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Background: The interaction between mesenchymal stem cells (MSC) and Glioblastoma (GBM), although potentially of the highest importance, is ill-understood. This is due, in part, to the lack of relevant experimental models. The similarity between the in vitro situations and the in vivo situation can be improved by 3D co-culture as it reproduces key cell-cell interactions between the tumor microenvironment (TME) and cancer cells., Methods: MSC Can acquired characteristics of cancer associated fibroblasts (CAF) by being cultured with conditioned medium from GBM cultures and thus are called MSC CAF . We co Cultured MSC CAF with patient derived GBM in a scaffold 3D bioprinted model. We studied the response to current GBM therapy (e.g. Temozolomide + /Radiation) on the co cultures by bulk transcriptomic (RNA Seq) and epigenetic (ATAC Seq) analyses RESULTS: The transcriptomic modifications induced by standard GBM treatment in bioprinted scaffolds of mono- or co-cultures of GBM ± MSC can be analyzed. We found that mitochondrial encoded OXPHOS genes are overexpressed under these conditions and are modified by both co-culture and treatment (chemotherapy ± radiation). We have identified two new markers of MSC/GBM interactions, one epigenetically regulated (i.e. TREM-1) associated with an increased overall survival in GBM patients and another implicated in post-transcriptional regulation (i.e. the long non-coding RNA, miR3681HG), which is associated with a reduced overall survival in GBM patients., Competing Interests: Declarations Ethics approval and consent to participate The bio-collection used for this analysis is the Glioblastoma collection belonging to the approved project, “pediatric research program of the University Hospital of Nantes, France (Ref. MESR DC-2014–2206)”, having obtained an institutional approval from committee patients protection board, “CPP Ouest IV, approval number “Dossier 06/15”, date of approval 08/04/2015. The patients or their guardians/legally authorized representatives/next of kin provided written informed consent for participation in the use of samples. After informed consent, tumor samples classified as GBM, based on the World Health Organization criteria, were obtained from patients undergoing surgical intervention at the Department of Neurosurgery at “Centre Hospitalier Universitaire de Nantes” and the “Tumorothèque IRCNA”. Declaration of use of AI The authors declare that artificial intelligence is not used in this study. Competing Interests The authors declare that they have no competing of interest., (© 2024. The Author(s).)

The Cu-catalyzed Ullmann-Goldberg cross-coupling between aryl iodides and oxamates is shown to afford the corresponding N-aryloxamates with yields ranging from moderate to excellent, when the oxamate precursor incorporates a bulky tertiary alkyl group effectively preventing product degradation under the strongly basic reaction conditions. The final oxamic acids are then generated through the acid hydrolysis of the oxamate in high yields. These acids were then converted into urethanes using PIDA under thermal conditions or a visible-light Fe-LMCT process. While electron-deficient N-aryl oxamic acids provide urethanes with high efficiencies, electron-rich counterparts led to diminished yields due to aryl group over-oxidation induced by PIDA., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

Polyurethane (PU) thermoplastics and thermosets were prepared through the step-growth polymerization of in situ generated polyisocyanates through the decarboxylation of polyoxamic acids, in the presence of phenyliodine diacetate (PIDA), and polyols. The CO 2 produced during the reaction allowed the access to self-blown polyurethane foams through an endogenous chemical blowing. The acetic acid released from ligand exchange at the iodine center was also shown to accelerate the polymerization reaction, avoiding the recourse to an additional catalyst. Changing simple parameters during the production process allowed us to access flexible PU foams with a wide range of properties., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Aging is associated with a decline in the number and fitness of adult stem cells 1-4 . Aging-associated loss of stemness is posited to suppress tumorigenesis 5,6 , but this hypothesis has not been tested in vivo . Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells 7,8 , we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.

