupivacaine on HEK293 cells expressing the hTLR4 and the hTLR2 genes and challenged with LPS or Pam3CSK4. Finally, molecular docking simulations of R(+)- and S(-)-bupivacaine binding to the TLR4-myeloid differentiation protein 2 (MD-2) complex and to the TLR2/TLR1 heterodimer were performed. In PBMCs, bupivacaine from 0.1 to 100 μM inhibited LPS-induced TNF-α and PGE2 secretion, phosphorylation of p38 and nuclear translocation of NF-κB in monocytes. Bupivacaine similarly inhibited the effects of Pam3CSK4 on TNF-α secretion. Bupivacaine inhibited the effect of LPS on HEK293 cells expressing the human TLR4 receptor and the effect of Pam3CSK4 on HEK293 cells expressing the human TLR2 receptor. Molecular docking showed that bupivacaine binds to the MD-2 co-receptor of TLR4 and to the TLR2 receptor. Contrary to numerous experiments performed with supratherapeutic doses, our results were obtained with concentrations of bupivacaine as low as 0.1 μM. We conclude that bupivacaine modulates the inflammatory reactions such as those observed after surgery or trauma, at least partly by inhibiting the TLR4- and TLR2-NF-κB pathways.

Cellulose is an interesting biopolymer offering numerous functionalization possibilities for various applications. Yet, cellulose functionalization usually involves expensive chemicals and complex processes. Here, we aim to utilize inexpensive fertilizer-grade phosphate for cellulose functionalization. Cellulose microfibers (CMF) were isolated from Giant Reed (GR) and were then phosphorylated using either a reagent-grade or a fertilizer-grade diammonium hydrogen phosphate (DAP) in the presence of urea following a water-based protocol. The effect of DAP on the phosphorylation reaction was mainly studied by conductometric titration, ICP-OES and FTIR, while further characterization was performed by SEM/EDX, TGA and XRD to investigate the morphology, composition, charge content, structure, and thermal degradation of the phosphorylated materials. It was found that cellulose phosphorylation using DAP fertilizer gave materials with the same charge content as that registered when using the reagent-grade DAP. Optimizing the reaction conditions with respect to the amount of fertilizer-grade DAP used for the phosphorylation gave high charge content (7000 mmol·g

While spatial proteomics by fluorescence imaging has quickly become an essential discovery tool for researchers, fast and scalable methods to classify and embed single-cell protein distributions in such images are lacking. Here, we present the design and analysis of the results from the competition Human Protein Atlas – Single-Cell Classification hosted on the Kaggle platform. This represents a crowd-sourced competition to develop machine learning models trained on limited annotations to label single-cell protein patterns in fluorescent images. The particular challenges of this competition include class imbalance, weak labels and multi-label classification, prompting competitors to apply a wide range of approaches in their solutions. The winning models serve as the first subcellular omics tools that can annotate single-cell locations, extract single-cell features and capture cellular dynamics.

At the diagnosis of hepatocellular carcinoma (HCC), more than 90% of HCC patients present cirrhosis, a clinical condition often associated to malnutrition. Sarcopenia is an indirect marker of malnutrition assessable on computed tomography (CT).To evaluate the prognostic value of sarcopenia in patients with HCC treated by trans-arterial (chemo)-embolization.Patients with HCC treated by a first session of trans-arterial (chemo)embolization and an available CT scan before treatment were included. Sarcopenia was assessed using skeletal muscle index at baseline and at the first radiological assessment. Radiological response was recorded after the first session of treatment using mRECIST.Of 225 patients treated by trans-arterial bland embolization (Sarcopenia is associated with tumor progression and poor survival outcomes after trans-arterial (chemo)-embolization for HCC.

Two-dimensional Dirac fermions in HgTe quantum wells close to the topological phase transition can generate significant cyclotron emission that is magnetic field tunable in the Terahertz (THz) frequency range. Due to their relativistic-like dynamics, their cyclotron mass is strongly dependent on their electron concentration in the quantum well, providing a second tunability lever and paving the way for a gate-tunable, permanent-magnet Landau laser. In this work, we demonstrate the proof-of-concept of such a back-gate tunable THz cyclotron emitter at fixed magnetic field. The emission frequency detected at 1.5 Tesla is centered on 2.2 THz and can already be electrically tuned over 250 GHz. With an optimized gate and a realistic permanent magnet of 1.0 Tesla, we estimate that the cyclotron emission could be continuously and rapidly tunable by the gate bias between 1 and 3 THz, that is to say on the less covered part of the THz gap., 6 pages, 4 figures

