Metal-organic frameworks constructed from flexible ditopic ligands: Conformational diversity of an aliphatic ligand

The solvothermal reaction of adipic acid as a flexible ditopic ligand and the metal ions MnII, CoII, and TbIII afforded three novel metal-organic frameworks (MOFs), {[Mn2(adipate) 2(DMA)]} (1), {[Co2(adipate)2(DMF)] ??1DMF??1.5H2O} (2), and {[Tb3(adipate) 4.5(DMF)2]} (3) (DMA = N,N-dimethylacetamide; DMF = N,N-dimethylformamide), respectively, which were structurally characterized by single-crystal X-ray diffraction. Depending on the kind of metal ion and solvent system, the conformations and coordination modes of the adipate ligands were diverse and governed the entire MOF structure. Compound 1 consists of the secondary building units (SBUs) of Mn-O chains that were linked by adipate ligands extending in two-dimensional sheets, which were infinitely stacked in a layer-by-layer manner. Compound 2 presented a three-dimensional MOF constructed from Co-O chains and bridging adipate ligands extending in four different directions. Compound 3 also had a three-dimensional structure which was formed by Tb-O chains connected with adipate ligands in six directions. From these structures, ten different adipate ligands with diverse conformations were found, and the potential energy of each conformation was calculated by the first-principles density function. In addition, the luminescence properties of the Tb-based MOF 3 were investigated in the solid state at room temperature.close0

Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation

Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of VRK3 is still unknown despite its etiological potential in human autism spectrum disorder (ASD). Here, we report that VRK3-deficient mice exhibit typical symptoms of autism-like behavior, including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory. A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor-mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKII alpha. Notably, TrkB stimulation with 7,8-dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in VRK3-deficient mice. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD.112Ysciescopu

User Recognition Based on Human Body Impulse Response: A Feasibility Study

Human recognition technologies for security systems require high reliability and easy accessibility in the advent of the internet of things (IoT). While several biometric approaches have been studied for user recognition, there are demands for more convenient techniques suitable for the IoT devices. Recently, electrical frequency responses of the human body have been unveiled as one of promising biometric signals, but the pilot studies are inconclusive about the characteristics of human body as a transmission medium for electric signals. This paper provides a multi-domain analysis of human body impulse responses (HBIR) measured at the receiver when customized impulse signals are passed through the human body. We analyzed the impulse responses in the time, frequency, and wavelet domains and extracted representative feature vectors using a proposed accumulated difference metric in each domain. The classification performance was tested using the k-nearest neighbors (KNN) algorithm and the support vector machine (SVM) algorithm on 10-day data acquired from five subjects. The average classification accuracies of the simple classifier KNN for the time, frequency, and wavelet features reached 92.99%, 77.01%, and 94.55%, respectively. In addition, the kernel-based SVM slightly improved the accuracies of three features by 0.58%, 2.34%, and 0.42%, respectively. The result shows potential of the proposed approach for user recognition based on HBIR

Glycogen synthase kinase 3 beta suppresses polyglutamine aggregation by inhibiting Vaccinia-related kinase 2 activity

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the N-terminal of huntingtin. The amount of aggregate-prone protein is controlled by various mechanisms, including molecular chaperones. Vaccinia-related kinase 2 (VRK2) is known to negatively regulate chaperonin TRiC, and VRK2-facilitated degradation of TRiC increases polyQ protein aggregation, which is involved in HD. We found that VRK2 activity was negatively controlled by glycogen synthase kinase 3 beta (GSK3 beta). GSK3 beta directly bound to VRK2 and inhibited the catalytic activity of VRK2 in a kinase activity-independent manner. Furthermore, GSK3 beta increased the stability of TRiC and decreased the formation of HttQ103-GFP aggregates by inhibiting VRK2. These results indicate that GSK3 beta signaling may be a regulatory mechanism of HD progression and suggest targets for further therapeutic trials for HD.1131Ysciescopu

Vaccinia-Related Kinase 2 Mediates Accumulation of Polyglutamine Aggregates via Negative Regulation of the Chaperonin TRiC

Misfolding of proteins containing abnormal expansions of polyglutamine (polyQ) repeats is associated with cytotoxicity in several neurodegenerative disorders, including Huntington's disease. Recently, the eukaryotic chaperonin TRiC hetero-oligomeric complex has been shown to play an important role in protecting cells against the accumulation of misfolded polyQ protein aggregates. It is essential to elucidate how TRiC function is regulated to better understand the pathological mechanism of polyQ aggregation. Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not. Interestingly, VRK2-mediated downregulation of TRiC increased aggregate formation of a polyQ-expanded huntingtin fragment. This effect was ameliorated by rescue of TRiC protein levels. Notably, small interference RNA-mediated knockdown of VRK2 enhanced TRiC protein stability and decreased polyQ aggregation. The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.open118Ysciescopu

Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition

Resveratrol (RSV) is a natural polyphenol that has a beneficial effect on health, and resveratrol-induced autophagy has been suggested to be a key process in mediating many beneficial effects of resveratrol, such as reduction of inflammation and induction of cancer cell death. Although various resveratrol targets have been suggested, the molecule that mediates resveratrol-induced autophagy remains unknown. Here, we demonstrate that resveratrol induces autophagy by directly inhibiting the mTOR-ULK1 pathway. We found that inhibition of mTOR activity and presence of ULK1 are required for autophagy induction by resveratrol. In line with this mTOR dependency, we found that resveratrol suppresses the viability of MCF7 cells but not of SW620 cells, which are mTOR inhibitor sensitive and insensitive cancer cells, respectively. We also found that resveratrol-induced cancer cell suppression occurred ULK1 dependently. For the mechanism of action of resveratrol on mTOR inhibition, we demonstrate that resveratrol directly inhibits mTOR. We found that resveratrol inhibits mTOR by docking onto the ATP-binding pocket of mTOR (i.e., it competes with ATP). We propose mTOR as a novel direct target of resveratrol, and inhibition of mTOR is necessary for autophagy inductionopen

Score-based Generative Modeling Secretly Minimizes the Wasserstein Distance

Score-based generative models are shown to achieve remarkable empirical performances in various applications such as image generation and audio synthesis. However, a theoretical understanding of score-based diffusion models is still incomplete. Recently, Song et al. showed that the training objective of score-based generative models is equivalent to minimizing the Kullback-Leibler divergence of the generated distribution from the data distribution. In this work, we show that score-based models also minimize the Wasserstein distance between them under suitable assumptions on the model. Specifically, we prove that the Wasserstein distance is upper bounded by the square root of the objective function up to multiplicative constants and a fixed constant offset. Our proof is based on a novel application of the theory of optimal transport, which can be of independent interest to the society. Our numerical experiments support our findings. By analyzing our upper bounds, we provide a few techniques to obtain tighter upper bounds

Deep Residual CNN for Multi-Class Chest Infection Diagnosis

The advent of deep learning has significantly propelled the capabilities of automated medical image diagnosis, providing valuable tools and resources in the realm of healthcare and medical diagnostics. This research delves into the development and evaluation of a Deep Residual Convolutional Neural Network (CNN) for the multi-class diagnosis of chest infections, utilizing chest X-ray images. The implemented model, trained and validated on a dataset amalgamated from diverse sources, demonstrated a robust overall accuracy of 93%. However, nuanced disparities in performance across different classes, particularly Fibrosis, underscored the complexity and challenges inherent in automated medical image diagnosis. The insights derived pave the way for future research, focusing on enhancing the model's proficiency in classifying conditions that present more subtle and nuanced visual features in the images, as well as optimizing and refining the model architecture and training process. This paper provides a comprehensive exploration into the development, implementation, and evaluation of the model, offering insights and directions for future research and development in the field

Stress-induced nuclear translocation of CDK5 suppresses neuronal death by downregulating ERK activation via VRK3 phosphorylation

Although extracellular signal-related kinase 1/2 (ERK 1/2) activity is generally associated with cell survival, prolonged ERK activation induced by oxidative stress also mediates neuronal cell death. Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation. Overexpression of VRK3 protected human neuroblastoma SH-SY5Y cells against hydrogen peroxide (H2O2)-induced apoptosis. However the CDK5 was unable to phosphorylate mutant VRK3, and thus the mutant forms of VRK3 could not attenuate apoptotic process. Suppression of CDK5 activity results in increase of ERK activation and elevation of proapoptotic protein Bak expression in mouse cortical neurons. Results from VRK3-deficient neurons were further confirmed the role of VRK3 phosphorylation in H2O2-evoked ERK regulation. Importantly, we showed an association between phospho-VRK3 levels and the progression of human Alzheimer’s disease (AD) and Parkinson’s disease (PD). Together our work reveals endogenous protective mechanism against oxidative stress-induced neuronal cell death and suggest VRK3 as a potential therapeutic target in neurodegenerative diseases.1186Ysciescopu