A library of novel structurally related singlet carbenes, namely, acyclic amino(haloaryl)carbenes, was designed by a high-yielding two-step procedure, and their chemical stability explored both experimentally and theoretically. Thanks to a careful selection of both the amino and the aryl substitution pattern, these carbenes exhibit a wide range of stability and reactivity, spanning from rapid self-dimerization for carbenes featuring ortho -F substituents to very high chemical stability as bare carbenes, up to 60 °C for several hours for compounds carrying ortho -Br substituents. Their structure was determined through NMR and X-ray diffraction studies, and their reactivity evaluated in benchmark reactions, highlighting the ambiphilic character of this novel class of singlet carbenes. In contrast with previously reported aryl substituents incorporating o -CF 3 and t -Bu groups, which were considered "spectator", the high chemical stability of some of these carbenes relates to the stabilization of the σ-orbital of the carbene center by the π-accepting haloaryl substituent through delocalization. Kinetic protection of the carbene center is also provided by the ortho -halogen atoms, as demonstrated computationally. This push-pull stabilization effect makes acyclic amino(haloaryl) carbenes among the most ambiphilic stable carbenes reported to date, holding promise for a variety of applications.

Oxamic acids where shown to add to imines, providing a broad range of α-aminoacid amides in generally good yields. The process is efficient on pre-formed imines but may also be conducted using a 3-component strategy by simply mixing aldehydes, amines and oxamic acids in the presence of ferrocene, acting both as a photocatalyst under visible light and as a Lewis acid. The reaction proceeds through the addition onto the imine of a carbamoyl radical intermediate generated through a charge transfer from the carboxylate ligand to a Fe(iii) species (LMCT)., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Dual Ni and Ir catalysis enables the preparation of arylsilanes having a (TMS) 3 Si substituent from the corresponding aryl bromides and (TMS) 3 SiH at 30 °C using visible-light irradiation. This protocol avoids strong bases, high temperature and air and moisture sensitive silyl reagents, providing the expected arylsilanes in moderate to good yields. The reaction was shown to proceed through a silyl radical, likely generated by hydrogen atom abstraction from (TMS) 3 SiH by a bromide radical.

Visible-light-mediated intramolecular site-selective δ-C(sp 3 )-H bond arylation of aliphatic trifluoromethanesulfonamides was developed. The reaction proceeds through a radical cascade, including the generation of a sulfonamidyl radical, which triggers a 1,5-hydrogen atom transfer, affording a δ-C-centered radical, which finally cyclized onto a neighboring thiopolyfluoroaryl moiety to deliver a range of synthetically useful thiochromanes. The cyclization process occurs through two distinct pathways depending upon the nature of the substituent X ortho to the native C-S bond.

Signaling pathways can be activated through various cascades of genes depending on cell identity and biological context. Single-cell atlases now provide the opportunity to inspect such complexity in health and disease. Yet, existing reference tools for pathway scoring resume activity of each pathway to one unique common metric across cell types. Here, we present MAYA, a computational method that enables the automatic detection and scoring of the diverse modes of activation of biological pathways across cell populations. MAYA improves the granularity of pathway analysis by detecting subgroups of genes within reference pathways, each characteristic of a cell population and how it activates a pathway. Using multiple single-cell datasets, we demonstrate the biological relevance of identified modes of activation, the robustness of MAYA to noisy pathway lists and batch effect. MAYA can also predict cell types starting from lists of reference markers in a cluster-free manner. Finally, we show that MAYA reveals common modes of pathway activation in tumor cells across patients, opening the perspective to discover shared therapeutic vulnerabilities., (© 2023. The Author(s).)

The PIDA-mediated oxidative decarboxylation of oxamic acids in the presence of alcohols is shown to afford the corresponding urethanes under thermal conditions. Computational and experimental mechanistic exploration allows to rationalize the different reactivity of PIDA as compared to related cyclic BI-OAc and highlights the importance of the enhanced acidity of the proton in the carbamoyl radical intermediate., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Photocatalyzed oxidative decarboxylation of oxamic acids under near-infrared irradiation using Os(bptpy) 2 (PF 6 ) 2 as catalyst is reported. The reaction was applied to the synthesis of urethanes and heterocyclic amides. Mechanistic studies and comparative penetration depths between the NIR and the visible light mediated processes are discussed.

