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991.
Dr. Timo Broese Dr. Peter Ehlers Dr. Peter Langer Dr. Jan von Langermann 《Chembiochem : a European journal of chemical biology》2021,22(23):3314-3318
Fluoro-substituted and heteroaromatic compounds are valuable intermediates for a variety of applications in pharma- and agrochemistry and synthetic chemistry. This study investigates the chemoenzymatic preparation of chiral alcohols bearing a heteroaromatic ring with an increasing degree of fluorination in α-position. Starting from readily available picoline derivatives prochiral α-halogenated acyl moieties were introduced with excellent selectivity and 64–95 % yield. The formed carbonyl group was subsequently reduced to the corresponding alcohols using the alcohol dehydrogenase from Lactobacillus kefir, yielding an enantiomeric excess of 95–>99 % and up to 98 % yield. 相似文献
992.
Dr. Jisook Lee Dr. Nyssa Drinkwater Prof. Sheena McGowan Prof. Peter Scammells 《ChemMedChem》2021,16(1):234-249
Aminopeptidase N (APN/CD13) is a zinc-dependent ubiquitous transmembrane ectoenzyme that is widely present in different types of cells. APN is one of the most extensively studied metalloaminopeptidases as an anti-cancer target due to its significant role in the regulation of metastasis and angiogenesis. Previously, we identified a potent and selective APN inhibitor, N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide ( 3 ). Herein, we report the further modifications performed to explore SAR around the S1 subsite of APN and to improve the physicochemical properties. A series of hydroxamic acid analogues were synthesised, and the pharmacological activities were evaluated in vitro. N-(1-(3′-Fluoro-[1,1′-biphenyl]-4-yl)-2-(hydroxyamino)-2-oxoethyl)-4-(methylsulfonamido)benzamide ( 6 f ) was found to display an extremely potent inhibitory activity in the sub-nanomolar range. 相似文献
993.
Knut Brockow Katarzyna Plata-Nazar Magdalena Lange Bogusaw Nedoszytko Marek Niedoszytko Peter Valent 《International journal of molecular sciences》2021,22(5)
Mastocytosis is characterized by the pathological accumulation of mast cells (MC) in various organs. In these patients, MC may degranulate and thereby contribute to clinical symptoms, especially when a concomitant allergy is present. However, MC activation can not only be induced by high-affinity receptors for IgE, but also by anaphylatoxins, neuropeptides, IgG immune complexes, complement-components, drugs, products of bacteria or parasites, as well as physical factors such as heat, cold, vibration, stress, sun, or physical effort. Symptoms due to mediators released by activated MC may develop in adults suffering from systemic mastocytosis, but also evolve in children who usually have cutaneous mastocytosis (CM). Clinically, CM is otherwise characterized by typical brown, maculopapular skin lesions or mastocytoma associated with a positive Darier’s sign. Pruritus and flushing are common and blistering may also be recorded, especially in diffuse CM (DCM). Pediatric patients with mastocytosis may also have gastrointestinal, respiratory, and neurologic complaints. Although anaphylaxis is not a typical finding, pediatric patients with massive skin involvement and high tryptase levels have a relatively high risk to develop anaphylaxis. This paper reviews MC mediator-related symptoms and anaphylaxis in children with mastocytosis, with special emphasis on risk factors, triggers, and management. 相似文献
994.
Peter E. Neerincx Martin Hofmann Oleksandr Gorodetskyi Kirill Feldman Jan Vermant Han E. H. Meijer 《Polymer Engineering and Science》2021,61(4):1257-1269
Relatively recently, we advanced a route to create, in a controlled fashion, combined horizontal and vertical stratified structures by simple and energy-efficient processing operations employing static mixing elements. While in state-of-the-art static mixing the focus is on layer multiplication, here the aim is to create hierarchical fractal structures. Therefore, the main question addressed in this article is how structures, rather than layers, can be multiplied. The key aspect is the addition of layers on the sides or in the midplane of the flow during the process; every addition step increases the hierarchy by one level. This article derives the general formalism for forming fractal structures with controlled hierarchy, and we develop the language required to design and construct the dies. The main part of the article addresses this main topic and is based on the splitting serpentine static mixer geometry that can be easily made on the parting surfaces of a mold on both the micro- and the macroscale. The second part of the article addresses the strategy to minimize the number of mirroring steps, eventually avoiding mirroring completely, and is based on the rotation-free multiflux static mixer geometry. With the design language derived, complex hierarchical fractal structures can be generated simply by changing the number and sequence of operators within extrusion dies or molds, providing a one-step solution to produce material structures for potential use in diverse applications ranging from advanced mechanical systems to photovoltaic devices, where controlled assembly of dissimilar materials, and the realization of huge interfaces and genuine cocontinuity throughout the cross section, is critical. 相似文献
995.
