39 research outputs found
Stereoselective synthesis of biologically relevant dihydropyridines and pyrans via ring-expansion of monocyclopropanated heterocycles
A stereoselective, scalable and metal-free ring-expansion of monocyclopropanated pyrroles and furans has been developed, leading to value-added, highly functionalized dihydropyridine and pyran derivatives. Featuring a cyclopropylcarbinyl cation rearrangement as the key step, the selective cleavage of the unactivated endocyclic cyclopropane C-C bond is achieved. Targeted transformations of the so obtained 6-membered heterocycles give access to versatile building blocks with relevance for drug synthesis
Stereoselective Synthesis of Tropanes via a Retro-6 p Electrocyclic Ring-Opening / Huisgen [3+2]-Cycloaddition Cascade of Monocyclopropanated Heterocycles. Stereoselektive Synthese von Tropanen über eine 6π-elektrocyclische Ringöffnung/ Huisgen-[3+2]-Cycloadditionskaskade von monocyclopropanierten Heterocyclen
The synthesis of tropanes via a microwave-assisted, stereoselective 6 pi-electrocyclic ring-opening/ Huisgen [3+2]-cycloaddition cascade of cyclopropanated pyrrole and furan derivatives with electron-deficient dipolarophiles is demonstrated. Starting from furans or pyrroles, 8-aza- and 8-oxabicyclo[3.2.1]octanes are accessible in two steps in dia- and enantioselective pure form, being versatile building blocks for the synthesis of pharmaceutically relevant targets, especially for new cocaine analogues bearing various substituents at the C-6/C-7 positions of the tropane ring system. Moreover, the 2-azabicyclo[2.2.2]octane core (isoquinuclidines), being prominently represented in many natural and pharmaceutical products, is accessible via this approach
Transglutaminase 1 Replacement Therapy Successfully Mitigates the Autosomal Recessive Congenital Ichthyosis Phenotype in Full-Thickness Skin Disease Equivalents
hiPSC-Derived Epidermal Keratinocytes from Ichthyosis Patients Show Altered Expression of Cornification Markers
Inherited ichthyoses represent a large heterogeneous group of skin disorders characterised by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines suffer from severe epidermal barrier defects causing neonatal death and human keratinocytes have very limited proliferation ability in vitro. Therefore, the development of disease models based on patient derived human induced pluripotent stem cells (hiPSCs) is highly relevant. For this purpose, we have generated hiPSCs from patients with congenital ichthyosis, either non-syndromic autosomal recessive congenital ichthyosis (ARCI) or the ichthyosis syndrome trichothiodystrophy (TTD). hiPSCs were successfully differentiated into basal keratinocyte-like cells (hiPSC-bKs), with high expression of epidermal keratins. In the presence of higher calcium concentrations, terminal differentiation of hiPSC-bKs was induced and markers KRT1 and IVL expressed. TTD1 hiPSC-bKs showed reduced expression of FLG, SPRR2B and lipoxygenase genes. ARCI hiPSC-bKs showed more severe defects, with downregulation of several cornification genes. The application of hiPSC technology to TTD1 and ARCI demonstrates the successful generation of in vitro models mimicking the disease phenotypes, proving a valuable system both for further molecular investigations and drug development for ichthyosis patients
Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan
Background Autosomal recessive congenital ichthyosis (ARCI) is a genetically and phenotypically heterogeneous skin disease, associated with defects in the skin permeability barrier. Several but not all genes with underlying mutations have been identified, but a clear correlation between genetic causes and clinical picture has not been described to date. Methods Our study included 19 families from Saudi Arabia, Yemen, and Pakistan. All patients were born to consanguineous parents and diagnosed with ARCI. Mutations were analyzed by homozygosity mapping and direct sequencing. Results We have detected mutations in all families in five different genes: TGM1, ABCA12, CYP4F22, NIPAL4, and ALOXE3. Five likely pathogenic variants were unknown so far, a splice site and a missense variant in TGM1, a splice site variant in NIPAL4, and missense variants in ABCA12 and CYP4F22. We attributed TGM1 and ABCA12 mutations to the most severe forms of lamellar and erythematous ichthyoses, respectively, regardless of treatment. Other mutations highlighted the presence of a phenotypic spectrum in ARCI. Conclusion Our results contribute to expanding the mutational spectrum of ARCI and revealed new insights into genotype/phenotype correlations. The findings are instrumental for a faster and more precise diagnosis, a better understanding of the pathophysiology, and the definition of targets for more specific therapies for ARCI
Cystatin M/E Variant Causes Autosomal Dominant Keratosis Follicularis Spinulosa Decalvans by Dysregulating Cathepsins L and V
Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing X-linked KFSD have been described in MBTPS2, the gene for a membrane-bound zinc metalloprotease that is involved in the cleavage of sterol regulatory element binding proteins important for the control of transcription. Few families have been identified with an autosomal dominant inheritance of KFSD. We present two members of an Austrian family with a phenotype of KFSD, a mother and her son. The disease was not observed in her parents, pointing to a dominant inheritance with a de novo mutation in the index patient. Using whole-exome sequencing, we identified a heterozygous missense variant in CST6 in DNA samples from the index patient and her affected son. In line with family history, the variant was not present in samples from her parents. CST6 codes for cystatin M/E, a cysteine protease inhibitor. Patient keratinocytes showed increased expression of cathepsin genes CTSL and CTSV and reduced expression of transglutaminase genes TGM1 and TGM3. A relative gain of active, cleaved transglutaminases was found in patient keratinocytes compared to control cells. The variant found in CST6 is expected to affect protein targeting and results in marked disruption of the balance between cystatin M/E activity and its target proteases and eventually transglutaminases 1 and 3. This disturbance leads to an impairment of terminal epidermal differentiation and proper hair shaft formation seen in KFSD
Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy
Review article[Abstract] The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy
High temperature (HT) polymer electrolyte membrande fuel cells (PEMFC) - A review
One possible solution of combating issues posed by climate change is the use of the High Temperature (HT) Polymer Electrolyte Membrane (PEM) Fuel Cell (FC) in some applications. The typical HT-PEMFC operating temperatures are in the range of 100e200 o C which allows for co-generation of heat and power, high tolerance to fuel impurities and simpler system design. This paper reviews the current literature concerning the HT-PEMFC, ranging from cell materials to stack and stack testing. Only acid doped PBI membranes meet the US DOE (Department of Energy) targets for high temperature membranes operating under no humidification on both anode and cathode sides (barring the durability). This eliminates the stringent requirement for humidity however, they have many potential drawbacks including increased degradation, leaching of acid and incompatibility with current state-of-the-art fuel cell materials. In this type of fuel cell, the choice of membrane material determines the other fuel cell component material composition, for example when using an acid doped system, the flow field plate material must be carefully selected to take into account the advanced degradation. Novel research is required in all aspects of the fuel cell components in order to ensure that they meet stringent durability requirements for mobile applications.Web of Scienc
"Irgendwie fühle ich mich als Angehörige alleine gelassen". Eine automatisierte Analyse eines Onlineforums für Angehörige von Inhaftierten
Der Entzug der Freiheit aufgrund einer Straftat bedeutet nicht nur für die inhaftierte Person, sondern auch für deren Angehörige eine tiefgreifende lebensweltliche Veränderung und Zäsur sowie ein erhöhtes Risiko für soziale, psychische oder materielle Problemlagen. Online-Selbsthilfeforen können in dieser Lebensphase eine Unterstützung darstellen. In diesem Beitrag wird ein Forum für Angehörige textanalytisch untersucht und folgende Frage verfolgt: Welche Themen sind für Betroffene von Inhaftierung von besonderer Relevanz und inwiefern lassen sich diese Themen automatisiert erkennen? Nach einer grundlegenden Einführung in die Bedeutung von Onlineforen für die Soziale Arbeit und Straffälligenhilfe (Kap. 1) wird das methodische Vorgehen des Topic Modelings erläutert (Kap. 2). Durch die Analyse konnten die am häufigsten diskutierten Themen identifiziert werden, wobei Forumsbeiträge insbesondere durch das Thema Hoffnung geprägt sind (Kap. 3). Da die Ergebnisse vielfältige Implikationen zulassen und derartige Studiendesigns mit spezifischen rechtlichen und ethischen Herausforderungen konfrontiert sind, wird dies in einem abschließenden Kapitel erörtert (Kap. 5). (DIPF/Orig.
Catalyst-free, scalable heterocyclic flow photocyclopropanation
Industrial process development is driven by several factors, including safety, cost, robustness and environmental aspects. However, attempts to establish aryl diazo esters - which are highly valued in academic research for their reactivity as carbene precursors - in the chemical industry have been limited by their explosivity and toxicity. Their catalyst-free photolysis in continuous flow improves safety, sustainability and scalability compared to batch reactions. Herein, we report the continuous flow catalyst-free photocyclopropanation of heterocycles in up to grams per h productivity in a non-chlorinated, biodegradable solvent. Highly-functionalized cyclopropanated products are key intermediates in the synthesis of drugs and pharmaceutically-relevant compounds. Optimal conditions and process understanding were obtained by a Design of Experiments approach. In comparison with a large scale batch experiment, continuous flow conditions improved yield, productivity and process safety