Biomedical applications of molecules that are able to modulate β-adrenergic signaling have become increasingly attractive over the last decade, revealing that β-adrenergic receptors (β-ARs) are key ...targets for a plethora of therapeutic interventions, including cancer. Despite successes in β-AR drug discovery, identification of β-AR ligands that are useful as selective chemical tools in pharmacological studies of the three β-AR subtypes, or lead compounds for drug development is still a highly challenging task. This is mainly due to the intrinsic plasticity of β-ARs as G protein-coupled receptors in conjunction with the requirement for functional receptor subtype selectivity, tissue specificity and minimal off-target effects. With the aim to provide insight into structure-activity relationships for the three β-AR subtypes, we have synthesized and obtained the pharmacological profile of a series of structurally diverse compounds (named MC) that were designed based on the aryloxy-propanolamine scaffold of SR59230A. Comparative analysis of their predicted binding mode within the active and inactive states of the receptors in combination with their pharmacological profile revealed key structural elements that control their activity as agonists or antagonists, in addition to clues about substituents that mediate selectivity for one receptor subtype over the others. We anticipate that these results will facilitate selective β-AR drug development efforts.
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•A series of new β-adrenoreceptor (β-AR) ligands, MC1-34, were synthesized based on the aryloxy propanolamine scaffold.•Their pharmacological profile was evaluated as agonist responses and antagonist affinity for the three β-AR subtypes.•Structure-activity relationships were extracted from docking calculations using the active and inactive states of the β-ARs.•Among the new compounds, MC28 is the most selective β3-AR blocker, and MC30–33 are β2-AR selective antagonists.•The known antagonist SR59230A is clearly not a β3-AR selective ligand, while it exhibits β1-/β2-/β3-AR partial agonism.
Abstract
The discovery that the surfaces of Gram-negative bacteria often carry unique polysaccharide signatures pre-dates most seminal discoveries of molecular biology and biochemistry of the 20th ...century. The O-antigen component of the lipopolysaccharide has been one of the most intensely studied bacterial polysaccharide surface structures for over 80 years. Yet, many questions about the mechanism of biosynthesis of the O-antigen and its transport to the cell surface remain unanswered. In this review we provide an overview of how the molecular basis of the O-antigen assembly and trafficking were unraveled in a historical context. We pay particular attention to the emergence of novel technological approaches and how they fueled the elucidation of the O-antigen maturation process. Moreover, we provide a brief perspective on the biosynthesis of enterobacterial common antigen and underline the similarities and differences between the pathways used to assemble these two surface polysaccharides. Finally, we highlight key discoveries that led to the understanding of the mechanistic basis of bacteriophage-induced O-antigen modifications. We place special emphasis on the regulation of the length of O-antigen polymers and provide a detailed overview of the models explaining the O-antigen length determination. Finally, we highlight outstanding questions that need to be addressed both structurally and functionally to advance our understanding of the O-antigen assembly, trafficking and export within cellular and molecular contexts.
This review provides a historical perspective of how the molecular basis of the O-antigen assembly was elucidated, and to underscore some of the most intriguing questions that remain to be addressed.
Records of the environmental occurrence of organothiophosphate esters (OTPEs), which are used as flame retardants and food and industrial additives, are unavailable. In this study, we discovered ...three OTPEs, namely O,O,O-tris(2,4-di-tert-butylphenyl) phosphorothioate (AO168S), O-butyl O-(butyl-methylphenyl) O-(di-butylphenyl) phosphorothioate (BBMDBPt)/O,O-bis(dibutylphenyl) O-methyl phosphorothioate (BDBPMPt), and O-butyl O-ethyl O-hydrogen phosphorothioate (BEHPt), in the surface water of the Yangtze River Basin by applying a characteristic phosphorothioate fragment-directed high-resolution mass spectrometry method. Among the 17 water samples tested, the detection frequencies of AO168S and BEHPt were 100% and that of BBMDBPt/BDBPMPt was 29%. The mean concentration of AO168S was 56.9 ng/L (30.5–148 ng/L), and semi-quantitative analysis revealed that the mean concentrations of BEHPt and BBMDBPt/BDBPMPt were 17.2 ng/L (5.5–65.4 ng/L) and 0.8 ng/L (<the limit of quantification, LOQ, to 6.3 ng/L), respectively. Twelve organophosphate esters were also detected, of which the highest mean concentration was found for tris(2,4-di-tert-butylphenyl) phosphate (AO168O, 366 ng/L), followed by triphenyl phosphate (84.3 ng/L), triethyl phosphate (19.3 ng/L), and tributyl phosphate (15.7 ng/L). The Spearman’s correlation coefficient between AO168S and AO168O was 0.547 (p < 0.05), suggesting that AO168S commonly transforms into AO168O or that these chemicals have a similar source and behavior in the environment. Future studies are warranted to assess the potential toxicity, environmental behavior, and health risks posed by OTPEs.
