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Molecules (Basel, Switzerland) Dec 2023By reducing the 2-nitrophenylhydrazone of cyclohexanone with sodium dithionite, an unexpected yellow compound was obtained instead of the corresponding colorless amino... (Review)
Review
By reducing the 2-nitrophenylhydrazone of cyclohexanone with sodium dithionite, an unexpected yellow compound was obtained instead of the corresponding colorless amino derivative. Many years later, the structure of this compound, namely, cyclohexane-3-spiro-3,4-dihydro-1,2,4-benzotriazine, was demonstrated. From that time, the reduction of 2-nitrophenylhydrazones of different kinds of ketones, followed by air oxidation of the initially formed amino compounds, has represented a general way to synthesize a variety of 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines. Many derivatives have been obtained so far by a single research group, and most of them have demonstrated interesting pharmacological activities, mainly antihypertensive, anti-inflammatory, and diuretic effects and other activities with lower diffusion. Moreover, 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines represent a novel class of ligands for sigma receptors, with nanomolar affinity to the σ subtype. This property might promote the development of agents for cardiovascular, neurodegenerative, and proliferative pathologies. The present commentary, by collecting compounds and biological results obtained so far, intends to celebrate the centennial of the discovery of the first member of this class of compounds and to promote further investigation in the field.
Topics: Receptors, sigma; Antihypertensive Agents; Diffusion; Ketones; Triazines
PubMed: 38202715
DOI: 10.3390/molecules29010132 -
Angewandte Chemie (International Ed. in... Feb 2024Electrocatalytic CO reduction has developed into a broad field, spanning fundamental studies of enzymatic 'model' catalysts to synthetic molecular catalysts and... (Review)
Review
Electrocatalytic CO reduction has developed into a broad field, spanning fundamental studies of enzymatic 'model' catalysts to synthetic molecular catalysts and heterogeneous gas diffusion electrodes producing commercially relevant quantities of product. This diversification has resulted in apparent differences and a disconnect between seemingly related approaches when using different types of catalysts. Enzymes possess discrete and well understood active sites that can perform reactions with high selectivity and activities at their thermodynamic limit. Synthetic small molecule catalysts can be designed with desired active site composition but do not yet display enzyme-like performance. These properties of the biological and small molecule catalysts contrast with heterogeneous materials, which can contain multiple, often poorly understood active sites with distinct reactivity and therefore introducing significant complexity in understanding their activities. As these systems are being better understood and the continuously improving performance of their heterogeneous active sites closes the gap with enzymatic activity, this performance difference between heterogeneous and enzymatic systems begins to close. This convergence removes the barriers between using different types of catalysts and future challenges can be addressed without multiple efforts as a unified picture for the biological-synthetic catalyst spectrum emerges.
Topics: Carbon Dioxide; Diffusion; Electrodes; Thermodynamics
PubMed: 37983571
DOI: 10.1002/anie.202310547 -
Scientific Reports Sep 2023Misfolded proteins in Alzheimer's disease and Parkinson's disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein...
Misfolded proteins in Alzheimer's disease and Parkinson's disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit in clinical trials despite substantial target engagement in the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake of oligomeric protein from the synaptic cleft. We built a quantitative systems pharmacology (QSP) model to quantitatively simulate intrasynaptic secretion, diffusion and antibody capture in the synaptic cleft, postsynaptic membrane binding and internalization of monomeric and oligomeric tau and aSyn proteins. Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. Maximal target engagement for monomeric tau was simulated as 45% (semorinemab) to 99% (gosuranemab) in CSF, 30% to 99% in ISF but only 1% to 3% in the synaptic cleft, leading to a reduction of less than 1% in uptake of oligomeric tau. Simulations for prasineuzumab and cinpanemab suggest target engagement of free monomeric aSyn of only 6-8% in CSF, 4-6% and 1-2% in the ISF and synaptic cleft, while maximal target engagement of aggregated aSyn was predicted to reach 99% and 80% in the synaptic cleft with similar effects on neuronal uptake. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies.
Topics: Humans; Network Pharmacology; Antibodies, Monoclonal; Biological Transport; Diffusion; Parkinson Disease
PubMed: 37658103
DOI: 10.1038/s41598-023-41382-0 -
Communications Biology May 2024Vesicles carry out many essential functions within cells through the processes of endocytosis, exocytosis, and passive and active transport. This includes transporting...
Vesicles carry out many essential functions within cells through the processes of endocytosis, exocytosis, and passive and active transport. This includes transporting and delivering molecules between different parts of the cell, and storing and releasing neurotransmitters in neurons. To date, computational simulation of these key biological players has been rather limited and has not advanced at the same pace as other aspects of cell modeling, restricting the realism of computational models. We describe a general vesicle modeling tool that has been designed for wide application to a variety of cell models, implemented within our software STochastic Engine for Pathway Simulation (STEPS), a stochastic reaction-diffusion simulator that supports realistic reconstructions of cell tissue in tetrahedral meshes. The implementation is validated in an extensive test suite, parallel performance is demonstrated in a realistic synaptic bouton model, and example models are visualized in a Blender extension module.
