Comparative analysis of the duodenojejunal microbiome with the oral and fecal microbiomes reveals its stronger association with obesity and nutrition

The intestinal microbiota is increasingly recognized as a crucial player in the development and maintenance of various chronic conditions, including obesity and associated metabolic diseases. While most research focuses on the fecal microbiota due to its easier accessibility, the small intestine, as a major site for nutrient sensing and absorption, warrants further investigation to determine its microbiota composition and functions. Here, we conducted a clinical research project in 30 age- and sex-matched participants with (n = 15) and without (n = 15) obesity. Duodenojejunal fluid was obtained by aspiration during endoscopy. Phenotyping included clinical variables related to metabolic status, lifestyle, and psychosocial factors using validated questionnaires. We performed metagenomic analyses of the oral, duodenojejunal, and fecal microbiome, alongside metabolomic data from duodenojejunal fluid and feces, integrating these data with clinical and lifestyle information. Our results highlight significant associations between duodenojejunal microbiota composition and usual dietary intake, as well as clinical phenotypes, with larger effect sizes than the associations between these variables and fecal microbiota. Notably, we found that the duodenojejunal microbiota of patients with obesity exhibited higher diversity and showed distinct differences in the abundance of several duodenojejunal microbiota species compared with individuals without obesity. Our findings support the relevance of studying the role of the small intestinal microbiota in the pathogenesis of nutrition-related diseases

Requirements for measurement and validation of biochemical methane potential (BMP).

This document presents the minimal requirements for measurement and validation of biochemical methane potential (also called biomethane potential) (BMP) in batch tests. It represents the consensus of more than 50 biogas researchers. The list of requirements is the same as in the open-access commentary by Holliger et al. [2021]. For details on development of these requirements see the open-access papers Holliger et al. [2016] and Hafner et al. [2020c]

Cardiovascular Risk Factors and MRI Markers of Cerebral Small Vessel Disease

Background and objectives: Cardiovascular risk factors have been implicated in the etiology of cerebral small vessel disease (CSVD); however, whether the associations are causal remains unclear in part due to the susceptibility of observational studies to reverse causation and confounding. Here, we use mendelian randomization (MR) to determine which cardiovascular risk factors are likely to be involved in the etiology of CSVD. Methods: We used data from large-scale genome-wide association studies of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type 2 diabetes, smoking initiation, cigarettes per day, and alcohol consumption. MR was performed to assess their association with 3 neuroimaging features that are altered in CSVD (white matter hyperintensities [WMH], fractional anisotropy [FA], and mean diffusivity [MD]) using genetic summary data from the UK Biobank (N = 31,855). Our primary analysis used inverse-weighted median MR, with validation using weighted median, MR-Egger, and a pleiotropy-minimizing approach. Finally, multivariable MR was performed to study the effects of multiple risk factors jointly. Results: MR analysis showed consistent associations across all methods for higher genetically proxied systolic and diastolic blood pressures with WMH, FA, and MD and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, low-density lipoprotein, smoking initiation, pulse pressure, and type 2 diabetes liability and at least 1 CSVD imaging feature, but these associations were not reproducible across all validation methods used. Multivariable MR analysis for blood pressure traits found that the effect was primarily through genetically proxied diastolic blood pressure across all CSVD traits. Discussion: Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and to higher BMI is associated with a higher burden of CSVD, suggesting a causal role. Improved management and treatment of these risk factors could reduce the burden of CSVD

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Observation of γγ → ττ in proton-proton collisions and limits on the anomalous electromagnetic moments of the τ lepton

