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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 -
Biophysical Journal Nov 2023Transcription factor (TF) proteins regulate gene expression by binding to specific sites on the genome. In the facilitated diffusion model, an optimized search process...
Transcription factor (TF) proteins regulate gene expression by binding to specific sites on the genome. In the facilitated diffusion model, an optimized search process is achieved by the TF alternating between 3D diffusion in the bulk and 1D diffusion along DNA. While undergoing 1D diffusion, the protein can switch from a search mode for fast diffusion along nonspecific DNA to a recognition mode for stable binding to specific DNA. It was recently noticed that, for a small TF domain protein, reorientations on DNA happen between the nonspecific and specific DNA binding. We here conducted all-atom molecular dynamics simulations with steering forces to reveal the protein-DNA binding free energetics, confirming that the search and recognition modes are distinguished primarily by protein orientations on the DNA. As the binding free energy difference between the specific and nonspecific DNA system slightly deviates from that being estimated directly from dissociation constants on 15-bp DNA constructs, we hypothesize that the discrepancy can come from DNA sequences flanking the 6-bp central binding sites that impact on the dissociation kinetics measurements. The hypothesis is supported by a simplified spherical protein-DNA model along with stochastic simulations and kinetic modeling.
Topics: Transcription Factors; DNA; Binding Sites; Gene Expression Regulation; Protein Binding; Diffusion; Kinetics
PubMed: 37897044
DOI: 10.1016/j.bpj.2023.10.025 -
Bulletin of Mathematical Biology Dec 2023Recent experimental studies on primary hair follicle formation and feather bud morphogenesis indicate a coupling between Turing-type diffusion driven instability and...
Recent experimental studies on primary hair follicle formation and feather bud morphogenesis indicate a coupling between Turing-type diffusion driven instability and chemotactic patterning. Inspired by these findings we develop and analyse a mathematical model that couples chemotaxis to a reaction-diffusion system exhibiting diffusion-driven (Turing) instability. While both systems, reaction-diffusion systems and chemotaxis, can independently generate spatial patterns, we were interested in how the coupling impacts the stability of the system, parameter region for patterning, pattern geometry, as well as the dynamics of pattern formation. We conduct a classical linear stability analysis for different model structures, and confirm our results by numerical analysis of the system. Our results show that the coupling generally increases the robustness of the patterning process by enlarging the pattern region in the parameter space. Concerning time scale and pattern regularity, we find that an increase in the chemosensitivity can speed up the patterning process for parameters inside and outside of the Turing space, but generally reduces spatial regularity of the pattern. Interestingly, our analysis indicates that pattern formation can also occur when neither the Turing nor the chemotaxis system can independently generate pattern. On the other hand, for some parameter settings, the coupling of the two processes can extinguish the pattern formation, rather than reinforce it. These theoretical findings can be used to corroborate the biological findings on morphogenesis and guide future experimental studies. From a mathematical point of view, this work sheds a light on coupling classical pattern formation systems from the parameter space perspective.
Topics: Chemotaxis; Models, Biological; Mathematical Concepts; Models, Theoretical; Morphogenesis; Diffusion
PubMed: 38038776
DOI: 10.1007/s11538-023-01225-5 -
Frontiers in Neuroscience 2023The differential diagnosis between solid glioma and brain inflammation is necessary but sometimes difficult. We assessed the effectiveness of multiple diffusion metrics...
BACKGROUND AND PURPOSE
The differential diagnosis between solid glioma and brain inflammation is necessary but sometimes difficult. We assessed the effectiveness of multiple diffusion metrics of diffusion-weighted imaging (DWI) in differentiating solid glioma from brain inflammation and compared the diagnostic performance of different DWI models.
MATERIALS AND METHODS
Participants diagnosed with either glioma or brain inflammation with a solid lesion on MRI were enrolled in this prospective study from May 2016 to April 2023. Diffusion-weighted imaging was performed using a spin-echo echo-planar imaging sequence with five b values (500, 1,000, 1,500, 2000, and 2,500 s/mm) in 30 directions for each b value, and one b value of 0 was included. The mean values of multiple diffusion metrics based on diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), mean apparent propagator (MAP), and neurite orientation dispersion and density imaging (NODDI) in the abnormal signal area were calculated. Comparisons between glioma and inflammation were performed. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) of diffusion metrics were calculated.