International audience; Boolean network modeling of gene regulation but also of post-transcriptomic systems has proven over the years that it can bring powerful analyses and corresponding insight to the many cases where precise biological data is not sufficiently available to build a detailed quantitative model. Besides simulation, the analysis of such models is mostly based on attractor computation, since those correspond roughly to observable biological phenotypes.The recent use of trap spaces made a real breakthrough in that field allowing to consider medium-sized models that used to be out of reach. However,with the continuing increase in model size and complexity of Boolean update functions, the state-of-the-art computation of minimal trap spaces based onprime implicants shows its limits due to the difficulty of the prime-implicant computation. In this article we explore and prove for the first time a connection between trap spaces of a general Boolean network and siphons of its Petri net encoding. Besides important theoretical applications in studying propertiesof trap spaces, the connection enables us to propose an alternative approach to compute minimal trap spaces, and hence complex attractors, of a generalBoolean network. It replaces the need for prime implicants by a completely different technique, namely the enumeration of maximal siphons in the Petri net encoding of the original model. We then demonstrate its efficiency and compare it to the state-of-the-art methods on a large collection of real-world and randomly generated models.

We continue the study of the Galvin property. In particular, we deepen the connection between certain diamond-like principles and non-Galvin ultrafilters. We also show that any Dodd sound ultrafilter that is not a $p$-point is non-Galvin. We use these ideas to formulate an essentially optimal large cardinal hypothesis that ensures the existence of a non-Galvin ultrafilter, improving on results of Benhamou and Dobrinen. Finally, we use a strengthening of the Ultrapower Axiom to prove that in all the known canonical inner models, a $\kappa$-complete ultrafilter on $\kappa$ has the Galvin property if and only if it is an iterated sum of $p$-points.

Despite technological progress and a large amount of research on Industry 4.0, digital transformation remains a complex process that most manufacturers are hesitant to invest in. Interest in digital Kanban, for example, remains low compared with traditional Kanban, which is widely used. This applies to the other card-based production control systems, including CONstant Work-In-Process (CONWIP), which is the focus of this paper. In an industrial context where digitization and Industry 4.0 are the main trends, one may wonder why traditional CONWIP is preferred to digital CONWIP. Following a praxeological approach (i.e., study of practice and instrumentation), this article explores the strengths and weaknesses of the CONWIP practice, in both its paper and electronic versions, while taking into account the human dimension. The aim is to motivate potential CONWIP users to implement it in its digital mode and to show them how a Digital Twin-based solution can overcome the managerial problems that arise with digitization while enabling improved performance. As an illustration, experience feedback from several companies using Digital Twin with CONWIP is provided.

Objectives: In this large multicentre study, we compared the effectiveness and safety of tocilizumab intravenous versus subcutaneous (SC) in 109 Takayasu arteritis (TAK) patients.Methods: We conducted a retrospective multicentre study in referral centres from France, Italy, Spain, Armenia, Israel, Japan, Tunisia and Russia regarding biological-targeted therapies in TAK, since January 2017 to September 2019.Results: A total of 109 TAK patients received at least 3 months tocilizumab therapy and were included in this study. Among them, 91 and 18 patients received intravenous and SC tocilizumab, respectively. A complete response (NIH

International audience; Abstract Motivation Boolean networks are simple but efficient mathematical formalism for modelling complex biological systems. However, having only two levels of activation is sometimes not enough to fully capture the dynamics of real-world biological systems. Hence, the need for multi-valued networks (MVNs), a generalization of Boolean networks. Despite the importance of MVNs for modelling biological systems, only limited progress has been made on developing theories, analysis methods, and tools that can support them. In particular, the recent use of trap spaces in Boolean networks made a great impact on the field of systems biology, but there has been no similar concept defined and studied for MVNs to date. Results In this work, we generalize the concept of trap spaces in Boolean networks to that in MVNs. We then develop the theory and the analysis methods for trap spaces in MVNs. In particular, we implement all proposed methods in a Python package called trapmvn. Not only showing the applicability of our approach via a realistic case study, we also evaluate the time efficiency of the method on a large collection of real-world models. The experimental results confirm the time efficiency, which we believe enables more accurate analysis on larger and more complex multi-valued models. Availability and implementation Source code and data are freely available at https://github.com/giang-trinh/trap-mvn.