The production of a pair of τ leptons via photon–photon fusion, γγ → ττ, is observed for the f irst time in proton–proton collisions, with a significance of 5.3 standard deviations. This observation is based on a data set recorded with the CMS detector at the LHC at a center-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 138 fb−1. Events with a pair of τ leptons produced via photon–photon fusion are selected by requiring them to be back-to-back in the azimuthal direction and to have a minimum number of charged hadrons associated with their production vertex. The τ leptons are reconstructed in their leptonic and hadronic decay modes. The measured fiducial cross section of γγ → ττ is σfid obs = 12.4+3.8 −3.1 fb. Constraints are set on the contributions to the anomalous magnetic moment (aτ) and electric dipole moments (dτ) of the τ lepton originating from potential effects of new physics on the γττ vertex: aτ = 0.0009+0.0032 −0.0031 and |dτ| < 2.9×10−17ecm (95% confidence level), consistent with the standard model

The synthesis & optimisation of irreversible ITK inhibitors as a potential new treatment for severe asthma

Previously held under moratorium from 13 October 2013 until 13 October 2015. GSK - held in Chemistry Department during moratorium.Interleukin-2-inducible tyrosine kinase (ITK) is a member of the Tec family of non-receptor tyrosine kinases and plays an important role in T cell receptor signalling. Phosphorylation of ITK ultimately results in the release of several cytokines from T cells which are involved in the inflammatory response in asthmatic patients. ITK inhibitors could represent useful anti-inflammatory agents for severe asthma. This thesis describes the design and development of irreversible ITK inhibitors. It was envisaged that these compounds could provide a better duration of action in vivo compared to typical reversible inhibitors. After explaining first how irreversible ITK inhibition may be achieved, the medicinal chemistry undertaken to synthesise the designed molecules, and assess their activity profiles in various biological assays, is presented. Evidence of the covalent binding between some specific analogues and ITK is illustrated, the most explicit proof being a crystal structure of a kinase/inhibitor complex, clearly displaying a bond between the inhibitor and the cysteine residue present in the ITK active site. However, the early irreversible ITK inhibitors developed did not possess the required profile (cellular activity, duration of action) expected from an irreversible ITK inhibitor drug candidate. Three approaches are then described to improve the cellular activity of these irreversible ITK inhibitors. Firstly, the nature of the electrophilic moieties was investigated. Compounds presenting improved irreversible ITK inhibitor profiles (activities and rate of the covalent reaction) have been developed but these species could not be progressed further due to their high probability of toxicity issues in the body. Secondly, the positioning of the electrophilic group with respect to the ITK active site cysteine is then discussed; this strategy did not lead to any improved compounds. Finally, moving to a chemically more challenging pyridine template provided inhibitors with enhanced non-covalent ITK recognition. Optimisation of the compounds from this series provided irreversible inhibitors with the required in vitro and in vivo activity profiles for a drug candidate within our laboratories. The progression of the lead covalent ITK inhibitor from this research programme was ultimately halted due to toxicology findings from a 14 day rat study. The final part of the thesis studies the Buchwald-Hartwig amination reaction used in the synthetic route leading to the best covalent ITK inhibitors. This coupling required 30 mol % of palladium catalyst, which, on large scale, represents a significant amount of metal waste. The investigation of this coupling strongly suggested that the substrates involved in the reaction were poisoning the catalyst. The final results from this study indicate that an alternative palladium catalyst, allowing full conversion to the required product at room temperature, has been identified.Interleukin-2-inducible tyrosine kinase (ITK) is a member of the Tec family of non-receptor tyrosine kinases and plays an important role in T cell receptor signalling. Phosphorylation of ITK ultimately results in the release of several cytokines from T cells which are involved in the inflammatory response in asthmatic patients. ITK inhibitors could represent useful anti-inflammatory agents for severe asthma. This thesis describes the design and development of irreversible ITK inhibitors. It was envisaged that these compounds could provide a better duration of action in vivo compared to typical reversible inhibitors. After explaining first how irreversible ITK inhibition may be achieved, the medicinal chemistry undertaken to synthesise the designed molecules, and assess their activity profiles in various biological assays, is presented. Evidence of the covalent binding between some specific analogues and ITK is illustrated, the most explicit proof being a crystal structure of a kinase/inhibitor complex, clearly displaying a bond between the inhibitor and the cysteine residue present in the ITK active site. However, the early irreversible ITK inhibitors developed did not possess the required profile (cellular activity, duration of action) expected from an irreversible ITK inhibitor drug candidate. Three approaches are then described to improve the cellular activity of these irreversible ITK inhibitors. Firstly, the nature of the electrophilic moieties was investigated. Compounds presenting improved irreversible ITK inhibitor profiles (activities and rate of the covalent reaction) have been developed but these species could not be progressed further due to their high probability of toxicity issues in the body. Secondly, the positioning of the electrophilic group with respect to the ITK active site cysteine is then discussed; this strategy did not lead to any improved compounds. Finally, moving to a chemically more challenging pyridine template provided inhibitors with enhanced non-covalent ITK recognition. Optimisation of the compounds from this series provided irreversible inhibitors with the required in vitro and in vivo activity profiles for a drug candidate within our laboratories. The progression of the lead covalent ITK inhibitor from this research programme was ultimately halted due to toxicology findings from a 14 day rat study. The final part of the thesis studies the Buchwald-Hartwig amination reaction used in the synthetic route leading to the best covalent ITK inhibitors. This coupling required 30 mol % of palladium catalyst, which, on large scale, represents a significant amount of metal waste. The investigation of this coupling strongly suggested that the substrates involved in the reaction were poisoning the catalyst. The final results from this study indicate that an alternative palladium catalyst, allowing full conversion to the required product at room temperature, has been identified