Katarzyna Jasieniecka-Gazarkiewicz Kamil Demski Satinder K. Gidda Sylwia Kliska Janusz Niedojado Ida Lager Anders S. Carlsson Elena A. Minina Robert T. Mullen Peter V. Bozhkov Sten Stymne Antoni Bana 《International journal of molecular sciences》2021,22(6)
Arabidopsis thaliana possesses two acyl-CoA:lysophosphatidylethanolamine acyltransferases, LPEAT1 and LPEAT2, which are encoded by At1g80950 and At2g45670 genes, respectively. Both single lpeat2 mutant and double lpeat1 lpeat2 mutant plants exhibit a variety of conspicuous phenotypes, including dwarfed growth. Confocal microscopic analysis of tobacco suspension-cultured cells transiently transformed with green fluorescent protein-tagged versions of LPEAT1 or LPEAT2 revealed that LPEAT1 is localized to the endoplasmic reticulum (ER), whereas LPEAT2 is localized to both Golgi and late endosomes. Considering that the primary product of the reaction catalyzed by LPEATs is phosphatidylethanolamine, which is known to be covalently conjugated with autophagy-related protein ATG8 during a key step of the formation of autophagosomes, we investigated the requirements for LPEATs to engage in autophagic activity in Arabidopsis. Knocking out of either or both LPEAT genes led to enhanced accumulation of the autophagic adaptor protein NBR1 and decreased levels of both ATG8a mRNA and total ATG8 protein. Moreover, we detected significantly fewer membrane objects in the vacuoles of lpeat1 lpeat2 double mutant mesophyll cells than in vacuoles of control plants. However, contrary to what has been reported on autophagy deficient plants, the lpeat mutants displayed a prolonged life span compared to wild type, including delayed senescence. 相似文献
996.
Peter K. Windsor Stephen P. Plassmeyer Dominic S. Mattock Jonathan C. Bradfield Erika Y. Choi Bill R. Miller III Byung Hee Han 《International journal of molecular sciences》2021,22(6)
Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the π–π interactions. Moreover, docking scores correlate well with the ThT EC50 values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease. 相似文献
997.
Dora Szabo Zsolt Sarszegi Beata Polgar Eva Saghy Adam Nemeth Dora Reglodi Andras Makkos Aniko Gorbe Zsuzsanna Helyes Peter Ferdinandy Robert Herczeg Attila Gyenesei Attila Cziraki Andrea Tamas 《International journal of molecular sciences》2021,22(6)
Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a translational porcine MI model and plasma PACAP-38 levels in patients with ST-segment elevation myocardial infarction (STEMI). Significantly lower PACAP-38 levels were detected in the non-ischemic region of the left ventricle (LV) in MI heart compared to the ischemic region of MI-LV and also to the Sham-operated LV in porcine MI model. In STEMI patients, plasma PACAP-38 level was significantly higher before percutaneous coronary intervention (PCI) compared to controls, and decreased after PCI. Significant negative correlation was found between plasma PACAP-38 and troponin levels. Furthermore, a significant effect was revealed between plasma PACAP-38, hypertension and HbA1c levels. This was the first study showing significant changes in cardiac tissue PACAP levels in a porcine MI model and plasma PACAP levels in STEMI patients. These results suggest that PACAP, due to its cardioprotective effects, may play a regulatory role in MI and could be a potential biomarker or drug target in MI. 相似文献
998.
Nazanin Farahi Tamas Lazar Shoshana J. Wodak Peter Tompa Rita Pancsa 《International journal of molecular sciences》2021,22(6)
Liquid–liquid phase separation (LLPS) is a molecular process that leads to the formation of membraneless organelles, representing functionally specialized liquid-like cellular condensates formed by proteins and nucleic acids. Integrating the data on LLPS-associated proteins from dedicated databases revealed only modest agreement between them and yielded a high-confidence dataset of 89 human LLPS drivers. Analysis of the supporting evidence for our dataset uncovered a systematic and potentially concerning difference between protein concentrations used in a good fraction of the in vitro LLPS experiments, a key parameter that governs the phase behavior, and the proteomics-derived cellular abundance levels of the corresponding proteins. Closer scrutiny of the underlying experimental data enabled us to offer a sound rationale for this systematic difference, which draws on our current understanding of the cellular organization of the proteome and the LLPS process. In support of this rationale, we find that genes coding for our human LLPS drivers tend to be dosage-sensitive, suggesting that their cellular availability is tightly regulated to preserve their functional role in direct or indirect relation to condensate formation. Our analysis offers guideposts for increasing agreement between in vitro and in vivo studies, probing the roles of proteins in LLPS. 相似文献
999.
Dong Quan Peter Moloney Declan Carolan Hisham Abourayana Calvin Ralph Alojz Ivankovic Denis Dowling Neal Murphy 《应用聚合物科学杂志》2021,138(1):49605
This work studied the effects of adding short basalt fibers (BFs) and multi-walled carbon nanotubes (MWCNTs), both separately and in combination, on the mechanical properties, fracture toughness, and electrical conductivity of an epoxy polymer. The surfaces of the short BFs were either treated using a silane coupling agent or further functionalized by atmospheric plasma to enhance the adhesion between the BFs and the epoxy. The results of a single fiber fragmentation test demonstrated a significantly improved BF/epoxy adhesion upon applying the plasma treatment to the BFs. This resulted in better mechanical properties and fracture toughness of the composites containing the plasma-activated BFs. The improved BF/epoxy adhesion also affected the hybrid toughening performance of the BFs and MWCNTs. In particular, synergistic toughening effects were observed when the plasma-activated BFs/MWCNTs hybrid modifiers were used, while only additive toughening effects occurred for the silane-sized BFs/MWCNTs hybrid modifiers. This work demonstrated a potential to develop strong, tough, and electrically conductive epoxy composites by adding hybrid BF/MWCNT modifiers. 相似文献
1000.
Helena Kratochvílov Milo Mrz Barbora J. Kasperov Daniel Hlav
ek Jakub Mahrík Ivana Lakov Anna Cinkajzlov Zdenk Matloch Zdeka Lacinov Jaroslava Trnovsk Peter Ivk Peter Novodvorský Ivan Netuka Martin Haluzík 《International journal of molecular sciences》2021,22(9)
The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery; mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis. 相似文献