Mechanical properties are cues for many biological processes in health or disease. In the heart, changes to the extracellular matrix composition and cross-linking result in stiffening of the cellular ...microenvironment during development. Moreover, myocardial infarction and cardiomyopathies lead to fibrosis and a stiffer environment, affecting cardiomyocyte behavior. Here, we identify that single cardiomyocyte adhesions sense simultaneous (fast oscillating) cardiac and (slow) non-muscle myosin contractions. Together, these lead to oscillating tension on the mechanosensitive adaptor protein talin on substrates with a stiffness of healthy adult heart tissue, compared with no tension on embryonic heart stiffness and continuous stretching on fibrotic stiffness. Moreover, we show that activation of PKC leads to the induction of cardiomyocyte hypertrophy in a stiffness-dependent way, through activation of non-muscle myosin. Finally, PKC and non-muscle myosin are upregulated at the costameres in heart disease, indicating aberrant mechanosensing as a contributing factor to long-term remodeling and heart failure.
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•Talin in cardiomyocytes is unstretched, cyclically stretched, or continuously stretched•Talin stretching depends on stiffness, myofibrillar tension, and non-myofibrillar tension•Non-myofibrillar contractility requires PKC, Src, FHOD1, and non-muscle myosin•PKC and non-muscle myosin activity are enhanced in cardiac disease
Pandey et al. identify that cardiomyocytes sense the rigidity of the heart by measuring the combined forces from non-muscle and muscle myosin. This can result in cyclic or continuous stretching of the mechanosensitive protein talin, depending on the substrate stiffness and the level of non-muscle myosin activity.
The diruthenium(II,II) complex Ru2(L1)(OAc)3Cl (1), spanned by a naphthyridine-diimine ligand and bridged by three acetates, has been synthesized. The catalytic efficacy of complex 1 has been ...evaluated for the acceptorless dehydrogenation (AD) of alcohols and for the dehydrogenative coupling reactions of alcohols with Wittig reagents. The diruthenium(II,II) complex is an excellent catalyst for AD of a diverse range of alcohols, and it is shown to be particularly effective for the conversion of primary alcohols to the corresponding aldehydes without undesired side products such as esters. Triphenylphosphonium ylides in a one-pot reaction with alcohols afforded the corresponding olefins in high yields with excellent E selectivity. The liberated dihydrogen gas was identified and measured to be 1 equiv with respect to alcohol. Deuteration studies with PhCD2OH revealed the absence of isotope scrambling in the product, indicating the involvement of a Ru-monohydride intermediate. Kinetic studies and DFT calculations suggest a low-energy bimetallic β-hydride elimination pathway where rate-limiting intramolecular proton transfer from alcohol to metal-bound hydride constitutes the dehydrogenation step. The general utility of metal–metal bonded compounds for alcohol AD and subsequent coupling reactions is demonstrated here.
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•Naphthyridine based oxazoline and camphor-pyrazole chiral ligands are synthesized.•Di- and tetranuclear Cu(I) and Ag(I) complexes containing chiral ligands are isolated.•Each ligand ...displays bridge-chelate motif holding two metals in proximity.•A combination of Cu salt/L3 ligand affords appreciable yields with very low e.e.
Oxazoline and camphor-pyrazole units are introduced on the 1,8-naphthyridine scaffold to access chiral ligands L1, L2 and L3. Metalation of these chiral ligands with Cu(I) and Ag(I) precursors afforded di- and tetranuclear complexes Cu4I4(L1)2 (1), Cu4I4(L2)2 (2), Cu2I2(L3) (3), Cu2I(L2)2(OTf) (4), Ag2(L1)2(OTf)2 (5) and Ag4(L2)4Br(OTf)3 (6), containing M4Xn (n = 1,4 and X = Br, I) or M2Xn (n = 0, 1, 2 and X = I) core. All complexes are structurally characterized. Naphthyridine-derived ligands reveal bridge-chelate coordination motif and hold two metal centers in close proximity. The tetranuclear complexes are dimer of dinuclear complexes bridged by the halides. Electronic absorption and emission spectra of copper complexes are reported. Catalytic utility of all complexes are examined for asymmetric transformations but they showed poor activity probably due to limited solubility and coordinative saturation at the metal centers. The best results are obtained with L3/Cu salt combination for cyclopropanation of styrene, NH bond insertion and nitroaldol (Henry) reactions with very low enantioselectivity.
