Brain development, sensory information processing, and learning and memory processes depend on Hebbian forms of synaptic plasticity, and on the remodeling and pruning of synaptic connections. Neurons ...in networks implicated in these processes carry out their functions while facing constant perturbation; homeostatic responses are therefore required to maintain neuronal activity within functional ranges for proper brain function. Here, we will review in vitro and in vivo studies demonstrating that several mechanisms underlie homeostatic plasticity of excitatory synapses, and identifying participant molecular players. Emerging evidence suggests a link between disrupted homeostatic synaptic plasticity and neuropsychiatric and neurologic disorders.
Hebbian forms of synaptic plasticity, such as long‐term potentiation (LTP), induce long‐lasting changes in synaptic strength, which can be destabilizing and drive activity to saturation. Conversely, homeostatic plasticity operates to compensate for prolonged activity changes, stabilizing neuronal firing within a dynamic physiological range. We review mechanisms underlying homeostatic plasticity, and address how neurons integrate distinct forms of plasticity for proper brain function.
This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
Hebbian forms of synaptic plasticity, such as long‐term potentiation (LTP), induce long‐lasting changes in synaptic strength, which can be destabilizing and drive activity to saturation. Conversely, homeostatic plasticity operates to compensate for prolonged activity changes, stabilizing neuronal firing within a dynamic physiological range. We review mechanisms underlying homeostatic plasticity, and address how neurons integrate distinct forms of plasticity for proper brain function.
This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
1,2‐Disubstituted benzimidazoles play an important role in several areas and particularly as drug discovery targets. Herein, several methods to assemble these structures are reviewed, from the ...classical approaches to the more recently developed metal‐catalyzed intramolecular amination process, the cascade arylamination/condensation reaction and polymer‐supported benzimidazole assembly under microwave conditions.
From classical to modern: 1,2‐Disubstituted benzimidazoles play an important role in several areas and particularly as drug‐discovery targets. Several methods to assemble these structures are reviewed, from the classical approaches to the more recently developed processes.
Oligosaccharides and glycoconjugates play an important role in biological processes. The use of these complex polymers as biocompatible materials for medicinal applications as well as therapeutic ...agents for the treatment of several diseases has attracted considerable interest. However, these investigations require large and pure amounts of glycostructures. Glucosamine is one of the major building blocks of these highly important glycoconjugates. Recently, considerable synthetic efforts have been devoted to improving stereoselective glycosylation. In this Focus review, the role of the amine protecting group in the outcome of the glucosamine glycosylation reaction is highlighted.
•Genetic and functional studies have provided important evidence pointing toward a central role for dendritic spines on the pathogenesis of neuropsychiatric conditions.•Many of the synaptic proteins ...associated to psychiatric disorders are implicated in the regulation of the actin cytoskeleton.•Studies using human tissue suggest that changes in dendritic arborization, spine density, and spine pruning might underlie the development of neuropsychiatric disorders.•Recent studies point to a role of microglia dysfunction in regulating synapse remodeling in brain pathology.•Adult restoration of synaptic function and behavior has been demonstrated in animal models of ASD.
Growing evidence implicates synaptic proteins in the pathogenesis of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia. In fact, mutations in genes encoding synaptic proteins are enriched and overlap among different conditions highlighting the complex and pleiotropic nature of these disorders. In this review, we discuss recently described candidate genes that affect excitatory synapse function and result in changes in spine number and morphology. Spine pathology has been observed in several animal models of disease and in human brain post-mortem samples from ID, ASD, and schizophrenia patients. Recent data point to convergent mechanisms, such as dysregulation of the actin cytoskeleton and dysfunction of microglia synaptic remodeling, underlying dendritic spine dysgenesis. Interestingly, the reversion of important pathologic features, including spine abnormalities, has been observed in adult animal models of neuropsychiatric disorders, suggesting that therapies may not be restricted to a specific developmental window. Shedding light on the specific mechanisms impacted in neuropsychiatric disorders will undeniably contribute to the development of more directed and personalized therapies.
Plant phenotyping is an emerging science that combines multiple methodologies and protocols to measure plant traits (e.g., growth, morphology, architecture, function, and composition) at multiple ...scales of organization. Manual phenotyping remains as a major bottleneck to the advance of plant and crop breeding. Such constraint fostered the development of high throughput plant phenotyping (HTPP), which is largely based on imaging approaches and automatized data retrieval and processing. Field phenotyping still poses major challenges and the progress of HTPP for field conditions can be relevant to support selection and breeding of grapevine. The aim of this review is to discuss potential and current methods to improve field phenotyping of grapevine to support characterization of inter- and intravarietal diversity.
Vitis vinifera
has a large genetic diversity that needs characterization, and the availability of methods to support selection of plant material (polyclonal or clonal) able to withstand abiotic stress is paramount. Besides being time consuming, complex and expensive, field experiments are also affected by heterogeneous and uncontrolled climate and soil conditions, mostly due to the large areas of the trials and to the high number of traits to be observed in a number of individuals ranging from hundreds to thousands. Therefore, adequate field experimental design and data gathering methodologies are crucial to obtain reliable data. Some of the major challenges posed to grapevine selection programs for tolerance to water and heat stress are described herein. Useful traits for selection and related field phenotyping methodologies are described and their adequacy for large scale screening is discussed.