This review article describes the recent development in the chemistry of carbamoyl radicals generated from oxamic acids. This mild and efficient method compares well with previous methods of generation of these nucleophilic radicals. The oxidative decarboxylation of oxamic acids can be mediated through thermal, photochemical, electrochemical or photoelectrochemical means, generating carbamoyl radicals, which may further add to unsaturated systems to provide a broad range of important amides. Oxidative decarboxylation of oxamic acids also offers a straightforward entry for the preparation of urethanes, ureas, and thioureas.

The total enantioselective synthesis of (+)-eucophylline 1 was achieved using as a key-structural motif a chiral piperidinone bearing the natural product all-carbon quaternary stereocenter. The elaboration of the latter is based on two strategies relying on the free-radical carbo-cyanation and sulfonyl-cyanation respectively of enantiopure substituted cyclopropenes and cyclobutenes. Co- or Ni-boride reduction of the nitrile functional group along with the cyclopropane and cyclobutane ring-opening then led to the formation of the chiral piperidinone ring. Further elaboration of the latter into the key 1-azabicyclo[3.3.1]nonane motif followed by its coupling with a 2-cyanoaniline allowed the formation of the tetrahydrobenzo[b][1,8]-naphthyridine skeleton of 1, which was finally accessible in 17 steps and 5.9 % overall yield from 1,1-dibromobutene., (© 2022 Wiley-VCH GmbH.)

The structure determination of a series of biphenylsilyloxonium cations through NMR and XRD studies, supported by DFT calculations was carried out, allowing to get insights into the origin of the oxygen pyramidalization in biphenyl and binaphthylsilyl oxoniums. Low barrier of inversion in the oxygenyl series points toward a key role of the biaryl axis in the inversion of configuration at the oxygen center., (© 2021 Wiley-VCH GmbH.)

Despite the ubiquity of singlet carbenes in chemistry, their utility as true monomeric building blocks for the synthesis of functional organic polymers has been underexplored. In this work, we exploit the capability of purposely designed mono- and bis-acyclic amino(aryl)carbenes to selectively dimerize as a general strategy to access diaminoalkenes and hitherto unknown amino-containing poly(p-phenylene vinylene)s (N-PPV's). The unique selectivity of the dimerization of singlet amino(aryl)carbenes, relative to putative C-H insertion pathways, is rationalized by DFT calculations. Of particular interest, unlike classical PPV's, the presence of amino groups in α-position of C=C double bonds in N-PPV's allows their physico-chemical properties to be manipulated in different ways by a simple protonation reaction. Hence, depending on the nature of the amino group (iPr 2 N vs. piperidine), either a complete loss of conjugation or a blue-shift of the maximum of absorption is observed, as a result of the protonation at different sites (nitrogen vs. carbon). Overall, this study highlights that singlet bis-amino(aryl)carbenes hold great promise to access functional polymeric materials with switchable properties, through a proper selection of their substitution pattern.

Cyclic silylated chalconium borates 13[B(C 6 F 5 ) 4 ] and 14[B(C 6 F 5 ) 4 ] with peri-acenaphthyl and peri-naphthyl skeletons were synthesized from unsymmetrically substituted silanes 3, 4, 6, 7, 9 and 10 using the standard Corey protocol (Chalcogen Ch=O, S, Se, Te). The configuration at the chalcogen atom is trigonal pyramidal for Ch=S, Se, Te, leading to the formation of cis- and trans-isomers in the case of phenylmethylsilyl cations. With the bulkier tert-butyl group at silicon, the configuration at the chalcogen atoms is predetermined to give almost exclusively the trans-configurated cyclic silylchalconium ions. The barriers for the inversion of the configuration at the sulfur atoms of sulfonium ions 13 c and 14 a are substantial (72-74 kJ mol -1 ) as shown by variable temperature NMR spectroscopy. The neighboring group effect of the thiophenyl substituent is sufficiently strong to preserve chiral information at the silicon atom at low temperatures., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

A new efficient strategy to access benzylic carbamates through C-H activation is reported. The use of a catalytic amount of a Cu(i)/diimine ligand in combination with NFSI ((PhSO2)2NF) or F-TEDA-PF6 as oxidants and H2NCO2R as an amine source directly leads to the C-N bond formation at the benzylic position. The mild reaction conditions and the broad substrate scope make this transformation a useful method for the late-stage incorporation of a ubiquitous carbamate fragment onto hydrocarbons.

