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Enantioconvergent transformations from racemic mixtures are attractive since they allow the generation of optically active products with full conversion despite the possibly adverse kinetic resolution process. When dealing with gold(I)-catalyzed cycloisomerizations, chirality transfer from the precursor is another possible diverting pathway, which renders enantioconvergence challenging. Not surprisingly, enantioconvergent Au(I)-catalyzed processes have remained extremely rare. Herein we show that cavity-driven catalysis using ß-cyclodextrin-NHC-Au(I) complexes brings opportunities to conduct highly enantioconvergent cycloisomerizations of 1,5-enynes, -enynols, and, -enynyl esters.
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Hypoimmune gene edited human pluripotent stem cells (hPSCs) are a promising platform for developing reparative cellular therapies that evade immune rejection. Existing first-generation hypoimmune strategies have used CRISPR/Cas9 editing to modulate genes associated with adaptive (e.g., T cell) immune responses, but have largely not addressed the innate immune cells (e.g., monocytes, neutrophils) that mediate inflammation and rejection processes occurring early after graft transplantation. We identified the adhesion molecule ICAM-1 as a novel hypoimmune target that plays multiple critical roles in both adaptive and innate immune responses post-transplantation. In a series of studies, we found that ICAM-1 blocking or knock-out (KO) in hPSC-derived cardiovascular therapies imparted significantly diminished binding of multiple immune cell types. ICAM-1 KO resulted in diminished T cell proliferation responses in vitro and in longer in vivo retention/protection of KO grafts following immune cell encounter in NeoThy humanized mice. The ICAM-1 KO edit was also introduced into existing first-generation hypoimmune hPSCs and prevented immune cell binding, thereby enhancing the overall hypoimmune capacity of the cells. This novel hypoimmune editing strategy has the potential to improve the long-term efficacy and safety profiles of regenerative therapies for cardiovascular pathologies and a number of other diseases.
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The unique properties of conjugated polymers (CPs) in various optoelectronic applications are mainly attributed to their different self-assembly processes and superstructures. Various methods are utilized to tune and control CP structure and properties with less attention paid to the use of chirality. CPs with main chain chirality are rare and their microscopic and macroscopic properties are still unknown. In this work, the first experimental results are provided along these lines by synthesizing a series of racemic and enantiopure CPs containing statistical and alternating carbo[6]helicene and indacenodithiophene moieties and evaluating their microscopic (optical, energy levels) and macroscopic properties (hole mobilities, photovoltaic performance). It is demonstrated that a small statistical insertion of either the racemic or enantiopure helicene into the polymer backbone finely tunes the microscopic and macroscopic properties as a function of the statistical content. The microscopic properties of the enantiopure versus the racemic polymers with the same helicene loading remain similar. On the contrary, the macroscopic properties, and more interestingly those between the two enantiomeric forms, are altered as a function of the statistical content. Once incorporated into a solar cell device, these chiral CPs display better performance in their enantiopure versus racemic forms.
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The synthesis of several new compounds containing a chromophore and a helicenic moiety is reported. The preparation, characterisation and some physico-chemical studies are detailed. In particular, the two enantiomers of several chiral molecules of this type were separated by chiral HPLC (both analytically and in a preparative way) and their racemisation rates were determined for short-lived species. Electronic circular dichroism (ECD) and circular polarised luminescence (CPL) measurements were performed for the compounds with a very long racemisation half-life. Chiral porphyrins and Bodipys both gave ECD and CPL responses over a large area of the visible spectrum.
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Reductive amination plays a key role in the medicinal chemistry toolbox since it allows the mono alkylation of an amine or aniline. In this work, reductive amination of functionalized aldehydes with aniline derivatives of adenine and closely related 7-deazapurines has been successfully performed using H-cube technology so that imine formation and its reduction are performed "in situ". The set-up procedure surmounts some of the drawbacks of "in batch" protocols by avoiding the handling of reductant reagents, long reaction times and tedious work-ups. The here described procedure allows a high conversion into the reductive amination products together with an easy work-up by just evaporation. More interestingly, this set-up does not require the presence of acids so that acid-sensitive protecting groups can be present both at the aldehyde and at the heterocycle.
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Humanized mouse models, created via transplantation of human hematopoietic tissues into immune-deficient mice, support a number of research applications, including transplantation immunology, virology and oncology studies. As an alternative to the bone marrow, liver, thymus humanized mouse, which uses fetal tissues for generating a chimeric human immune system, the NeoThy humanized mouse uses nonfetal tissue sources. Specifically, the NeoThy model incorporates hematopoietic stem and progenitor cells from umbilical cord blood (UCB) as well as thymus tissue that is typically discarded as medical waste during neonatal cardiac surgeries. Compared with fetal thymus tissue, the abundant quantity of neonatal thymus tissue offers the opportunity to prepare over 1,000 NeoThy mice from an individual thymus donor. Here we describe a protocol for processing of the neonatal tissues (thymus and UCB) and hematopoietic stem and progenitor cell separation, human leukocyte antigen typing and matching of allogenic thymus and UCB tissues, creation of NeoThy mice, assessment of human immune cell reconstitution and all experimental steps from planning and design to data analysis. This entire protocol takes a total of ~19 h to complete, with steps broken up into multiple sessions of 4 h or less that can be paused and completed over multiple days. The protocol can be completed, after practice, by individuals with intermediate laboratory and animal handling skills, enabling researchers to make effective use of this promising in vivo model of human immune function.
