Individuals with pre‐manifest and early symptomatic Huntington's disease (HD) have shown deficits in solving arithmetic word‐problems. However, the neural correlates of these deficits in HD are ...poorly understood. We explored the structural (gray‐matter volume; GMV) and metabolic (18F‐FDG PET; SUVr) brain correlates of arithmetic performance using the recently developed HD‐word problem arithmetic task (HD‐WPA) in seventeen preHD and sixteen HD individuals. Symptomatic participants showed significantly lower scores in the HD‐WPA than preHD participants. Lower performance in the HD‐WPA was associated with reduced GMV in subcortical, medial frontal, and several posterior‐cortical clusters in HD participants. No significant GMV loss was found in preHD participants. 18F‐FDG data revealed a widespread pattern of hypometabolism in association with lower arithmetic performance in all participants. In preHD participants, this pattern was restricted to the ventrolateral and orbital prefrontal cortex, the insula, and the precentral gyrus. In HD participants, the pattern extended to several parietal–temporal regions. Word‐problem solving arithmetic deficits in HD is subserved by a pattern of asynchronous metabolic and structural compromise across the cerebral cortex as a function of disease stage. In preHD individuals, arithmetic deficits were associated with prefrontal alterations, whereas in symptomatic HD patients, more severe arithmetic deficits are associated with the compromise of several frontal‐subcortical and temporo‐parietal regions. Our results support the hypothesis that cognitive deficits in HD are not exclusively dominated by frontal‐striatal dysfunctions but also involve fronto‐temporal and parieto‐occipital damage.
Salicylanilides and Their Anticancer Properties Kauerová, Tereza; Pérez-Pérez, María-Jesús; Kollar, Peter
International journal of molecular sciences,
01/2023, Letnik:
24, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Salicylanilides are pharmacologically active compounds with a wide spectrum of biological effects. Halogenated salicylanilides, which have been used for decades in human and veterinary medicine as ...anthelmintics, have recently emerged as candidates for drug repurposing in oncology. The most prominent example of salicylanilide anthelmintic, that is intensively studied for its potential anticancer properties, is niclosamide. Nevertheless, recent studies have discovered extensive anticancer potential in a number of other salicylanilides. This potential of their anticancer action is mediated most likely by diverse mechanisms of action such as uncoupling of oxidative phosphorylation, inhibition of protein tyrosine kinase epidermal growth factor receptor, modulation of different signaling pathways as Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways or induction of B-Raf V600E inhibition. Here we provide a comprehensive overview of the current knowledge about the proposed mechanisms of action of anticancer activity of salicylanilides based on preclinical in vitro and in vivo studies, or structural requirements for such an activity.
Background
Huntington's disease (HD) is a genetically determined disease with motor, cognitive, and neuropsychiatric disorders. However, the links between clinical progression and disruptions to ...dynamics in motor and cognitive large‐scale networks are not well established.
Objective
To investigate changes in dynamic and static large‐scale networks using an established tool of disease progression in Huntington's disease, the composite Unified Huntington's Disease Rating Scale (cUHDRS).
Methods
Sixty‐four mutation carriers were included. Static and dynamic baseline functional connectivity as well as topological features were correlated to 2‐year follow‐up clinical assessments using the cUHDRS.
Results
Decline in cUHDRS scores was associated with higher connectivity between frontal default‐mode and motor networks, whereas higher connectivity in posterior, mainly visuospatial regions was associated with a smaller decline in cUHDRS scores.
Conclusions
Structural disruptions in HD were evident both in posterior parietal/occipital and frontal motor regions, with reciprocal increases in functional connectivity. However, although higher visuospatial network connectivity was tied to a smaller cUHDRS decline, increased motor and frontal default‐mode connections were linked to a larger cUHDRS decreases. Therefore, divergent functional compensation mechanisms might be at play in the clinical evolution of HD.
Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. ...However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD‐MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level‐1 Movement Disorders Society‐Task Force Criteria. Voxel‐based morphometry, functional connectivity and graph theoretical measures were obtained on a 3‐Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD‐MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.
Key points
Calcium‐activated chloride channels TMEM16A and TMEM16B support important physiological processes such as fast block of polyspermy, fluid secretion, control of blood pressure and sensory ...transduction.
Given the physiological importance of TMEM16 channels, it is important to study how incoming stimuli activate these channels. Here we study how channels open and close and how the process of gating is regulated.
We show that TMEM16A and TMEM16B display fast and slow gating. These gating modes are regulated by voltage and external chloride.
Dual gating explains the complex time course of the anion current.
Residues within the first intracellular loop of the channel influence the slow gating mode.
Dual gating is an intrinsic property observed in endogenous calcium‐activated chloride channels and could be relevant to physiological processes that require sustained chloride ion movement.