Urethane synthesis via oxidative decarboxylation of oxamic acids under mild electrochemical conditions is reported. This simple phosgene-free route to urethanes involves an in situ generation of isocyanates by anodic oxidation of oxamic acids in an alcoholic medium. The reaction is applicable to a wide range of oxamic acids, including chiral ones, and alcohols furnishing the desired urethanes in a one-pot process without the use of a chemical oxidant.

The formation of 3-methyl-2,4-nonanedione (MND) during red wine aging can contribute to the premature evolution of aroma, characterized by the loss of fresh fruit and development of dried fruit flavors. The identification of two new hydroxy ketones, 2-hydroxy-3-methylnonan-4-one (syn- and anti-ketol diastereoisomers) and 3-hydroxy-3-methyl-2,4-nonanedione (HMND), prompted the investigation of the precursors and pathways through which MND is produced and evolves. An HS-SPME-GC-MS method was optimized for their quantitation in numerous must and wine samples, providing insight into the evolution of MND, HMND, and ketols through alcoholic fermentation and wine aging. Alcoholic fermentation resulted in a significant decrease in MND and HMND and the simultaneous appearance of ketol diastereoisomers. The analysis of 167 dry red wines revealed significant increases in MND and anti-ketol contents through aging and a significant positive correlation between MND and anti-ketols. Additional experiments demonstrated that ketols are precursors to MND during red wine oxidation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The photosensitized p -anisaldehyde-mediated addition of sulfonylcyanides onto the π-system of cyclobutenes is shown to afford highly functionalized cyclobutanes in high yields and diastereocontrol. The homochiral cyclobutene precursors are accessible on multigram scale in two steps through an asymmetric [2 + 2] cycloaddition/vinyl thioether reduction sequence. The enantiopure cyclobutylnitriles can be elaborated further through SmI 2 -mediated ring opening or converted into new enantiopure cyclobutenes through base-mediated sulfone elimination.

Pyridine- and quinoline-stabilized silyl cations have been prepared, and their structure in condensed phases unambiguously assigned using 1 H, 13 C, 15 N, 29 Si, and 1 H DOSY NMR as well as X-ray diffraction studies. Solid state structures thus show in both cases a stabilization of the cationic silicon center through an N-Si interaction and formation of a highly strained four-membered ring system. Chiral memory at the silicon atom in these heterocycle-stabilized silyl cations was also established, leading to various levels of selectivity depending on the nature of the heterocycle. Lowest energy conformations of the starting silanes obtained through DFT calculations, along with the isolation and characterization of the Si-centered chiral silyl cation intermediates, finally allowed to propose a plausible hypothesis as to the configurational stability of these silyl cations.

Four-component coupling reactions between xanthogenates, alkenes, CO, and sulfonyl oxime ethers were studied. In the presence of hexabutylditin, working as a propagating radical reagent, the chain reaction proceeds, as expected, taking into account reagents polarities, affording the corresponding functionalized α-keto oximes. Although yields are modest, this rare one-pot four-component process is easy to carry out and the resulting compounds, bearing multiple functionalities, have the potential for further elaboration.

A general access to the spiroimine skeleton of gymnodimine and spirolides is described, relying on the construction of the cyclohexene fragment using an enantiocontrolled Diels-Alder reaction, the installation of the all-carbon quaternary stereocenter through a stereocontrolled alkylation or aldolisation and the elaboration of the lateral chains at C7 and C22 using Wittig-Horner olefinations. The spiroimine core of gymnodimine is made available through a 16-step linear sequence in a 21 % overall yield., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pd-nanoparticle-catalyzed dehydrogenative coupling between various hydrosilanes and alcohols was shown to provide silyl ethers in good and reproducible yields. The synthetic methodology is effective for a wide range of simple and bulky silanes and secondary alcohols, while keeping various other functional groups intact. The procedure also exhibits high selectivity for the silylation of primary versus secondary alcohols in 1,2-diols, and allows the successive silylation of alkynols and hydrogenation of the triple bond to afford Z-alkenols in good yields., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The generation of carbamoyl radicals, followed by their addition to heteroarenes, was performed under mild conditions through a metal-free photocatalyzed decarboxylation of oxamic acids. The process has been applied to the carbamoylation of heteroaromatic bases using α-aminoacid-derived oxamic acids, leading to the corresponding amides without racemization.