RESULTS
57 patients (39 patients with glioma and 18 patients with inflammation) were finally included. MAP model, with its metric non-Gaussianity (NG), shows the greatest diagnostic performance (AUC = 0.879) for differentiation of inflammation and glioma with atypical MRI manifestation. The AUC of DKI model, with its metric mean kurtosis (MK) are comparable to NG (AUC = 0.855), followed by NODDI model with intracellular volume fraction (ICVF) (AUC = 0.825). The lowest value was obtained in DTI with mean diffusivity (MD) (AUC = 0.758).
CONCLUSION
Multiple diffusion metrics can be used in differentiation of inflammation and solid glioma. Non-Gaussianity (NG) from mean apparent propagator (MAP) model shows the greatest diagnostic performance for differentiation of inflammation and glioma.
PubMed: 38352939
DOI: 10.3389/fnins.2023.1320296 -
Magma (New York, N.Y.) Dec 2023Diffusion weighting in optically detected magnetic resonance experiments involving diamond nitrogen-vacancy (NV) centers can provide valuable microstructural...
INTRODUCTION
Diffusion weighting in optically detected magnetic resonance experiments involving diamond nitrogen-vacancy (NV) centers can provide valuable microstructural information. Bi-planar gradient coils employed for diffusion weighting afford excellent spatial access, essential for integrating the NV-NMR components. Nevertheless, owing to the polar tilt of roughly [Formula: see text] of the diamond NV center, the primary magnetic field direction must be taken into account accordingly.
METHODS
To determine the most effective bi-planar gradient coil configurations, we conducted an investigation into the impact of various factors, including the square side length, surface separation, and surface orientation. This was accomplished by generating over 500 bi-planar surface configurations using automated methods.
RESULTS
We successfully generated and evaluated coil layouts in terms of sensitivity and field accuracy. Interestingly, inclined bi-planar orientations close to the NV-NMR setup's requirement, showed higher sensitivity for the transverse gradient channels than horizontal or vertical orientations. We fabricated a suitable solution as a three-channel bi-planar double-layered PCB system and experimentally validated the sensitivities at [Formula: see text] and [Formula: see text] for the transverse [Formula: see text] and [Formula: see text] gradients, and [Formula: see text] for the [Formula: see text] gradient.
DISCUSSION
We found that the chosen relative bi-planar tilt of [Formula: see text] represents a reasonable compromise in terms of overall performance and allows for easier coil implementation with a straight, horizontal alignment within the overall experimental setup.
Topics: Diamond; Nitrogen; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Diffusion
PubMed: 37578612
DOI: 10.1007/s10334-023-01111-0 -
Nature Communications Aug 2023Cell migration plays important roles in many biological processes, but how migrating cells orchestrate intracellular molecules and subcellular structures to regulate...
Cell migration plays important roles in many biological processes, but how migrating cells orchestrate intracellular molecules and subcellular structures to regulate their speed and direction is still not clear. Here, by characterizing the intracellular diffusion and the three-dimensional lamellipodium structures of fish keratocyte cells, we observe a strong positive correlation between the intracellular diffusion and cell migration speed and, more importantly, discover a switching of cell migration modes with reversible intracellular diffusion variation and lamellipodium structure deformation. Distinct from the normal fast mode, cells migrating in the newly-found slow mode have a deformed lamellipodium with swollen-up front and thinned-down rear, reduced intracellular diffusion and compartmentalized macromolecule distribution in the lamellipodium. Furthermore, in turning cells, both lamellipodium structure and intracellular diffusion dynamics are also changed, with left-right symmetry breaking. We propose a mechanism involving the front-localized actin polymerization and increased molecular crowding in the lamellipodium to explain how cells spatiotemporally coordinate the intracellular diffusion dynamics and the lamellipodium structure in regulating their migrations.
Topics: Animals; Cell Movement; Diffusion; Erythrocytes, Abnormal; Pseudopodia
PubMed: 37620390
DOI: 10.1038/s41467-023-40858-x -
Exploring the EM-wave diffusion capabilities of axicon coding metasurfaces for stealth applications.Optics Express Nov 2023Coding metasurfaces for diffusion scattering of electromagnetic (EM) waves are important for stealth applications and have recently attracted researchers in physics and...