TMEM16A and TMEM16B are molecular components of the physiologically relevant calcium‐activated chloride channels (CaCCs) present in many tissues. Their gating is dictated by membrane voltage (Vm), intracellular calcium concentrations (Ca2+i) and external permeant anions. As a consequence, the chloride current (ICl) kinetics is complex. For example, TMEM16A ICl activates slowly with a non‐mono‐exponential time course while TMEM16B ICl activates rapidly following a mono‐exponential behaviour. To understand the underlying mechanism responsible for the complex activation kinetics, we recorded ICl from HEK‐293 cells transiently transfected with either TMEM16A or TMEM16B as well as from mouse parotid acinar cells. Two distinct Vm‐dependent gating modes were uncovered: a fast‐mode on the millisecond time scale followed by a slow mode on the second time scale. Using long (20 s) depolarizing pulses both gating modes were activated, and a slowly rising ICl was recorded in whole‐cell and inside‐out patches. The amplitude of ICl at the end of the long pulse nearly doubled and was blocked by 100 μm tannic acid. The slow gating mode was strongly reduced by decreasing the Cl−o from 140 to 30 mm and by altering the sequence of the first intracellular loop. Mutating 480RSQ482 to AVK in the first intracellular loop of TMEM16B nearly abolished slow gating, but, mutating 448AVK451 to RSQ in TMEM16A has little effect. Deleting 448EAVK451 residues in TMEM16A reduced slow gating. We conclude that TMEM16 CaCCs have intrinsic Vm‐ and Cl−‐sensitive dual gating that elicits complex ICl kinetics.
Key points
Calcium‐activated chloride channels TMEM16A and TMEM16B support important physiological processes such as fast block of polyspermy, fluid secretion, control of blood pressure and sensory transduction.
Given the physiological importance of TMEM16 channels, it is important to study how incoming stimuli activate these channels. Here we study how channels open and close and how the process of gating is regulated.
We show that TMEM16A and TMEM16B display fast and slow gating. These gating modes are regulated by voltage and external chloride.
Dual gating explains the complex time course of the anion current.
Residues within the first intracellular loop of the channel influence the slow gating mode.
Dual gating is an intrinsic property observed in endogenous calcium‐activated chloride channels and could be relevant to physiological processes that require sustained chloride ion movement.
The hydrothiolation of unsaturated carbon–carbon bonds is a practical and atom‐economical approach for the incorporation of sulfur into organic frameworks. In recent years, we have witnessed the ...development of a range of transition‐metal‐based catalytic systems for the control of the regio‐ and stereoselectivity. In this Minireview we highlight the mechanistic background behind this transformation so as to help the design of more specific and active organometallic hydrothiolation catalysts.
Juggling act: In recent years transition‐metal‐based catalysts for the control of the regio‐ and stereoselectivity in hydrothiolation of unsaturated carbon–carbon bonds have been developed. The complex mechanistic background of this transformation (see picture) is described to aid the design of better catalysts.
Hexagonal boron nitride is not only a promising functional material for the development of two-dimensional optoelectronic devices but also a good candidate for quantum sensing thanks to the presence ...of quantum emitters in the form of atom-like defects. Their exploitation in quantum technologies necessitates understanding their coherence properties as well as their sensitivity to external stimuli. In this work, we probe the strain configuration of boron vacancy centers (VB–) created by ion implantation in h-BN flakes thanks to wide-field spatially resolved optically detected magnetic resonance and submicro Raman spectroscopy. Our experiments demonstrate the ability of VB– for quantum sensing of strain and, given the omnipresence of h-BN in 2D-based devices, open the door for in situ imaging of strain under working conditions.
The three‐body recombination reaction, or ternary association, is a termolecular reaction leading to a molecule after a three‐body encounter that plays a vital role in many relevant scenarios in ...chemical physics. Here, we introduce the Python 3‐Body Recombination program, which is dedicated to the computation of atomic three‐body recombination rate coefficients. The software is based on a classical trajectory approach in hyperspherical coordinates after mapping the three‐body problem as a single particle in a higher‐dimensional space. This theoretical approach is fully general and applicable to any ion‐atom‐atom or atom‐atom‐atom three‐body process. The predictive power of the methodology has been tested in several different experimental scenarios, reaching a good description of every system. The code structure is presented alongside examples and tests to ensure the software's capacity. In addition, the performance of the software after parallelization is shown.
Three‐body recombination reactions in which three free atoms collide to form a molecule and a free atom appear in a multitude of scenarios, from atmospheric phenomena to ultracold experiments. Python 3‐Body Recombination is a software for the classical simulation of direct three‐body recombination to further the limited theoretical understanding of these reactions.
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