A sustainable metal-free route to urethanes and ureas based on a photocatalyzed oxidative decarboxylation of oxamic acids is described. The reaction includes in situ generation of an isocyanate from the oxamic acid, using an organic dye as a photocatalyst, a hypervalent iodine reagent as an oxidant and a light source, which trigger the free-radical decarboxylation. This protocol successfully avoids the isolation, purification and storage of carcinogenic isocyanates and allows elaboration of urethanes and ureas in a one-pot process from commercially available sources.

Eosin-Y (EY)-mediated alkylsulfonyl cyanation of olefins was shown to afford alkylsulfonyl nitriles in good yields. On the basis of transient absorption spectroscopy, the reaction was shown to proceed via photoinduced electron transfer from 3 EY* to an O-cyanated derivative of the photocatalyst, formed in situ, with generation of the corresponding sulfinate that is oxidized by EY •.+ into a sulfonyl radical. Addition of the latter on the olefin, followed by a radical cyano group transfer, then furnished the nitrile along with a RSO 2 radical sustaining the radical chain.

This review is an update on tris(trimethylsilyl)silane, TTMSS, in organic chemistry, focusing on the advancements of the past decade. The overview includes a wide range of chemical processes and synthetic strategies under different experimental conditions, including functional group insertion and transformations, as well as preparation of complex molecules, natural products, polymers, surfaces, and new materials. These results reveal how TTMSS has matured over the past 30 years, and they further establish its value as a free radical reagent with widespread academic and industrial applications.

Visible-light-promoted addition of α-bromoacetophenones onto the cyclopropene π-system in the presence of the fac-Ir(ppy) 3 catalyst was shown to afford the corresponding 1(4H)-naphthalenones. The syn-carboarylation of the cyclopropene is followed by a cyclopropane ring opening under the basic conditions, allowing the formation of two C-C bonds and the generation of 1(4H)-naphthalenones bearing an all-carbon benzylic quaternary stereocenter.

The free-radical three-component carbocyanation of electron-rich olefins was investigated with p-tosyl cyanide as cyanide source. The scope and limitations of the process were established by varying the nature of the alkene and radical precursor. Carbocyanation of chiral allylsilanes was shown to occur with high diastereocontrol, leading to syn β-silyl nitriles. The origin of the stereocontrol was rationalized by a Felkin-Anh-type transition-state model. Finally, a tin-free carbocyanation process was also devised, based on the use of a new alkylsulfonyl cyanide incorporating both carbon fragments to be added across the olefinic π system., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The three-component free-radical carbo-alkenylation of electron-rich olefins has been studied, varying the substitution pattern in the alkene, in the radical precursor and in the final acceptor. New vinylsulfones were also prepared and their reactivity investigated. The scope and limitations of the process was established, and the reaction mechanism clarified using selected dienes as radical clocks. It was thus recognised that the reversible addition onto the olefin of the released sulfonyl group is an important event, which should not be overlooked when using such multicomponent carbo-alkenylation reactions., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Free-radical carbocyanation of cyclopropenes offers straightforward access to tetrasubstituted cyclopropanes in satisfying yields with moderate diastereoselectivity. The incorporation of various functional groups on the cyclopropane ring allows a subsequent base-mediated ring-opening reaction leading to functionalized acyclic systems having an all-carbon quaternary stereocenter.

2,3,5-Trisubstituted tetrahydrofurans were prepared stereoselectively through a two-step process involving the addition of an acyl radical to a β-silyloxy acrylic ester followed by an acid-catalyzed desilylation-ketalization sequence and a final oxocarbenium reduction step. High levels of 1,2- and 1,3-stereocontrol were attained when (Me3Si)3SiH was used as a radical followed by a ionic hydrogen transfer agent.