Tofacitinib Synthesis – An Asymmetric Challenge Carvalho, Luísa C. R.; Lourenço, Ana; Ferreira, Luísa Maria ...
European journal of organic chemistry,
January 31, 2019, Letnik:
2019, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Tofacitinib is a Janus activated kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis and active psoriatic arthritis. Its synthesis normally involves long synthetic sequences due ...to the chirality associated to the piperidine ring. This review is a comprehensive analysis of the different synthetic methods used to prepare this active pharmaceutical ingredient (API), covering the related journal and patent literature.
The synthesis of tofacitinib, a Janus activated kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis and active psoriatic arthritis, normally involves long sequences due to the chirality of the piperidine ring. This review is a comprehensive analysis of the different methods to prepare this active pharmaceutical ingredient (API), covering the related journal and patent literature.
Microparticles of corn starch and chitosan crosslinked with glutaraldehyde, produced by the solvent exchange technique, are studied as reinforcement fillers for thermoplastic corn starch plasticized ...with glycerol. The presence of 10%
/
chitosan in the microparticles is shown to be essential to guaranteeing effective crosslinking, as demonstrated by water solubility assays. Crosslinked chitosan forms an interpenetrating polymer network with starch chains, producing microparticles with a very low solubility. The thermal stability of the microparticles is in agreement with their polysaccharide composition. An XRD analysis showed that they have crystalline fraction of 32% with V
-type structure, and have no tendency to undergo retrogradation. The tensile strength, Young's modulus, and toughness of thermoplastic starch increased by the incorporation of the crosslinked starch/chitosan microparticles by melt-mixing. Toughness increased 360% in relation to unfilled thermoplastic starch.
The present study envisaged the development of novel antioxidant candidates using the indole scaffold. Several tryptophan and tryptamine derivatives were synthesized, in particular prenylated indole ...compounds, and their scavenging activity for reactive oxygen species (ROS) and reactive nitrogen species (RNS) was investigated. The library substitution pattern included several alkyl chains at positions N-1, C-2 of the indole nucleus, including prenyl and isopentyl chain, as well as different groups at the side chain (C-3) that allowed the investigation of a possible radical stabilization. The results obtained showed that tryptophan (
8), tryptamine (
9),
N-phthaloyl tryptamine (
5) and
N-prenyl tryptophan (
13) were the most active against peroxyl radical (ROO
•)
with activities higher than Trolox, which was used as control. The scavenging of hypochlorous acid (HOCl) was also evaluated and tryptophan (
8) and tryptamine (
9) showed IC
50 of 3.50 ± 0.4 and 6.00 ± 0.60 μM, respectively. Significant activity was also found for the
N-prenyl tryptophan (
13) with an IC
50 of 4.13 ± 0.17 μM and C-2 prenylated derivative (
14), with 4.56 ± 0.48 μM. The studies were extended to RNS and best results were obtained against peroxynitrite anion (ONOO
−
) in the presence of NaHCO
3.
N-alkylated tryptophan (
18) showed a high activity with an IC
50 of 14.0 ± 6.8 μM. The results show that the tested compounds are effective scavengers of ROS and RNS, and suggest that the radical stabilization is strongly dependent on the type of substituents on the indolic moiety and on their relative positions. In addition, the radical dissipation inside the indolic system is mandatory for the observed antioxidant activity.
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The current chromatographic approaches used in protein purification are not keeping pace with the increasing biopharmaceutical market demand. With the upstream improvements, the bottleneck shifted ...towards the downstream process. New approaches rely in Anything But Chromatography methodologies and revisiting former techniques with a bioprocess perspective. Protein crystallization and precipitation methods are already implemented in the downstream process of diverse therapeutic biological macromolecules, overcoming the current chromatographic bottlenecks. Promising work is being developed in order to implement crystallization and precipitation in the purification pipeline of high value therapeutic molecules. This review focuses in the role of these two methodologies in current industrial purification processes, and highlights their potential implementation in the purification pipeline of high value therapeutic molecules, overcoming chromatographic holdups.
Lignin is a widely abundant renewable source of phenolic compounds. Despite the growing interest on using it as a substitute for its petroleum-based counterparts, only 1 to 2% of the global lignin ...production is used for obtaining value-added products. Lignosulphonates (LS), derived from the sulphite pulping process, account for 90% of the total market of commercial lignin. The most successful industrial attempts to use lignin for wood adhesives are based on using this polymer as a partial substitute in phenol-formaldehyde or urea-formaldehyde resins. Alternatively, formaldehyde-free adhesives with lignin and lignosulphonates have also been developed with promising results. However, the low number of reactive sites available in lignin’s aromatic ring and high polydispersity have hindered its application in resin synthesis. Currently, finding suitable crosslinkers for LS and decreasing the long pressing time associated with lignin adhesives remains a challenge. Thus, several methods have been proposed to improve the reactivity of lignin molecules. In this paper, techniques to extract, characterize, as well as improve the reactivity of LS are addressed. The most recent advances in the application of LS in wood adhesives, with and without combination with formaldehyde, are also reviewed.
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