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Aim:To evaluate the anti-Mycobacterium tuberculosis(Mtb) potential of the hybrid oxadiazol-4-methoxynaphthalene (6n) derived from N-acylhydrazone (4k).Materials & methods:The study determined the minimal inhibitory concentration of (6n)against MtbH37Rv and Mtbclinical isolates, potential combination of (6n)with anti-tuberculosis drugs and carried out time kill curve assay of MtbH37Rv. Additional contribution for the analysis of (6n)was explored by in silicopharmacokinetics, and in vitroand in vivocytotoxicity determinations.Results:The newly synthesized molecule (6n)demonstrated anti-Mtbactivity, low cytotoxicity and selectivity for Mtb.Conclusion:The derivative (6n) emerges as a potential anti-TB drug candidate.

Aim:Polymyxin B (PMB) is one of the few therapeutic options for treating infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB). However, the emergence of PMB-resistant CR-GNB strains has prompted the exploration of antibiotic adjuvants as potential therapeutic avenues. Thus, this study evaluates the potential of 3,5-dinitrobenzoic acid derivatives (DNH01, DNH11, DNH13 and DNH20) and isoniazid-N-acylhydrazones (INZ1-7, INZ9 and INZ11) as adjuvants to enhance PMB efficacy against CR-GNB.Materials & methods:MIC, MBC and drug combination assays were conducted using multidrug-resistant clinical isolates of Enterobacteralesand Acinetobacter baumannii. In addition, the effects of PMB and PMB + DNH derivatives were assessed through flow cytometry and scanning electron microscopy (SEM).Results:DNH01, DNH11 and DNH20, unlike the INH-acylhydrazones, significantly restored PMB activity (MIC ≤ 2 μg/ml) in 80% of the tested isolates. Flow cytometry and SEM assays confirmed that DNH derivatives rescued the activity of PMB, yielding results comparable to those expected for PMB alone but at 256-fold lower concentrations.Conclusion:These findings suggest DNH derivatives hold substantial promise as PMB adjuvants to combat PMB-resistant CR-GNB infections.

ABSTRACTIntroductionGastroesophageal reflux disease (GERD) is a chronic disease of the esophagus characterized by the regurgitation of stomach contents into the esophagus, causing troublesome symptoms and/or complications. Among patients with GERD, around 30% of patients have visible mucosal damage, while 70% have normal esophageal mucosa. Accordingly, the optimal pharmacological treatment of GERD should address different disease manifestations, including symptoms, the mucosal damage when present, and possible chronic complications, including strictures, Barrett’s esophagus, and esophageal adenocarcinoma.Areas coveredAvailable medical treatments for GERD include proton pump inhibitors (PPIs), potassium-competitive acid blockers (PCABs), histamine receptor antagonists (H2-RAs), prokinetics, and mucosal protectants, such as alginates, hyaluronic acid/chondroitin-sulfate, and poliprotect. Each compound has its own advantages and disadvantages, and knowledge of expected benefits and tips for their use is paramount for the success of treatment. In addition, the appropriateness of indications for initiating treatment is also crucial to achieve positive results when managing GERD patients.Expert opinionPPIs, PCABs, H2-RAs, prokinetics, and mucosal protectants can all be used in patients with GERD, but careful assessment of patients’ characteristics as well as advantages and disadvantages of each therapeutic compound is essential to ensure successful treatment of GERD.

Dans un contexte d’innovation et de développements cliniques intenses en oncologie, l’Institut national du cancer a développé depuis 2019, un horizon scanningdédié aux médicaments anticancéreux émergents. Cet outil a pour objectif d’apporter un éclairage complémentaire aux agences nationales en charge de l’accès au médicament et aux décideurs publics.

A closed loop flat plate pulsating heat pipe, filled with Opteon™ SF33 (with a filling ratio of 50%), was experimentally studied in different orientations: 0° (horizontal), 22.5°, 45°, 67.5°, and 90° (“;edge”: vertical with horizontal channels). The results confirm the interest of such configurations, rarely investigated in the literature, on the thermal behavior of the device and on the regularity of the temperatures and pressure signals: If dried-out occurred in horizontal orientation, increase of inclination angle (starting from 22.5°) led to regular oscillatory movement due to help of gravity pressure drop between channels. The thermal performance remains very similar for the device inclination angles from 45° to 90°. Both FFT and wavelet analyses of the pressure signal and temperatures of the external wall of the device (measured with IR camera) were done to characterize the dominant oscillatory frequencies. These orientations led to dominant frequencies, rarely detected in the literature for other classic configurations (with vertical/inclined channels). Similar internal pressure and temperature signals both showed that the dominant frequency increases with decreasing angle (from edge to horizontal orientation), but also with increasing applied heat power, and finally tends to spread and disappear for the highest heat loads.

Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A–C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus Leptothoe. Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three Leptothoestrains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.

ABSTRACTSearch engines match user queries with webpages. Search efficiency, increases when data-driven network effects attract more users and generate economies of scale and scope in data aggregation. Network effects enhance user welfare but also trigger antitrust concerns because they may “tip” the market towards a single dominant search engine – Google Search. The EU Digital Markets Act imposes an obligation on very large gatekeepers search engines to share their user data with smaller search engines to facilitate market entry and competition. The available empirical literature on search engine efficiency shows that asymmetric data sharing, from larger to smaller search engines, may increase competition but reduce user welfare because it fragments the user data pool that is crucial for efficiency, in particular for rare queries. Tension between competition and user welfare can be overcome by symmetric and mutual data sharing between all search engines, irrespective of market share.

ABSTRACTThermogenesis is well understood, but the relationships between cold water immersion (CWI), the post-CWI rewarming and the associated physiological changes are not. This study investigated muscle and systemic oxygenation, cardiorespiratory and hemodynamic responses, and gastrointestinal temperature during and after CWI. 21 healthy men completed randomly 2 protocols. Both protocols consisted of a 48 minutes heating cycling exercise followed by 3 recovery periods (R1-R3), but they differed in R2. R1 lasted 20 minutes in a passive semi-seated position on a physiotherapy table at ambient room temperature. Depending on the protocol, R2 lasted 15 minutes at either ambient condition (R2_AMB) or in a CWI condition at 10°C up to the iliac crest (R2_CWI). R3 lasted 40 minutes at AMB while favoring rewarming after R2_CWI. This was followed by 10 minutes of cycling. Compared to R2_AMB, R2_CWI ended at higher $\dot{{\rm V}}$V˙O2in the non-immersed body part due to thermogenesis (7.16(2.15) vs. 4.83(1.62) ml.min−1.kg−1) and lower femoral artery blood flow (475(165) vs. 704(257) ml.min−1) (p < 0.001). Only after CWI, R3 showed a progressive decrease in vastus and gastrocnemius medialis O2saturation, significant after 34 minutes (p < 0.001). As blood flow did not differ from the AMB protocol, this indicated local thermogenesis in the immersed part of the body. After CWI, a lower gastrointestinal temperature on resumption of cycling compared to AMB (36.31(0.45) vs. 37.30(0.49) °C, p < 0.001) indicated incomplete muscle thermogenesis. In conclusion, the rewarming period after CWI was non-linear and metabolically costly. Immersion and rewarming should be considered as a continuum rather than separate events.

We describe the preparation, characterization, and imaging studies of rhenium carbonyl complexes with a pyta (4-(2-pyridyl)-1,2,3-triazole) or tapy (1-(2-pyridyl)-1,2,3-triazole)-based heteroaromatic N∧N ligand and thiolate or selenoate X ligand. The stability and photophysical properties of the selenolate complexes are compared with parent chloride complexes and previously described analogues with benzenethiolate ligands. Two complexes were imaged in A549 cells upon excitation at 405 nm. Colocalization studies suggest a lysosomal accumulation, while one parent chloride complex was described to localize at the Golgi apparatus. Preliminary fluorescence lifetime measurements and imaging demonstrate potential for application in time-resolved microscopy techniques due to the long and variable lifetimes observed in cellular environments, including an increase in lifetime between the solution and solid state many times larger than previously reported.

Processing fluency, which describes the subjective sensation of ease with which information is processed by the sensory systems and the brain, has become one of the most popular explanations of aesthetic appreciation and beauty. Two metrics have recently been proposed to model fluency: the sparsity of neuronal activation, which describes the concentration of activity in a subset of neurons, and the statistical typicality of activations, which describes how well the encoding of a stimulus matches a reference representation of stimuli of the category to which it belongs. Using convolutional neural networks (CNNs) as a model for the human visual system, this study compares the ability of these metrics to explain variation in facial attractiveness. Our findings show that the sparsity of neuronal activations is a more robust predictor of facial attractiveness than statistical typicality. Refining the reference representation to a single ethnicity or gender does not increase the explanatory power of statistical typicality. However, statistical typicality and sparsity predict facial beauty based on different layers of the CNNs, suggesting that they describe different neural mechanisms underlying fluency.