Coding metasurfaces for diffusion scattering of electromagnetic (EM) waves are important for stealth applications and have recently attracted researchers in physics and engineering communities. Typically, the available design approaches of coding metasurfaces lack a coding sequence design formula and sometimes cannot simultaneously ensure uniform diffusion and low reflected power intensity without extensive computational optimization. To the authors' best knowledge, the diffusion and radar-cross-section reduction (RCSR) of 2D axicon metasurfaces for cloaking and stealth applications have not been explored before. This article presents a single-layer coding metasurface design that exhibits an axicon phase mask on its aperture for efficient diffusion of EM-waves and RCSR of metallic objects. The proposed approach is robust and ensures greater than 10 dB of RCSR for normal incidence and a wide-range of off-normal incident angles. Theoretical calculations, numerical simulations, and experimental validations of the proposed axicon coding metasurface demonstrate that the 10 dB RCSR covers the frequency range of 15 to 35 GHz (fractional bandwidth is 80%) under normal incidence. Under off-normal incidence, the RCSR and the diffusive scattering behavior are preserved up to 60° regardless of the polarization of the far-field incident radar wave. Compared to other available approaches, the presented design approach is fast, robust, and can achieve more uniform diffusive scattering patterns with remarkable RCSR, which makes it very attractive for potential stealth applications.
PubMed: 38017877
DOI: 10.1364/OE.502528 -
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 -
Frontiers in Radiology 2023Diffusion-weighted Imaging (DWI) is a non-invasive imaging technique based on Magnetic Resonance Imaging (MRI) principles to measure water diffusivity and reveal details...
Diffusion-weighted Imaging (DWI) is a non-invasive imaging technique based on Magnetic Resonance Imaging (MRI) principles to measure water diffusivity and reveal details of the underlying brain micro-structure. By fitting a tensor model to quantify the directionality of water diffusion a Diffusion Tensor Image (DTI) can be derived and scalar measures, such as fractional anisotropy (FA), can then be estimated from the DTI to summarise quantitative microstructural information for clinical studies. In particular, FA has been shown to be a useful research metric to identify tissue abnormalities in neurological disease (e.g. decreased anisotropy as a proxy for tissue damage). However, time constraints in clinical practice lead to low angular resolution diffusion imaging (LARDI) acquisitions that can cause inaccurate FA value estimates when compared to those generated from high angular resolution diffusion imaging (HARDI) acquisitions. In this work, we propose High Angular DTI Estimation Network (HADTI-Net) to estimate an enhanced DTI model from LARDI with a set of minimal and evenly distributed diffusion gradient directions. Extensive experiments have been conducted to show the reliability and generalisation of HADTI-Net to generate high angular DTI estimation from any minimal evenly distributed diffusion gradient directions and to explore the feasibility of applying a data-driven method for this task. The code repository of this work and other related works can be found at https://mri-synthesis.github.io/.
PubMed: 37766937
DOI: 10.3389/fradi.2023.1238566 -
Nucleic Acids Research Jul 2023Target search models of DNA-binding proteins in cells typically consider search mechanisms that include 3D diffusion and 1D sliding, which can be characterized by...
Target search models of DNA-binding proteins in cells typically consider search mechanisms that include 3D diffusion and 1D sliding, which can be characterized by single-molecule tracking on DNA. However, the finding of liquid droplets of DNA and nuclear components in cells cast doubt on extrapolation from the behavior in ideal non-condensed DNA conditions to those in cells. In this study, we investigate the target search behavior of DNA-binding proteins in reconstituted DNA-condensed droplets using single-molecule fluorescence microscopy. To mimic nuclear condensates, we reconstituted DNA-condensed droplets using dextran and PEG polymers. In the DNA-condensed droplets, we measured the translational movement of four DNA-binding proteins (p53, Nhp6A, Fis and Cas9) and p53 mutants possessing different structures, sizes, and oligomeric states. Our results demonstrate the presence of fast and slow mobility modes in DNA-condensed droplets for the four DNA-binding proteins. The slow mobility mode capability is correlated strongly to the molecular size and the number of DNA-binding domains on DNA-binding proteins, but only moderately to the affinity to single DNA segments in non-condensed conditions. The slow mobility mode in DNA-condensed droplets is interpreted as a multivalent interaction mode of the DNA-binding protein to multiple DNA segments.
Topics: DNA-Binding Proteins; Tumor Suppressor Protein p53; DNA; Protein Domains; Diffusion
PubMed: 37283050
DOI: 10.1093/nar/gkad471