Topics: Computer Simulation; Diffusion; Models, Biological; Software; Synaptic Vesicles; Exocytosis; Animals; Humans; Endocytosis; Neurons; Stochastic Processes
PubMed: 38750123
DOI: 10.1038/s42003-024-06276-5 -
Environmental Science & Technology May 2024Molecular diffusion of chemical species in subsurface environments─rock formations, soil sediments, marine, river, and lake sediments─plays a critical role in a...
Molecular diffusion of chemical species in subsurface environments─rock formations, soil sediments, marine, river, and lake sediments─plays a critical role in a variety of dynamic processes, many of which affect water chemistry. We investigate and demonstrate the occurrence of anomalous (non-Fickian) diffusion behavior, distinct from classically assumed Fickian diffusion. We measured molecular diffusion through a series of five chalk and dolomite rock samples over a period of about two months. We demonstrate that in all cases, diffusion behavior is significantly different than Fickian. We then analyze the results using a continuous time random walk framework that can describe anomalous diffusion in heterogeneous porous materials such as rock. This methodology shows extreme long-time tailing of tracer advance as compared to conventional Fickian diffusion processes. The finding that distinct anomalous diffusion occurs ubiquitously implies that diffusion-driven processes in subsurface zones should be analyzed using tools that account for non-Fickian diffusion.
Topics: Diffusion; Porosity; Geologic Sediments
PubMed: 38736287
DOI: 10.1021/acs.est.4c01386 -
Scientific Reports Sep 2023Due to the unrestricted movement of humans over a wide area, it is important to understand how individuals move between non-adjacent locations in space. In this...
Due to the unrestricted movement of humans over a wide area, it is important to understand how individuals move between non-adjacent locations in space. In this research, we introduce a nonlocal diffusion introduce for dengue, which is driven by integral operators. First, we use the semigroup theory and continuously Fréchet differentiable to demonstrate the existence, uniqueness, positivity and boundedness of the solution. Next, the global stability and uniform persistence of the system are proved by analyzing the eigenvalue problem of the nonlocal diffusion term. To achieve this, the Lyapunov function is derived and the comparison principle is applied. Finally, numerical simulations are carried out to validate the results of the theorem, and it is revealed that controlling the disease's spread can be achieved by implementing measures to reduce the transmission of the virus through infected humans and mosquitoes.
Topics: Animals; Humans; Culicidae; Diffusion; Movement; Dengue
PubMed: 37709860
DOI: 10.1038/s41598-023-42440-3 -
Journal of Visualized Experiments : JoVE Mar 2024Two-photon microscopy has emerged as a potent tool for evaluating deep tissue cells and characterizing the alignment of the extracellular matrix (ECM) in various...
Two-photon microscopy has emerged as a potent tool for evaluating deep tissue cells and characterizing the alignment of the extracellular matrix (ECM) in various biological systems. This technique relies on nonlinear light-matter interactions to detect two distinct signals: the second harmonic generated (SHG) diffusion signal, which facilitates the visualization of collagen fibers and their orientation, and the near-infrared excitation signal for imaging ultraviolet excited autofluorescence. SHG imaging proves especially effective in visualizing collagen fibers due to the non-centrosymmetric crystalline structure of fibrillar collagen I. Given that tendons are matrix-rich tissues with a limited number of cells, their high collagen content makes them ideal candidates for analysis using two-photon microscopy. Consequently, two-photon microscopy offers a valuable means to analyze and characterize collagen abnormalities in tendons. Its application extends to studying tendon development, injuries, healing, and aging, enabling the comprehensive characterization of tendon cells and their interactions with the ECM under various conditions using two-photon microscopy tools. This protocol outlines the use of two-photon microscopy in tendon biology and presents an adapted methodology to achieve effective imaging and characterization of tendon cells during development and after injury. The method allows the utilization of thin microscopic sections to create a comprehensive image of the ECM within tendons and the cells that interact with this matrix. Most notably, the article showcases a technique to generate 3D images using two-photon microscopy in animal models.
Topics: Animals; Microscopy; Aging; Diffusion; Tendons; Collagen
PubMed: 38619235
DOI: 10.3791/65853 -
Journal of Hazardous Materials Oct 2023Antibiotics are recognized as effective medicine that has been extensively used in human and veterinary. Since the rate of releasing into the environment is stronger... (Review)
Review
Antibiotics are recognized as effective medicine that has been extensively used in human and veterinary. Since the rate of releasing into the environment is stronger than the rate of elimination, antibiotics are regarded as persistent or "pseudo-persistent" organic compounds that result in the development of microbial antibiotic resistance. Therefore, assessment for their ecological risks to the environment are essential. Diffusive gradients in thin films for organic compounds (o-DGT) have been adapted to investigate the environmental behaviors of antibiotics. Currently, more than 20 compounds have been tested by o-DGT in waters and soil environments. In this review, we explained the theoretical reason that o-DGT is feasible to determine the labile fraction of antibiotics in different environmental media. The most used agarose diffusive gel, and various binding agents such as resin, porous carbon and nano-scale materials have been compared to optimize the sampling of antibiotics by o-DGT. Results of deploying o-DGT devices in waters and soils from previous studies were discussed to understand the bioavailability and dynamic transport of antibiotics. Also, we provided the feasibility analysis of using o-DGT in sediments for antibiotics measurements, which is required to be carried out in future studies. To have a deep view on the development of o-DGT, its technical limitations and viable improvements were summarized in this study for further applications on antibiotics research.