Bitcoin’s success as a global cryptocurrency has paved the way for the emergence of blockchain, a revolutionary category of distributed systems. However, the growing popularity of blockchain has led to a significant divergence from its core principles in many systems labeled as “blockchain.” This divergence has introduced complexity into the blockchain ecosystem, exacerbated by a lack of comprehensive reviews on blockchain and its variants. Consequently, gaining a clear and updated understanding of the diverse spectrum of current blockchain and blockchain-like systems has become challenging. This situation underscores the necessity for an extensive literature review and the development of thematic taxonomies. This survey seeks to offer a comprehensive and current assessment of existing blockchains and their variations while delineating the boundaries between blockchain and blockchain-like systems. To achieve this objective, we propose a holistic reference model for conceptualizing and analyzing these systems. Our layer-wise framework envisions all distributed ledger technologies (DLTs) as composed of four principal layers: data, consensus, execution, and application (DCEA). In addition, we introduce a new taxonomy that enhances the classification of blockchain and blockchain-like systems, offering a more useful perspective than existing works. Furthermore, we conduct a state-of-the-art review from a layered perspective, employing 23 evaluative criteria predefined by our framework. We perform a qualitative and quantitative comparative analysis of 44 DLT solutions and 26 consensus mechanisms while discussing differences and boundaries between blockchain and blockchain-like systems. We emphasize the significant challenges and tradeoffs encountered by distributed ledger designers, decision-makers, and project managers during the design or adoption of a DLT solution. Finally, we outline crucial research challenges and directions in the field of DLTs.

Successful collaborative innovation between startups and large firms can be considered fruitful complementary combinations that can respond effectively and rapidly to grand challenges. Further research is needed on the knowledge-based resources of entrepreneurial teams that influence their performance. Moreover, the relational dimension and processual view of asymmetric startup–large firm collaborations have rarely been investigated from the startups’ perspective. Our first objective is to understand which elements of startup founding teams’ human and social capital impact their R&D versus business engagement in collaborations with large firms. The second is to understand which fine-grained components of proximity forms contribute to collaborative success. In this article, we address these issues by employing structural equation modeling combined with Fisher's exact test contingency analysis, which results in a processual framework contributing to the literature on entrepreneurial teams, collaborations between startups and corporations, and operationalization of the proximity theory. Our results show that in addition to technological knowledge, educational diversity, entrepreneurial education, and open social capital are critical dimensions for startup founding teams to engage in an R&D collaboration with a large firm. Our results also underscore the significant positive effect of social proximity, organizational proximity (intermediary), and cognitive proximity (technology) on collaboration success.

Nanotechnology is making exceptional progress in the medical field. The development of new systems for the delivery of plant ingredients brings benefits such as good bioavailability, solubility, sustained release, and enhanced potential. To the best of our knowledge, there is no report on nanocomposites from Tetrapleura tetrapteradespite its wide range of ethnopharmacological uses including management of inflammatory diseases. This study aimed to prepare chitosan- and cellulose-based nanocomposites with anti-inflammatory potential. The biocomposites showed an encapsulation efficiency of 69.4%. Their formation was confirmed by a peak at 290 nm in UV–Vis. Infrared spectrophotometry proved the formation of a mixed polysaccharide and polyphenol system. No signs of toxicity and no deaths were found; therefore, the lethal dose 50 (LD50) is higher than 2000 mg/kg. The biocomposite has an anti-inflammatory activity in vitro with a maximum inhibition of 99.5% and an anti-inflammatory activity in vivo with a maximum inhibition of 98.7% for a dose of 200 mg/kg. The synthesized biocomposites from the aqueous extract of the fruits of Tetrapleura tetrapterashowed an anti-inflammatory property with satisfactory safety.