Nouveau manuel complet des poids et mesures, des monnaies, du calcul décimal et de la vérification ...

Mode of access: Internet.Nelson

Larval optic nerve and adult extra-retinal photoreceptors sequentially associate with clock neurons during<i>Drosophila</i>brain development

The visual system is one of the input pathways for light into the circadian clock of the Drosophila brain. In particular, extra-retinal visual structures have been proposed to play a role in both larval and adult circadian photoreception. We have analyzed the interactions between extra-retinal structures of the visual system and the clock neurons during brain development. We first show that the larval optic nerve, or Bolwig nerve, already contacts clock cells (the lateral neurons) in the embryonic brain. Analysis of visual system-defective genotypes showed that the absence of the afferent Bolwig nerve resulted in a severe reduction of the lateral neurons dendritic arborization, and that the inhibition of nerve activity induced alterations of the dendritic morphology. During wild-type development, the loss of a functional Bolwig nerve in the early pupa was also accompanied by remodeling of the arborization of the lateral neurons. Approximately 1.5 days later, visual fibers that came from the Hofbauer-Buchner eyelet, a putative photoreceptive organ for the adult circadian clock, were seen contacting the lateral neurons. Both types of extra-retinal photoreceptors expressed rhodopsins RH5 and RH6, as well as the norpA-encoded phospholipase C. These data strongly suggest a role for RH5 and RH6, as well as NORPA, signaling in both larval and adult extra-retinal circadian photoreception. The Hofbauer-Buchner eyelet therefore does not appear to account for the previously described norpA-independent light input to the adult clock. This supports the existence of yet uncharacterized photoreceptive structures in Drosophila.</jats:p

<i>In Situ</i> Generation of Zinc Carbenoids from Diazo Compounds and Zinc Salts: Asymmetric Synthesis of 1,2,3-Substituted Cyclopropanes

In Situ Generation of Zinc Carbenoids from Diazo Compounds and Zinc Salts: Asymmetric Synthesis of 1,2,3-Substituted Cyclopropane

<i>In Situ</i> Generation of Zinc Carbenoids from Diazo Compounds and Zinc Salts: Asymmetric Synthesis of 1,2,3-Substituted Cyclopropanes

In Situ Generation of Zinc Carbenoids from Diazo Compounds and Zinc Salts: Asymmetric Synthesis of 1,2,3-Substituted Cyclopropane