Topics: Humans; Anti-Bacterial Agents; Biological Availability; Carbon; Diffusion; Porosity; Soil
PubMed: 37597396
DOI: 10.1016/j.jhazmat.2023.132279 -
Neurology Jan 2024There is currently no validated disease-stage biomarker for amyotrophic lateral sclerosis (ALS). The identification of quantitative and reproducible markers of disease... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
There is currently no validated disease-stage biomarker for amyotrophic lateral sclerosis (ALS). The identification of quantitative and reproducible markers of disease stratification in ALS is fundamental for study design definition and inclusion of homogenous patient cohorts into clinical trials. Our aim was to assess the rearrangements of structural and functional brain connectivity underlying the clinical stages of ALS, to suggest objective, reproducible measures provided by MRI connectomics mirroring disease staging.
METHODS
In this observational study, patients with ALS and healthy controls (HCs) underwent clinical evaluation and brain MRI on a 3T scanner. Patients were classified into 4 groups, according to the King's staging system. Structural and functional brain connectivity matrices were obtained using diffusion tensor and resting-state fMRI data, respectively. Whole-brain network-based statistics (NBS) analysis and comparisons of intraregional and inter-regional connectivity values using analysis of covariance models were performed between groups. Correlations between MRI and clinical/cognitive measures were tested using Pearson coefficient.
RESULTS
One hundred four patients with ALS and 61 age-matched and sex-matched HCs were included. NBS and regional connectivity analyses demonstrated a progressive decrease of intranetwork and internetwork structural connectivity of sensorimotor regions at increasing ALS stages in our cohort, compared with HCs. By contrast, functional connectivity showed divergent patterns between King's stages 3 (increase in basal ganglia and temporal circuits [ = 0.04 and = 0.05, respectively]) and 4 (frontotemporal decrease [ = 0.03]), suggesting a complex interplay between opposite phenomena in late stages of the disease. Intraregional sensorimotor structural connectivity was correlated with ALS Functional Rating Scale-revised (ALSFRS-r) score ( = 0.31, < 0.001) and upper motor neuron burden ( = -0.25, = 0.01). Inter-regional frontal-sensorimotor structural connectivity was also correlated with ALSFRS-r ( = 0.24, = 0.02). No correlations with cognitive measures were found.
DISCUSSION
MRI of the brain allows to demonstrate and quantify increasing disruption of structural connectivity involving the sensorimotor networks in ALS, mirroring disease stages. Frontotemporal functional disconnection seems to characterize only advanced disease phases. Our findings support the utility of MRI connectomics to stratify patients and stage brain pathology in ALS in a reproducible way, which may mirror clinical progression.
Topics: Humans; Amyotrophic Lateral Sclerosis; Basal Ganglia; Brain; Diffusion; Motor Neurons; Male; Female
PubMed: 38165325
DOI: 10.1212/WNL.0000000000207946 -
Journal of the American Chemical Society Aug 2023Proteins play important roles in the therapeutic, medical diagnostic, and chemical catalysis industries. However, their potential is often limited by their fragile and...
Proteins play important roles in the therapeutic, medical diagnostic, and chemical catalysis industries. However, their potential is often limited by their fragile and dynamic nature outside cellular environments. The encapsulation of proteins in solid materials has been widely pursued as a route to enhance their stability and ease of handling. Nevertheless, the experimental investigation of protein interactions with rationally designed synthetic hosts still represents an area in need of improvement. In this work, we leveraged the tunability and crystallinity of metal-organic frameworks (MOFs) and developed a series of crystallographically defined protein hosts with varying chemical properties. Through systematic studies, we identified the dominating mechanisms for protein encapsulation and developed a host material with well-tailored properties to effectively encapsulate the protein ubiquitin. Specifically, in our mesoporous hosts, we found that ubiquitin encapsulation is thermodynamically favored. A more hydrophilic encapsulation environment with favorable electrostatic interactions induces enthalpically favored ubiquitin-MOF interactions, and a higher pH condition reduces the intraparticle diffusion barrier, both leading to a higher protein loading. Our findings provide a fundamental understanding of host-guest interactions between proteins and solid matrices and offer new insights to guide the design of future protein host materials to achieve optimal protein loading. The MOF modification technique used in this work also demonstrates a facile method to develop materials easily customizable for encapsulating proteins with different surface properties.
Topics: Ubiquitin; Catalysis; Diffusion; Metal-Organic Frameworks; Static Electricity
PubMed: 37463331
DOI: 10.1021/jacs.3c01989