Study objectives: This study attempts to describe the epidemiological and biological profiles as well as the common etiologies of thrombocytopenia in patients admitted to University Hospital center Mohammed VI in Marrakesh, Morocco, over a period of six months between March 2021 and August 2021. Patients and methods: This is a prospective study of 673 patients hospitalized in the University Hospital center -Mohammed VI-Marrakesh between March and August 2021 whose admission blood tests show thrombocytopenia. Results: Thrombocytopenia was found in 673 patients, mainly from the intensive care unit (28%) and the department of hematology & oncology (16%), the sex ratio was 1.3 with a male predominance of 58%, the average age of our patients was 37.1 years. On biological plan, prothrombin (PT) and CRP were the two most noticed disturbed biological markers in our series, at 50% and 79% respectively, the etiological profile of our patients demonstrated a predominance of peripheral thrombocytopenia at 83.2%, The most frequent causes were infectious (43%), bacterial, viral or parasitic, followed by anomaly of distribution of platets (12%) and immunological thrombocytopenia (9%). Conclusion: Our study shows that thrombocytopenia is a frequent biological anomaly that can affect both sexes, of any age, it is most often multifactorial, but the main cause is infection, requiring a correlation of epidemiological, clinical and biological profiles in order to adapt the treatment.

During the COVID-19 outbreak, numerous reports indicated a higher mortality rate among cardiovascular patients. We investigated how this trend applied to patients admitted to the cardiac intensive care unit (CICU).We retrospectively compared CICU patients admitted during the initial peak of the COVID outbreak between February and May 2020 (Covid Era, CE group) to a control group in pre-pandemic time in 2019. We interviewed patients to determine the symptom onset time and the time interval between symptomology and hospital arrival.The data of 292 patients were used in the analysis (119 patients in the CE group and 173 in the control group). CE patients had a higher incidence of ischemic heart disease (IHD) (p.03), heart failure (p.04), and psychiatric disorders (p.001). During COVID time, more patients were hospitalized with myocarditis (OR: 26.45), arrhythmias (OR: 2.88), and new heart failure (HF) (p.001) and less with STEMI (OR: 0.39; 95% CI: 0.24-0.63). Fewer PCIs were performed in the CE group (p.001), with an overall lower success rate (p.05) than reported in the control group. Patients in the CE group reported a longer period between symptom onset to hospital arrival (p.001, χ2 = 12.42). The six-month survival rate was significantly lower in CE patients (χ2 = 7.01, P = 0.008).Among CICU patients admitted to our center during the initial period of the COVID pandemic, STEMI events were less frequent while cases of newly diagnosed HF sharply increased. Patients waited longer after symptom onset before seeking medical care during the pandemic. The delay may have resulted in clinical deterioration that could explain the high mortality rate and the new HF admission rate.

Sub-stoichiometric aggregation inhibition of human islet amyloid polypeptide (IAPP), the hallmark of type 2 diabetes impacting millions of people, is crucial for developing clinic therapies, yet remains challenging given that many candidate inhibitors require high doses. Intriguingly, insulin, the key regulatory polypeptide on blood glucose levels that are co-synthesized, co-stored and co-secreted with IAPP by pancreatic β cells, has been identified as a potent inhibitor that can suppress IAPP amyloid aggregation at sub-stoichiometric concentrations. Here, we computationally investigated the molecular mechanisms of the sub-stoichiometric inhibition of insulin against the aggregation of IAPP and the incompletely processed IAPP (proIAPP) using discrete molecular dynamics simulations. Our results suggest that the amyloid aggregations of both IAPP and proIAPP might be disrupted by insulin through its binding with the shared amyloidogenic core sequences. However, the N-terminus of proIAPP competed with the amyloidogenic core sequences for the insulin interactions, resulting into attenuated inhibition by insulin. Moreover, insulin preferred to bind the elongation surfaces of IAPP seeds with fibril-like structure, with a stronger affinity than that of IAPP monomers. The capping of elongation surfaces by a small amount of insulin sterically prohibited the seed growth via monomer addition, achieving the sub-stoichiometric inhibition. Together, our computational results provided molecular insights for the sub-stoichiometric inhibition of insulin against IAPP aggregation, also the weakened effect on proIAPP. The uncovered sub-stoichiometric inhibition by capping the elongation of amyloid seeds or fibrils may guide the rational designs of new potent inhibitors effective at low doses.