A Cp*Ir(III) complex (1) bearing a proton-responsive hydroxy unit on an annulated imidazo1,2-a1,8naphthyridine based mesoionic carbene scaffold was synthesized by two different synthetic routes. ...The molecular structure of 1 revealed an anionic lactam form of the ligand. The acid–base equilibrium between the lactam-lactim tautomers on the ligand scaffold was examined by 1H NMR and UV–vis spectra. The pK a of the appendage −OH group in the lactim form of 1 was estimated to assess the proton transfer property of the catalyst. The catalytic efficacy of 1 for reductive amination of aldehyde was evaluated by utilizing three different hydrogen sources: molecular H2, i PrOH/KO t Bu combination, and HCOOH/Et3N (5:2) azeotropic mixture. The HCOOH/Et3N (5:2) azeotropic mixture protocol was found to be the best among the three different hydrogenation methods. Catalyst 1 hydrogenates imines chemoselectively over carbonyls under the reaction conditions. A range of aldehydes was reductively aminated to the corresponding secondary amines using the HCOOH/Et3N (5:2) azeotropic mixture. Further, catalyst 1 showed high efficiency for the reduction of a wide variety of N-heterocyclic imine derivatives. The lactam-lactim tautomerization of the ligand system is proposed for direct hydrogenation, whereas only the lactam form operates in the strongly basic medium ( i PrOH/KO t Bu). Under HCOOH/Et3N (5:2) conditions, the lactam scaffold is not protonated; rather, an outer-sphere hydride transfer from formate to the Ir is proposed, which is supported by 1H NMR and DFT calculations. Finally, ligand-promoted hydride transfer from metal-hydride to the protonated imine affords the corresponding amine. A close agreement between the experimentally estimated and computed thermodynamic/kinetic parameters gives credence to the metal-ligand cooperative mechanism for the imine hydrogenation reaction using the HCOOH/Et3N (5:2) azeotropic mixture.
Acceptorless Alcohol Dehydrogenation: A Mechanistic Perspective Pandey, Pragati; Dutta, Indranil; Bera, Jitendra K.
National Academy of Sciences, India. Proceedings. Section A. Physical Sciences,
12/2016, Letnik:
86, Številka:
4
Journal Article, Conference Proceeding
Recenzirano
Alcohols are unreactive and require strong inorganic oxidants to convert to synthetically useful carbonyl compounds. Acceptorless dehydrogenation of alcohol is a green and atom-economic alternative, ...which provides aldehyde (or ketone) without the use of sacrificial acceptor molecules and the side product is molecular hydrogen. This review provides a brief overview of the initial work followed by recent advances in the field of acceptorless alcohol dehydrogenation. Catalysts that employ metal–ligand cooperation for alcohol activation and dehydrogenation are covered in details. Different mechanisms are examined and clear advantages associated with a bifunctional pathway are outlined. Mechanistic understanding at the molecular level helps to develop new generation dehydrogenation catalysts. Recent works from our group on this area along with literature reports are discussed.
Drug resistance in leprosy is an emerging concern, leading to treatment failures, recurrences, and potential spread of resistant Mycobacterium leprae in the community. In this study, we aimed to ...assess drug resistance prevalence and patterns amongst leprosy patients at a tertiary care referral hospital in India.