AbstractPiperine (PPN) is a known inhibitor of efflux pumps in Mycobacterium tuberculosisand in vitrosynergism with rifampicin (RIF) has been proven. The current study evaluates the activity of PPN and synergism with RIF in rapidly and slowly growing nontuberculous mycobacteria (NTM). Also, to propose a possible mechanism of interaction of PPN with M. leprae(Mlp) RNA polymerase (RNAp). Minimal inhibitory concentration and drug combination assay was determined by resazurin microtiter assay and resazurin drug combination assay, respectively. In silicoevaluation of PPN binding was performed by molecular docking and molecular dynamics (MD). PPN showed higher antimicrobial activity against rapidly growing NTM (32-128 mg/L) rather than for slowly growing NTM (≥ 256 mg/L). Further, 77.8% of NTM tested exhibited FICI ≤ 0.5 when exposed to PPN and RIF combination, regardless of growth speed. Docking and MD simulations showed a possible PPN binding site at the interface between β and β’ subunits of RNAp, in close proximity to the trigger-helix and bridge-helix elements. MD results indicated that PPN binding hindered the mobility of these elements, which are essential for RNA transcription. We hypothesize that PPN binding might affect mycobacterial RNAp activity, and, possibly, RIF activity and that this mechanism is partially responsible for synergic behaviors with RIF reported in vitro. Communicated by Ramaswamy H. Sarma

Fourth order problems with the differential equation y(4)-(gy′)′=λ2y, where g∈C1[0,a]and a>0, occur in engineering on stability of elastic rods. They occur as well in aeronautics to describe the stability of a flexible missile. Fourth order Birkhoff regular problems with the differential equation y(4)-(gy′)′=λ2yand eigenvalue dependent boundary conditions are considered. These problems have quadratic operator representations with non-self-adjoint operators. The first four terms of the asymptotics of the eigenvalues of the problems as well as those of the eigenvalues of the problem describing the stability of a flexible missile are evaluated explicitly.

Salt threatens rice cultivation in many countries. Hence, breeding new varieties with high salt tolerance is important.

•What is the primary question addressed by this study?A nationwide cross-sectional study using medical administrative data study to estimate the prevalence of chronic pain among people living with dementia from 2017 to 2019 in French community.•What is the main finding of this study?The innovative capture-recapture method used to estimate chronic pain prevalence and avoid the problems of selection bias and generalization to the entire population. The prevalence of chronic pain ranged from 57.7% to 57.9% in patients with dementia. 24.5% of chronic pain patients were no longer treated for their pain after dementia diagnosis.•What is the meaning of the finding?These findings argue for policies and medical management that prevent and mitigate chronic pain in patients with dementia.

Equine lipid disorders are characterised by an increase in levels of circulating triglycerides resulting from a negative energy balance, which happens because of various factors such as inflammation or inadequate dietary intake. Lipids are absorbed from the equine diet as fatty acids and can be stored or directly used for energy depending on metabolic demand, with a positive energy balance favouring lipogenesis and a negative balance promoting lipolysis. Hyperlipaemia is a syndrome defined by high triglyceride concentrations and opalescent serum. It is common in ponies, donkeys and miniature breeds, especially during late gestation or early lactation. Stressful events like transportation or hospitalisation can precipitate the development of the condition. Although the prognosis is guarded in severe cases, clinical signs are often overlooked and diagnosis relies on measurement of triglyceride levels. Management involves treating the initial cause, where possible, and addressing negative energy balance through enteral or parenteral nutrition. A similar syndrome is described in sick neonatal foals, requiring similar management strategies.

This article reports the first accurate and physics-based Verilog-A implementation of the fully analytic form of photocurrent in SPICE compact models for uni-traveling carrier (UTC) photodiodes (PDs). To overcome the limitations of single-pole network implementations for modeling frequency dependence of the photo-response, especially at frequencies beyond 100 GHz, we explored different solutions for the complete analytic equation of the dynamic photocurrent. A new implementation has been proposed which requires three additional nodes in the UTC-PD electrical equivalent circuit and offers the best tradeoff between accuracy and computational efficiency. Model validation has been performed against on-wafer measurements from two UTC-PD technologies depicting very good accuracy over the entire frequency range.

