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Objectives: Healthy age-related cognitive changes are highly heterogeneous across individuals. This variability is increasingly explained through the lens of spontaneous fluctuations of brain activity, now considered a powerful index of age-related changes. However, brain activity is a biological process modulated by circadian rhythms, and how these fluctuations evolve throughout the day is under investigation., Methods: We analyzed data from 101 healthy late middle-aged participants from the Cognitive Fitness in Aging study (68 women and 33 men; aged 50-69 years). Participants completed 5 electroencephalographic (EEG) recordings of spontaneous resting-state activity on the same day. We used weighted phase-lag index (wPLI) analyses as an index of the functional synchrony between brain regions couplings, and we computed daily global PLI fluctuation rates of the 5 recordings to assess the association with cognitive performance and β-amyloid and tau/neuroinflammation pathological markers., Results: We found that theta and gamma daily fluctuations in the salience-control executive internetwork (SN-CEN) are associated with distinct mechanisms underlying cognitive heterogeneity in aging. Higher levels of SN-CEN theta daily fluctuations appear to be deleterious for memory performance and were associated with higher tau/neuroinflammation rates. In contrast, higher levels of gamma daily fluctuations are positively associated with executive performance and were associated with lower rate of β-amyloid deposition., Discussion: Thus, accounting for daily EEG fluctuations of brain activity contributes to a better understanding of subtle brain changes underlying individuals' cognitive performance in healthy aging. Results also provide arguments for considering the time of day when assessing cognition for old adults in a clinical context., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Vascular-disrupting agents (VDA) specifically target established neovasculature which results in vascular shutdown. This therapeutic strategy could improve the outcome of pathologies involving aberrant angiogenesis. Although several classes of VDA exist, inhibitors of tubulin assembly (ITA) represent the main category. A series of 21 conformationnally-restricted analogues of E7010, a known ITA-VDA, were designed and synthesised as novel inhibitors of tubulin assembly (ITA) and vascular-disrupting agents (VDA). Among them, indole 4j exhibited good potency against HUVEC and HIG-82 cell lines, as well as a good ability to inhibit tubulin assembly. Furthermore, indole 4j reduced HUVEC migration in a dose-dependent manner, indicating a vascular disrupting activity comparable to that of the gold standard, Combretastatin A4 (CA4)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sylvie DUCKI reports financial support, administrative support, equipment, drugs, or supplies, travel, and writing assistance were provided by Laboratoires Servier SAS Research Centre Croissy-sur-Seine. Sylvie DUCKI reports financial support, administrative support, equipment, drugs, or supplies, and travel were provided by French National Research Agency. Sylvie DUCKI reports financial support, administrative support, and equipment, drugs, or supplies were provided by Université of Clermont Auvergne ISITE., (Copyright © 2022. Published by Elsevier Masson SAS.)

A short and efficient synthesis, based on a one-step double elimination, of a key intermediate in the synthesis of various glucocorticosteroids has been developed. This method can be carried out on large scale for further industrial applications. The synthesis allowed us to identify a novel prednisolone derivative 10 and its anti-inflammatory activity was determined in an in vivo model of inflammation. In order to understand the regioselectivity of the double elimination under various conditions, mechanistic studies were undertaken and confirmed the experimental results. We also propose a mechanism for the formation of the new steroid 10 studied by molecular modeling., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The TWIK-related K + channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo. Furyl analogue 36 is the most promising of the series.

Potassium (K(+)) channels are membrane proteins expressed in most living cells that selectively control the flow of K(+) ions. More than 80 genes encode the K(+) channel subunits in the human genome. The TWIK-related K(+) channel (TREK-1) belongs to the two-pore domain K(+) channels (K2P) and displays various properties including sensitivity to physical (membrane stretch, acidosis, temperature) and chemical stimuli (signaling lipids, volatile anesthetics). The distribution of TREK-1 in the central nervous system, coupled with the physiological consequences of its opening and closing, leads to the emergence of this channel as an attractive therapeutic target. We review the TREK-1 channel, its structural and functional properties, and the pharmacological agents (agonists and antagonists) able to modulate its gating.

