The dynamic of the temporal correlations between brain areas, called functional connectivity (FC), undergoes complex transformations through the life span. In this review, we aim to provide an ...overview of these changes in the nonpathological brain from fetal life to advanced age. After a brief description of the main methods, we propose that FC development can be divided into four main phases: first, before birth, a strong change in FC leads to the emergence of functional proto‐networks, involving mainly within network short‐range connections. Then, during the first years of life, there is a strong widespread organization of networks which starts with segregation processes followed by a continuous increase in integration. Thereafter, from adolescence to early adulthood, a refinement of existing networks in the brain occurs, characterized by an increase in integrative processes until about 40 years. Middle age constitutes a pivotal period associated with an inversion of the functional brain trajectories with a decrease in segregation process in conjunction to a large‐scale reorganization of between network connections. Studies suggest that these processes are in line with the development of cognitive and sensory functions throughout life as well as their deterioration. During aging, results support the notion of dedifferentiation processes, which refer to the decrease in functional selectivity of the brain regions, resulting in more diffuse and less specialized FC, associated with the disruption of cognitive functions with age. The inversion of developmental processes during aging is in accordance with the developmental models of neuroanatomy for which the latest matured regions are the first to deteriorate.
The deprotonative functionalization of α,α‐difluoromethyl ketones is described herein. Using a catalytic organosuperbase and a silane additive, the corresponding difluoroenolate could be generated ...and trapped with aldehydes to deliver various α,α‐difluoro‐β‐hydroxy ketones in high yields. This new strategy tolerates numerous functional groups and represents the access to the difluoroenolate by direct deprotonation of the difluoromethyl unit. The diastereoselective version of the reaction was also investigated with d.r. up to 93 : 7. Several transformations were performed to demonstrate the synthetic potential of these α,α‐difluoro‐β‐hydroxy ketones. In addition, this method has been extended to the use of other electrophiles such as imines and chalcogen derivatives, and a difluoromethyl sulfoxide as nucleophile, thus leading to a diversity of difluoromethylene compounds.
The deprotonation of α,α‐difluoromethyl ketones is underinvestigated due to the instability of the generated carbanion that can evolve into a fluorocarbene. A method for the deprotonative functionalization of these compounds is described herein under an organocatalytic system using various electrophiles, and is also applied to a related α,α‐difluoromethyl sulfoxide. This strategy gives access to highly valuable difluoromethylene scaffolds.
Their natural functions in intercellular communication render extracellular vesicles (EV) highly attractive for drug delivery applications. However, the loading efficiency of present methods to ...incorporate particularly hydrophilic low molecular weight drugs of biomedical interest is largely unexplored, as is the impact these methods may have on the intrinsic structural and biological vesicle properties. Here, different methods are exploited to incorporate hydrophilic non‐membrane permeable compounds into stem cell‐derived small EV, and to assess the vesicle characteristics after the different loading processes. When comparing several methods head‐to‐head, the loading capacity increases in the order saponin ≤ sonication < fusion < freeze‐thawing ≤ osmotic shock. Interestingly, the structural and biological functions of small EV are dependent on the applied encapsulation process, with the functional properties being altered at a greater extent. Therefore, the importance of including additional characterization parameters to probe alterations of the biological functionality of small EV is clearly demonstrated. Here, freeze‐thawing and particularly the osmotic shock have proven to be the most appropriate methods for EV loading, as they achieve a high drug encapsulation and yet preserve the investigated structural and biological vesicle characteristics.
Small extracellular vesicles have inherent functions in cell‐to‐cell communication, which render them attractive for drug delivery applications. This study investigates the loading of hydrophilic compounds into stem cell‐derived small extracellular vesicles using different membrane permeabilization methods, and emphasizes the importance of a thorough characterization of the intrinsic structural and biological vesicle properties after the encapsulation process.
In this paper we are reporting the first regio- and stereoselective silylformylation of ynamides. This reaction is tolerant to a wide range of functional groups around the ynamides. The substitution ...of CO by an isocyanide makes this reaction safer and more practical than standard silylformylation reactions. It overall represents a versatile and rapid access to various tetrasubstituted 3-silyl-2-amidoacrolein derivatives. The synthetic potential of these new building blocks has been evaluated by performing several postfunctionalization.
The use of TFEDMA, a fluoroalkyl amino reagent, for the difluoromethylation and difluoroacylation of arenes, heteroarenes, and C–H acidic compounds is reported. This approach allows for an efficient ...access to difluoromethylated products of high added value in good to excellent yields and with scale-up possibilities.
An enantioselective direct oxygenation of propiophenone derivatives mediated by a catalytic or stoichiometric amount of new chiral non-C2-symmetric iodoarenes(III) is reported. The reaction gives an ...easy entry to optically active α-sulfonyl- and α-phosphoryl oxyketones in respectable yields and enantioselectivities.
Among the general interest in fluorinated compounds, trifluoromethoxylated molecules play a specific role. However, despite this interest, the development of efficient reagents to perform ...trifluoromethoxylation reactions remains a challenge. Here, 2,4‐dinitro‐trifluoromethoxybenzene (DNTFB) is used as a trifluoromethoxylating reagent to perform nucleophilic substitution under mild metal‐free conditions with different leaving groups, including direct dehydroxytrifluoromethoxylation. A mechanistic study rationalized the reaction and subsequently proposed only three reaction conditions, depending on the reactivity of the starting substrates.
Metal‐free trifluoromethoxylation by nucleophilic substitution under mild conditions was developed based on the inexpensive DNTFB/DMAP system. An efficient rationalization was developed to propose optimal conditions depending on the characteristics of the starting substrates. A mechanistic study proved the crucial role of potassium salts in the transient formation of the CF3OK species, which has promising properties.
In this paper we report the annulation reaction between 2-iodobenzaldehyde derivatives and various ynamides. This palladium-catalyzed reaction leads to rare polysubstituted amino-indenones in good ...yields with a regioselectivity up to complete. Remarkably, a regiodivergent selectivity has been identified between aryl and alkyl or silyl ynamides, with the first leading mainly to 2-amido-indenones and the second to 3-amido-indenones.
Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 ...year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes.
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