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The association between vaccines and peripheral facial palsy (PFP), an issue that has been the subject of debate for many years, has been raised again following results of clinical trials assessing mRNA based COVID-19 vaccines. To review the available literature on this topic, PubMed was searched from inception until February 25, 2022. Inclusion criteria were case reports with documented rechallenge and comparative epidemiological studies. Cases of COVID-19 vaccine-induced PFP with available data on vaccine rechallenge were also identified from Vigibase until December 31, 2021. Of the 347 articles retrieved, 32 comparative epidemiological studies, 1 meta-analysis and 4 case reports met our criteria, of which 13 involved COVID-19 vaccines. Eight studies found an association between at least one vaccine and the occurrence of PFP, whereas 24 did not. Positive studies involved seasonal or pandemic H1N1 influenza vaccines administered parenterally (4 studies) or intranasally (1 study with a toxin-adjuvanted vaccine), BNT162b2, a mRNA COVID-19 vaccine (1 disproportionality analysis and 1 observed-to-expected analysis) and an inactivated virus COVID-19 vaccine (CoronaVac®) (1 study combining a case-control and an observed-to-expected approach). Strong evidence was found only for the intranasal influenza vaccine while other positive studies detected only a marginal association between PFP and vaccination. Of the four case reports with documented rechallenge, only two were positive and involved an influenza vaccine and tozinameran in one case each. In Vigibase, rechallenge was documented in 49 reports with 29 (59.2%) cases being negative and 20 (40.8%) positive. The available data did not confirm an excess risk of PFP after vaccination in most studies. Moreover, of the eight epidemiological studies suggesting a possible excess risk of PFP after any vaccine, three were disproportionality analyses and two observed-to excepted analyses, suggesting great caution should be taken when interpreting these results.

Objective We aimed to evaluate the rate of patient requiring Surgical Repositioning of the Premaxilla in a population carrying BCL  ±  P, retrieve age and operative indication. Our secondary objective was to present further facial growth characteristics.Settings This was a retrospective, single-center cohort study conducted in Nantes University Hospital, Oral and Maxillofacial Surgery department, tertiary cleft center.Patients Patients with BCL  ±  P born between 1980 and 2019 treated at Nantes University Hospital were included.Main outcome measure Our primary outcome measure was the rate of patient requiring SRP.Results Over the whole period, 189 patients with BCL  ±  P were identified. Three patients (1,58%) underwent SRP. Patients who underwent SRP all had BCLP. SRP was performed during their primary dentition period. The indication for surgical repositioning was always premaxilla vertical overgrowth with an overbite over 10 mm. Facial growth features in the three patients were mostly comparable with a population carrying BCLP who had no premaxillary surgery.Conclusion Our results showed a low incidence of SRP. No SRP was necessary during early infancy (ie, before lip repair) or during adulthood. Surgical repositioning of the premaxilla is beneficial for patient with orthodontically uncorrectable vertical premaxillary excess, even more since facial development compared with other patients with BCLP appears comparable.

Acute hematogenous musculoskeletal infections (MSKI) are medical emergencies with the potential for life-altering complications in afflicted children. Leveraging administrative data to study pediatric MSKI is difficult as many infections are chronic, nonhematogenous, or occur in children with significant comorbidities. The objective of this study was to validate a case-finding algorithm to accurately identify children hospitalized with acute hematogenous MSKI using administrative billing codes.This was a multicenter validation study using the Pediatric Health Information System (PHIS) database. Hospital admissions for MSKI were identified from 6 PHIS hospitals using discharge diagnosis codes. A random subset of admissions underwent manual chart review at each site using predefined criteria to categorize each admission as either “acute hematogenous MSKI” (AH-MSKI) or “not acute hematogenous MSKI.” Ten unique coding algorithms were developed using billing data. The sensitivity and specificity of each algorithm to identify AH-MSKI were calculated using chart review categorizations as the reference standard.Of the 492 admissions randomly selected for manual review, 244 (49.6%) were classified as AH-MSKI and 248 (50.4%) as not acute hematogenous MSKI. Individual algorithm performance varied widely (sensitivity 31% to 91%; specificity 52% to 98%). Four algorithms demonstrated potential for future use with receiver operating characteristic area under the curve greater than 80%.Identifying children with acute hematogenous MSKI based on discharge diagnosis alone is challenging as half have chronic or nonhematogenous infections. We validated several case-finding algorithms using administrative billing codes and detail them here for future use in pediatric MSKI outcomes.

•23 studies on chronic pain (CP) prevalence in patients treated with OST were assessed.•78.3% of the studies had a low risk of bias.•The prevalence of CP in patients treated with OST is high (45.3 %).•Prevalence did not vary according to gender, OST, and CP duration.•Primary care sites were associated with a lower CP prevalence than medical clinics.