Mutations in drug resistance determining regions for dapsone, rifampicin, and ofloxacin of the M. leprae genome in DNA extracted from skin biopsies of 136 leprosy patients (treatment-naive = 67, with persistent skin lesions = 35, with recurrence = 34) were analysed by polymerase chain reaction followed by Sanger sequencing. Wild-type strain (Thai-53) was used as a reference strain.
Resistance mutations were identified in a total of 23 patients, constituting 16.9% of the cohort. Within this subset of 23 cases, resistance to ofloxacin was observed in 17 individuals (12.5%), while resistance to both dapsone and rifampicin was detected in three patients each (2.2% for both). The occurrence of ofloxacin resistance showed minimal disparity between recurrent and treatment-naive cases, at 17.6% and 16.4%, respectively. Dapsone resistance emerged in two treatment-naive cases and one case with persistent skin lesions. Notably, none of the treatment-naive cases or those with recurrence/relapse exhibited rifampicin resistance. Subsequently, no statistically significant correlation was identified between other clinical variables and the presence of antimicrobial resistance.
The occurrence of resistance to the current multidrug therapy regimen (specifically dapsone and rifampicin) and to ofloxacin, a secondary antileprosy medication in M. leprae, represents a concerning scenario. This calls for an expansion towards bactericidal drug options and the establishment of robust surveillance for drug resistance in countries burdened with high leprosy rates. Moreover, the introduction of stringent antimicrobial stewardship initiatives is imperative. As a single centre study, it represents a limited, cross-sectional view of the real situation in the field.
Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be a novel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more data ...are needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5 mm) consisting of up to 20 million human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarction model was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs in EHTs became more aligned over 28 days and had improved contraction kinetics and faster calcium transients. Blinded echocardiographic analysis revealed a significant improvement in function in infarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularization from the host to the patch was observed at week 1 and stable to week 4, but electrical coupling between patch and host heart was not observed. In vivo telemetry recordings and ex vivo arrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTs improved function and reduced scar size without causing arrhythmia, which may be due to the lack of electrical coupling between patch and host heart.
A terminal Ni-OH complex
1
, supported by triflamide-functionalized NHC ligands, catalyzes the hydrosilylative reduction of a range of primary amides into primary amines in good to excellent yields ...under base-free conditions with key functional group tolerance. Catalyst
1
is also effective for the reduction of a variety of tertiary and secondary amides. In contrast to literature reports, the reactivity of
1
towards amide reduction follows an inverse trend,
i.e.
, 1° amide > 3° amide > 2° amide. The reaction does not follow a usual dehydration pathway.
A terminal Ni-OH complex, stabilized by triflamide-tethered NHC ligands, selectively catalyses the deoxygenative reduction of primary amides to primary amines using phenylsilane as the reductant, without proceeding
via
a nitrile intermediate.
The Ni
complex 1 containing pyridyl- and hydroxy-functionalized N-heterocyclic carbenes (NHCs) is synthesized and its catalytic utility for the selective nitrile hydration to the corresponding amide ...under base-free conditions is evaluated. The title compound exploits a hemilabile pyridyl unit to interact with a catalytically relevant water molecule through hydrogen-bonding and promotes a nucleophilic water attack to the nitrile. A wide variety of nitriles is hydrated to the corresponding amides including the pharmaceutical drugs rufinamide, Rifater, and piracetam. Synthetically challenging α-hydroxyamides are accessed from cyanohydrins under neutral conditions. Related catalysts that lack the pyridyl unit (i.e., compounds 2 and 4) are not active whereas those containing both the pyridyl and the hydroxy or only the pyridyl pendant (i.e., compounds 1 and 3) show substantial activity. The linkage isomer 1' where the hydroxy group is bound to the metal instead of the pyridyl group was isolated under different crystallization conditions insinuating a ligand hemilabile behavior. Additional pK
measurements reveal an accessible pyridyl unit under the catalytic conditions. Kinetic studies support a ligand-promoted nucleophilic water addition to a metal-bound nitrile group. This work reports a Ni-based catalyst that exhibits functional hemilability for hydration chemistry.
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