Ophiocordyceps species infecting ants - the so-called zombie-ant fungi - comprise one of the most intriguing and fascinating relationships between microbes and animals. They are widespread within ...tropical forests worldwide, with relatively few reports from temperate
ecosystems. These pathogens possess the ability to manipulate host behaviour in order to increase their own fitness. Depending on the fungal species involved the infected ants are manipulated either to leave the nest to ascend understorey shrubs, to die biting onto vegetation, or descend from
the canopy to die at the base of trees. Experimental evidence has demonstrated that the behavioural change aids spore dispersal and thus increases the chances of infection, because of the existing behavioural immunity expressed inside ant colonies that limits fungal development and transmission.
Despite their undoubted importance for ecosystem functioning, these fungal pathogens are still poorly documented, especially regarding their diversity, ecology and evolutionary relationships. Here, we describe 15 new species of Ophiocordyceps with hirsutella-like asexual morphs that
exclusively infect ants. These form a monophyletic group that we identified in this study as myrmecophilous hirsutelloid species. We also propose new combinations for species previously described as varieties and provide for the first time important morphological and ecological information.
The species proposed herein were collected in Brazil, Colombia, USA, Australia and Japan. All species could readily be separated using classic taxonomic criteria, in particular ascospore and asexual morphology.
In the early 1980s, while using purified glycosyltransferases to probe glycan structures on surfaces of living cells in the murine immune system, we discovered a novel form of serine/threonine ...protein glycosylation (O-linked β-GlcNAc; O-GlcNAc) that occurs on thousands of proteins within the nucleus, cytoplasm, and mitochondria. Prior to this discovery, it was dogma that protein glycosylation was restricted to the luminal compartments of the secretory pathway and on extracellular domains of membrane and secretory proteins. Work in the last 3 decades from several laboratories has shown that O-GlcNAc cycling serves as a nutrient sensor to regulate signaling, transcription, mitochondrial activity, and cytoskeletal functions. O-GlcNAc also has extensive cross-talk with phosphorylation, not only at the same or proximal sites on polypeptides, but also by regulating each other’s enzymes that catalyze cycling of the modifications. O-GlcNAc is generally not elongated or modified. It cycles on and off polypeptides in a time scale similar to phosphorylation, and both the enzyme that adds O-GlcNAc, the O-GlcNAc transferase (OGT), and the enzyme that removes O-GlcNAc, O-GlcNAcase (OGA), are highly conserved from C. elegans to humans. Both O-GlcNAc cycling enzymes are essential in mammals and plants. Due to O-GlcNAc’s fundamental roles as a nutrient and stress sensor, it plays an important role in the etiologies of chronic diseases of aging, including diabetes, cancer, and neurodegenerative disease. This review will present an overview of our current understanding of O-GlcNAc’s regulation, functions, and roles in chronic diseases of aging.
The invasive species Spartina anglica arose in Europe by a cross between the Afro-European species S. maritima (native, paternal ancestor) and the introduced North American S. alterniflora (invasive, ...maternal ancestor). Aqueous methanolic extracts were prepared from plant tissue for chemotaxonomical comparison between the three species and determination of the phenolic pattern inheritance in S. anglica. A total of 20 phenolic compounds were detected in the aerial tissues of S. anglica and S. alterniflora, but only seven in S. maritima. They were isolated from their respective crude extracts, and their structures were determined according to spectroscopic data analysis and chemical evidence. They all belong to the flavonoid class, with 13 of them identified as C-glycoflavonoid and seven as O-glycoflavonoid. All these products were detected for the first time from S. anglica, fourteen of them for the first time from S. alterniflora, and three of them for the first time from S. maritima. The individual concentrations in the three species were determined by quantitative HPLC. The two parental species were found to differ markedly in their foliar phenolic fingerprint, whereas that of S. anglica showed a clear maternal dominance. Eight of the fourteen major compounds identified were of maternal origin among which, six were over-expressed, only three were from paternal origin but under-regulated, while two originated from the two parents. As far as we know, this work represents the first exhaustive report of the phenolic fingerprints of S. alterniflora and S. anglica and of the phenolic pattern inheritance in S. anglica. The similarity in the phenolic chemistry of the introduced and invasive S. alterniflora to its progeny could play a role in the physiological vigour and invasion success of S. anglica. This work provide a foundation for further studies, considering the reported biological activities of C-glycosidic flavonoids and tricin derivatives, and the lack of knowledge of the ecological chemistry of the genus Spartina.