Asunto(s)
Sistema Inmunológico , Timo , Humanos , Animales , Ratones , Modelos Animales de Enfermedad , Hígado , InvestigadoresRESUMEN
The preparation of the first enantiopure cycloplatinated complexes bearing a bidentate, helicenic N-heterocyclic carbene and a diketonate ancillary ligand is presented, along with their structural and spectroscopic characterization based on both experimental and computational studies. The systems exhibit long-lived circularly polarized phosphorescence in solution and in doped films at room temperature, and also in a frozen glass at 77 K, with dissymmetry factor glum values ≥10-3 in the former and around 10-2 in the latter.
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The superimposition of the X-ray complexes of cyclohexanediones (i.e., TUB015), described by our research group, and nocodazole, within the colchicine binding site of tubulin provided an almost perfect overlap of both ligands. This structural information led us to propose hybrids of TUB015 and nocodazole using a salicylanilide core structure. Interestingly, salicylanilides, such as niclosamide, are well-established signal transducers and activators of transcription (STAT3) inhibitors with anticancer properties. Thus, different compounds with this new scaffold have been synthesized with the aim to identify compounds inhibiting tubulin polymerization and/or STAT3 signaling. As a result, we have identified new salicylanilides (6 and 16) that showed significant antiproliferative activity against a panel of cancer cells. Both compounds were able to reduce the levels of p-STAT3Tyr705 without affecting the total expression of STAT3. While compound 6 inhibited tubulin polymerization and arrested the cell cycle of DU145 cells at G2/M, similar to TUB015, compound 16 showed a more potent effect on inhibiting STAT3 phosphorylation and arrested the cell cycle at G1/G0, similar to niclosamide. In both cases, no toxicity towards PBMC cells was detected. Thus, the salicylanilides described here represent a new class of antiproliferative agents affecting tubulin polymerization and/or STAT3 phosphorylation.
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An N,P-heterocyclic germylene/B(C6 F5 )3 Lewis adduct 2 presenting multi-reactive sites (P/B Lewis pair, germylene, Ge=P π-bond) is reported. In contrast to classical frustrated Lewis pairs or divalent Groupâ 14 element species, 2 is able to activate two small molecules simultaneously. Of particular interest, 2 reacts with silanes leading to the formation of original cationic germylenes 3, and can be used as a metal-free catalyst for selective CO2 -hydrosilylation to H2 C(OSiEt3 )2 .
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A new stable heterocyclic germylene, in which the divalent germanium atom lies between a nitrogen atom and a phosphanylidene phosphorane group, was synthesized. Experimental and theoretical studies revealed the peculiar effect of phosphanylidene phosphorane substituent, which is a stronger π-donor towards germanium than an amino group is. Because of the weak phosphorus-germanium π-bond, this new germylene compound shows an enhanced reactivity compared to classical N-heterocyclic germylenes.
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Enamel defects in the permanent teeth of patients with coeliac disease (CD) are often reported as an atypical manifestation, sometimes being suggestive of an undiagnosed atypical disease. We proposed to explore the pathogenesis of these oral defects, which are poorly studied. Sequence analyses of proteins from gluten (gliadins) and of proline-rich enamel proteins (amelogenin and ameloblastin) suggested the presence of common antigenic motifs. Therefore, we analyzed, by ELISA and western blotting, the reactivity of sera from patients with CD against gliadin and enamel-derived peptides. Correlation analyses between the levels of specific antibodies against gliadin and enamel derived peptides and inhibition experiments confirmed the presence of cross-reactive antibodies. Immunoblot analysis revealed that the most prominent component in enamel matrix derivative (of approximately 18.6 kDa), identified by an amelogenin-specific antibody, is recognized by sera from patients with CD; in addition, several fractions of pure gliadin were recognized by amelogenin-specific antibody. In agreement, sera from mice immunized with enamel matrix-derived proteins generated antibodies that recognized a peptide (of approximately 21.2 kDa) derived from gliadin. In conclusion, antibodies against gliadin generated in patients with CD can react in vitro with a major enamel protein. The involvement of anti-gliadin serum in the pathogenesis of enamel defects in children with untreated CD can be hypothesized on the basis of these novel results.
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Amelogenina/inmunología , Enfermedad Celíaca/inmunología , Hipoplasia del Esmalte Dental/etiología , Hipoplasia del Esmalte Dental/inmunología , Proteínas del Esmalte Dental/inmunología , Gliadina/inmunología , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Western Blotting , Estudios de Casos y Controles , Enfermedad Celíaca/sangre , Reacciones Cruzadas , Hipoplasia del Esmalte Dental/sangre , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Análisis de Secuencia de Proteína , Estadísticas no Paramétricas , Adulto JovenRESUMEN
PROBLEM: Untreated celiac disease (CD) is often associated with early miscarriages, infertility, and alterations in menstrual cycle. Tissue transglutaminase (tTG) antibodies could be involved by interfering with tTG transamidating activity and/or biological functions mediated by its interaction with fibronectin (FN). METHOD OF STUDY: The correlation between the presence of extra-digestive disorders and the reactivity of sera against tTG-FN and its effects on tTG transamidating activity was analyzed in a group or 50 women with recently diagnosed CD. RESULTS: Heterogeneous behavior was observed among serum samples derived from patients with different complaints, suggesting that differences in fine specificity patterns could condition clinical outcome. Sera from women with gynecological and/or obstetric problems induced significant inhibition of in vitro enzymatic activity in comparison with those without these kinds of disorders. CONCLUSIONS: The significant correlation observed between serum effects and clinical profile suggests a putative involvement of tTG-specific antibodies in gynecological and/or obstetric disorders during active CD.