The TWIK-related K(+) channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted caffeate esters (12a-u) based on the hit compound CDC 2 (cinnamyl 3,4-dihydroxyl-α-cyanocinnamate). These analogs were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid induced-writhing assay) leading to the identification a series of novel molecules able to activate TREK-1 and displaying potent analgesic activity in vivo., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Cardiac diverticulum is an infrequent congenital malformation, it's even more rare in adulthood. It's often associated with other thoraco-abdominal diverticulums, and rarely isolated. The diagnosis relies on echocardiography. By the way, the magnetic resonance imagery (MRI) allows a finer analysis of the diverticulum, its topography and its situation contributed to vascular and cardiac structures, it has largely replaced the ventriculography. We report in this article the case of a patient of 36 years whose diagnosis of the diverticulum was made by transthoracic echocardiography (TTE) at the time of an assessment of dyspnea, this exam also objectified a mitral insufficiency by deformation and dilatation of the mitral annulus. Radiological assessment was completed by a transoesophageal echocardiography (TOE) and magnetic resonance imagery (MRI). Surgical treatment consisted of surgical closing of the diverticulum and mitral annuloplasty., (Copyright © 2012. Published by Elsevier SAS.)

Photodynamic therapy (PDT) and vascular-disrupting agents (VDA) each have their advantages in the treatment of solid tumors, but also present drawbacks. In PDT, hypoxia at the center of the tumor limits conversion of molecular oxygen into singlet oxygen, while VDAs are deficient at affecting the rim of the tumor. A phthalocyanine-chalcone conjugate combining the VDA properties of chalcones with the PDT properties of phthalocyanines was designed to address these deficiencies. Its vascular targeting, photophysical, photochemical, photodynamic activities are reported herein.

Introduction: The repair of facial self-mutilation often fails if the reconstruction is not protected. The authors report a case of a lip self-mutilation treated by an orthodontic device: the "lip bumper"., Observation: A four-year-old patient presented with self-mutilation of the lower lip in a context of multiple malformations. The defect concerned two third of the lower lip. The treatment combined antibiotics, local care, psychiatric management and a lip bumper. The evolution was favorable without need for secondary reconstruction., Discussion: The lip bumper is a simple orthodontic device. It pushes the lower lip away from the dental arch. It is used to stop the pattern "agitation-mutilation-infection".

We are investigating the synthesis of thioanalogues of nodulation factors that will be resistant to degradation by chitinases. To study the influence of our protecting group strategy, the glycosylation of 1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranoside (7) with two trichloroacetimidate glycosyl donors carrying an azido group at C-2 and either benzyl or benzoyl protecting groups on O-3 and O-4 was first attempted under catalysis with BF(3).Et(2)O in toluene. While glycosylation with the benzoylated glycosyl donor gave only a poor yield (27%) of the disaccharide, a similar reaction with the benzylated donor gave the corresponding disaccharide in good yield (77%). Although both products were obtained as anomeric mixtures, the benzylated donor led to improved stereoselectivity in favor of the desired beta-anomer (alpha:beta 3:7). Based on these results, a novel thiotrisaccharide was synthesized via the coupling of 7 with 6-O-acetyl-4-S-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-beta-D-glucopyranosyl)-2-azido-3-O-benzyl-2-deoxy-4-thio-alpha-D-glucopyranosyl trichloroacetimidate (25) also newly synthesized. After optimization of the reaction conditions, the desired thiotrisaccharide 4-O-[6-O-acetyl-4-S-(3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-beta-D-glucopyranosyl)-2-azido-3-O-benzyl-2-deoxy-4-thio-beta-D-glucopyranosyl]-1,6-anhydro-2-azido-3-O-benzyl-2-deoxy-beta-D-glucopyranoside (26beta) was obtained in 57% yield. These conditions led to an anomeric mixture in favor of the desired beta-anomer (alpha:beta 1:4.7) that was separated from the alpha-anomer by normal-phase HPLC on a PrepNova Pack(R) silica gel cartridge. The work described here shows that thiodisaccharide glycosyl donors behave quite differently from the analogous O-disaccharide used previously to synthesize nodulation factors.