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•S. anglica arose from a cross between S. maritima and S. alterniflora.•Phenolic fingerprints of the 3 species revealed 20 flavonoid compounds.•Flavonoid diversity is greater in S. alterniflora than in S. maritima.•S. anglica kept all the flavonoids from S. alterniflora (maternal parent).•This inheritance pattern might play a role in the invasiveness of S. anglica.
As the aim of the research, the author set the task of searching for new ways of conducting educational activity when teaching Project Management at the university taking into account the dominating ...mosaic thinking of modern students. There is a need to teach students of the given field logical thinking, the ability to work in the financial and humanitarian spheres of current business. In order to get a result, the analysis of the existing scientific views and approaches to teaching students with dominating mosaic thinking was conducted. The existing views by both Russian and foreign authors of mosaic thinking were considered, its different educational, psychological and philosophical aspects. As a result of the synthesis of the given approaches, taking into account the author’s inventions, proposals were developed on solving the problems of mosaic thinking in teaching students. Taking a constructive approach as a basis, the mosaic thinking is suggested to be considered as a phenomenon having both advantages and disadvantages. Changing the content of the educational process is done through updating standard methods and patterns of education, wide use of innovation approaches, intensifying cooperation and online collaboration of the teacher and the student in the process of study. The basis is formed by the emotional impact on the student in the course of studies, which will allow using logic and form the intention to learn the presented fact. Teaching Project Management to students is proposed taking into account their mosaic thinking, in four stages. During the lecture students receive a chain of images structured by the lecturer in the sequence embracing basic issues of the theme under consideration and presented in such a way as to inspire them to study the given questions independently. At the second stage, the students search for the solution of the assigned tasks in the course of independent work with the opportunities available for their level of perception. During the seminar classes (practical studies) at the third stage, the lecturer evaluates the quantity and quality of the solutions of practical tasks (case problems) found by the students. In the course of discussion, the students share their variants of solving practical problems, grounding the relevance of the proposed variants. At the fourth stage (midterm assessment – examination) the students develop a project as a whole or one of its stages, solving a set of interrelated practical problems. Since mosaic thinking is the reality of a new information society now, a conclusion was made of the necessity not to fight mosaic thinking, but to reorganize the educational process taking into account, on the one hand, the peculiarities of students having mosaic thinking, on the other hand, needs of business which requires project managers capable of both processing great amounts of information and arranging logical chains and determining cause and effect relationships. The given modification of education is proposed to be implemented in regards to changing the content of lectures and seminar classes, adding figurativeness and emotionalism into them, which will make it possible to set the cognitive activity of the students having mosaic thinking, and changing the direction and content of students’ independent work, setting the independent search for solving problems and case tasks as its goal.
Palladium nanoparticles immobilized on amino‐functionalized mesocellular foam constitute an efficient catalyst for the aerobic oxidation of primary and secondary alcohols to their corresponding ...carbonyl compounds in high to excellent yields (see figure). An exceptionally high TON of 365 000 was reached for the oxidation of 1‐phenylethanol under solvent‐free reaction conditions. The catalyst can be recycled many times with retained activity as shown by the identical rate curves of the first and fifth runs.
Three flavonol glycosides, kaempferol 3-
O-(2″-
O-α-rhamnosyl-6″-
O-malonyl)-β-glucoside, quercetin 3-
O-(2″-
O-α-rhamnosyl-6″-
O-malonyl)-β-glucoside, and myricetin 3-
O-(2″,6″-di-
...O-α-rhamnosyl)-β-glucoside were isolated from the petals of
Clitoria ternatea cv. Double Blue, together with eleven known flavonol glycosides. Their structures were identified using UV, MS, and NMR spectroscopy. They were characterized as kaempferol and quercetin 3-(2
G
- rhamnosylrutinoside)s, kaempferol, quercetin, and myricetin 3-neohesperidosides, 3-rutinosides, and 3-glucosides in the same tissue. In addition, the presence of myricetin 3-
O-(2″-
O-α-rhamnosyl-6″-
O-malonyl)-β-glucoside was inferred from LC/MS/MS data for crude petal extracts. The flavonol compounds identified in the petals of
C.
ternatea differed from those reported in previous studies.
Two malonylated kaempferol and quercetin glycosides and one myricetin glycoside were isolated from the petals of
Clitoria ternatea, together with eleven known flavonol glycosides. Their structures were identified by UV, MS, and NMR spectroscopic methods. The flavonol compounds identified in the petals of
C.
ternatea differed from those reported in previous studies.
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